DEMENTIA

F I F T H E D I T I O N
DEMENTIA
F I F T H E D I T I O N

Edited by
David Ames BA, MD, BS, FRCPsych, FRANZCP
Emeritus Professor
University of Melbourne Department of Psychiatry and
National Ageing Research Institute,
Parkville, Victoria, Australia

John O’Brien MA DM, FRCPsych, FMedSci

Foundation Professor of Old Age Psychiatry
Department of Psychiatry
University of Cambridge, Cambridge, UK

Alistair Burns CBE, MD, FRCP, FRCPsych

Professor of Old Age Psychiatry
University of Manchester, Manchester, UK
CRC Press
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Contents

Foreword ix
Preface x
Acknowledgements xii
Contributors xiii

PaRT 1 DEMENTIA: General aspects 1

1 Dementia: Historical overview 3

German Berrios
2 The lived experience of dementia 19
Shirley Nurock
3 Prevalence and incidence of dementia 24
Daniel W. O’Connor
4 What is dementia, and how do you assess it? Definitions, diagnostic criteria and assessment 33
Joseph P.M. Kane and Alan Thomas
5 Screening and assessment instruments for the detection and measurement of cognitive impairment 44
Leon Flicker
6 Neuropsychological assessment of dementia 52
Greg Savage
7 Neuropsychiatric aspects of dementia 59
Nilika Perera, Mehran Javeed, Constantine G. Lyketsos and Iracema Leroi
8 Measurement of behaviour disturbance, non-cognitive symptoms and quality of life 67
Ajit Shah
9 Cross-cultural issues in the assessment of cognitive impairment 79
Ajit Shah
10 Structural brain imaging 92
Robert Barber and John T. O’Brien
11 Functional brain imaging and connectivity in dementia 107
Klaus P. Ebmeier, Nicola Filippini, Clare E. Mackay, Sana Suri and Vyara Valkanova
12 Molecular brain imaging in dementia 119
Victor L. Villemagne and Christopher C. Rowe
13 Services for people with dementia 135
Sube Banerjee
14 Family carers of people with dementia 142
Katrin Seeher and Henry Brodaty
15 Dementia care in the community: Challenges for primary health and social care 161
Steve Iliffe, Jill Manthorpe and Vari Drennan
16 Managing people with dementia in the general hospital 172
Andrew Teodorczuk, Rowan Harwood and Elizabeth Sampson
17 The role of nursing in the management of dementia 183
Maree Mastwyk and Beverley Williams
18 Social work and care/case management in dementia 192
David Challis, Jane Hughes and Caroline Sutcliffe

v
vi Contents

19 Occupational therapy in dementia care 199

Alissa Westphal
20 Speech and language therapy in dementia assessment and management 208
Bronwyn Moorhouse and Caroline A. Fisher
21 Role of the physiotherapist in the management of dementia 220
Sue Lord and Lynn Rochester
22 Therapeutic effects of music in persons with dementia 229
Linda A. Gerdner and Ruth Remington
23 Psychological, behavioural and psychosocial interventions for neuropsychiatric symptoms in dementia:
What works, what does not and what needs more evidence? 235
Gill Livingston and Claudia Cooper
24 Treating problem behaviours in dementia by understanding their biological, social and psychological causes 244
Ian James and Louisa Jackman
25 Treatments for behavioural and psychological symptoms in Alzheimer’s disease and other dementias 257
Anna Burke, William J. Burke and Pierre N. Tariot
26 Psychological approaches for the practical management of cognitive impairment in dementia 279
Anne Unkenstein
27 Sexuality and dementia 285
Joe Stratford
28 Residential care for people with dementia 292
David Conn, John Snowdon and Nitin Purandare
29 Design and dementia 304
June Andrews
30 Legal issues and dementia 308
Hugh Series and Robin Jacoby
31 Driving and dementia 314
Aoife Fallon and Desmond O’Neill
32 Quality of life in dementia: Conceptual and practical issues 325
Betty S. Black and Peter V. Rabins
33 Ethical issues 339
Julian C. Hughes and Daniel Strech
34 End-of-life and palliative care in dementia 344
Julian C. Hughes and Jenny T. van der Steen
35 Advanced dementia and care at the end of life 349
Kirsten Moore and Elizabeth Sampson
36 Alzheimer’s associations and societies 359
Henry Brodaty, Nicole Pesa and Glenn Rees
37 Health economic aspects of dementia 371
Anders A. Wimo, Linus Jönsson and Bengt Winblad
38 Global challenge of dementia: What can be done? 388
Cleusa P. Ferri, Maëlenn Guerchet and Martin Prince
39 The international challenge of dementia 402
Karim Saad
40 The pharmaceutical industry and dementia: How can clinicians, researchers and industry work together for the
betterment of people with dementia and their families? Continuous vigilance and transparency is the answer 411
Martin M. Bednar and Leon Flicker

PaRT 2 MILD COGNITIVE IMPAIRMENT 418

41 Mild cognitive impairment (MCI): A historical perspective 419

Karen Ritchie and Sylvaine Artero
42 Clinical characteristics of mild cognitive impairment 426
Yonas E. Geda, Janina Krell-Roesch, Anna Pink, Kathleen A. Spangehl and Ronald C. Petersen
43 Managing the patient with mild cognitive impairment 439
Nicola T. Lautenschlager and Alexander F. Kurz
 Contents vii

PaRT 3 ALZHEIMER’S DISEASE: Clinical Aspects 446

44 Risk factors for Alzheimer’s disease 447

Patricia A. Boyle and Robert S. Wilson
45 The natural history of Alzheimer’s disease 453
Jody Corey-Bloom and Michael S. Rafii
46 The neuropathology of Alzheimer’s disease 470
Colin L. Masters
47 Neurochemistry of Alzheimer’s disease 486
Paul T. Francis
48 The central role of Aβ amyloid and tau in the pathogenesis of Alzheimer’s disease 492
Craig W. Ritchie and Colin L. Masters
49 Inflammation in Alzheimer’s disease 508
Clive Holmes
50 Genetics of Alzheimer’s disease 519
Margie Smith
51 Blood and cerebrospinal fluid biomarkers for Alzheimer’s disease 528
Simone Lista, Henrik Zetterberg, Sid E. O’Bryant, Kaj Blennow and Harald Hampel
52 Established treatments for Alzheimer’s disease 539
Alexander Kurz and Nicola T. Lautenschlager
53 Drug treatments in development for Alzheimer’s disease 554
Paul Yates and Michael Woodward
54 Vitamins and complementary therapies used to treat Alzheimer’s disease 587
Dennis Chang, Genevieve Z. Steiner, Dilip Ghosh and Alan Bensoussan
55 Prevention of Alzheimer’s disease and Alzheimer’s dementia 598
Tom C. Russ, Karen Ritchie and Craig W. Ritchie
56 Trial designs 613
Serge Gauthier

PaRT 4 THE OVERLAP AND INTERACTION BETWEEN ALZHEIMER’S DISEASE AND CEREBROVASCULAR
DISEASE 618

57 Vascular factors and Alzheimer’s disease 619

Robert Stewart

PaRT 5 CEREBROVASCULAR DISEASE AND COGNITIVE IMPAIRMENT 629

58 What is vascular cognitive impairment? 630

Timo Erkinjuntti, Leonardo Pantoni and Susanna Melkas
59 The neuropathology of vascular dementia 643
Raj N. Kalaria
60 Therapeutic strategies for vascular cognitive disorders 660
Gustavo C. Román

PaRT 6 DEMENTIA WITH LEWY BODIES AND PARKINSON’S DISEASE 702

61 Dementia with Lewy bodies: A clinical overview 703

Ian G. McKeith
62 Pathology of dementia with Lewy bodies 714
Glenda Halliday, Simon Lewis and Paul Ince
63 The treatment of dementia with Lewy bodies 730
John-Paul Taylor
64 Cognitive impairment and dementia in Parkinson’s disease 740
Dag Aarsland, Kolbjørn Brønnick, Milica G. Kramberger and Joana B. Pereira
viii Contents

PaRT 7 FOCAL DEMENTIAS AND OTHER NEUROPSYCHIATRIC SYNDROMES INVOLVING COGNITIVE DECLINE 748

65 Frontotemporal dementia 749

Peter J. Nestor
66 Pick’s disease: Its relationship to progressive aphasia, semantic dementia and frontotemporal dementia 759
John Hodges
67 The genetics and molecular pathology of frontotemporal lobar degeneration 771
David M.A. Mann
68 Semantic dementia 783
Julie S. Snowden and Matthew Jones
69 Primary progressive aphasia and posterior cortical atrophy 795
Jonathan D. Rohrer, Sebastian J. Crutch and Jason D. Warren
70 The cerebellum and cognitive impairment 812
Elsdon Storey and Evelyn A. Lindsay
71 Delirium: A clinical overview 823
Andrew Teodorczuk and Daniel Davis
72 Depression with cognitive impairment 832
Sarah Shizuko Morimoto, Genevieve S. Yuen, Stephen Beres and George S. Alexopoulos
73 Schizophrenia, cognitive impairment and dementia 846
Flavie Waters, Andrew Ford and Osvaldo P. Almeida
74 Dementia in intellectual disabilities 852
Jennifer Torr
75 Alcohol-related dementia and Wernicke–Korsakoff syndrome 857
Stephen C. Bowden and Simon J. Scalzo
76 Huntington’s disease 868
Phyllis Chua, Samantha Loi and Edmond Chiu
77 Uncommon dementias (including the prion diseases) 885
Matthew Jones and David Neary
Index 898
Foreword
The modern study of dementia began 50 years ago with the
pioneering work of Martin Roth and colleagues. In the mid-
1960s, their ground-breaking epidemiologic study demon-
strated both the high prevalence of dementia in the elderly
and its association with ageing. Several years later they dem-
onstrated that the neuropathology first described by Alois
Alzheimer in 1907 in a woman who died from dementia at
the age of 56 is the commonest neuropathological abnor-
mality seen in dementia.
This 5th edition of Dementia demonstrates how much
knowledge has been gained in the past half-century since
these studies were conducted. Epidemiological studies
throughout the world have identified many risk factors for
dementia and Alzheimer’s disease and these are beginning
to translate into prospective intervention studies. Advances
in molecular biology and genetic medicine have identified
specific protein abnormalities that underlie many of the
neurodegenerative causes of dementia, identified genes act-
ing in classic Mendelian patterns in some dementias and
via non-Mendelian mechanisms in most, identified prions
as the causative ‘agent’ of Creutzfeldt–Jacob disease (CJD)
and variant CJD (vCJD); they also raised the possibility that
prion-like mechanisms explain the ‘spread’ of neurodegen-
eration in many diseases.
As extraordinary as these biological discoveries are, this
edition of Dementia also highlights the equally impres-
sive advances that have been made in treatment. Except for
HIV-AIDS dementia, no dramatic cures have been discov-
ered, but an extensive research literature demonstrates the
effectiveness and benefits of environmental and behavioural
interventions that target the symptoms of dementia, the
efficacy of interventions that target the emotional distress
experienced by many family members and care providers,
the importance of organizations that provide education
and support and the limited but necessary role of pharma-
cotherapeutic treatment of Behavioural and Psychological
Symptoms of Dementia (BPSD).
In addition to highlighting these extraordinary advances,
this 5th edition of Dementia reviews the development of
many techniques and approaches that were not dreamed of
50 years ago. Computerized imaging has been available for
40 years, but the recent development of positron emission
tomography (PET) imaging ligands specific for the molecu-
lar abnormalities characteristic of several dementias is likely
to dramatically change the evaluation of people presenting
the earliest symptoms of cognitive disorder, to lead to the
identification of people at high risk of developing a dementia
syndrome in 10–20 years before they become symptomatic
and, possibly, to reshape the assessment of therapeutics. The
ability to identify genetic variants inexpensively, accurately
and quickly is already helping to identify multiple causes
of what had appeared to be single dementia syndromes and
might lead to revolutionary treatments that target the cause
of dementia in specific individuals.
Finally, this edition of Dementia highlights the recogni-
tion that extensive overlap exists between disorders that tra-
ditionally have been considered conceptually distinct. The
concept that ‘functional’ disorders are categorically distinct
from the disorders of cognition with identifiable neuropa-
thology, which is now passé as cognitive impairment and
has been identified as a central feature of schizophrenia
and impaired cognitive performance, has been identified as
present in individuals of all ages with major depression and
bipolar disorder. Even the dichotomous distinction between
Alzheimer’s dementia and vascular dementia (VaD), so cen-
tral to Martin Roth’s pioneering work, is coming under
question as the co-occurrence of these two cases of demen-
tia is now being shown to result from shared neurobiology.
In summary, this 5th edition of Dementia stands as a
marker of the tremendous progress that has been made in
understanding the pathophysiology of the various demen-
tias and of the advances in symptomatic treatment. Just as
importantly, it provides hope that these gains in knowledge
will lead to preventative strategies that abolish or greatly
lessen the morbidity associated with these devastating
disorders.
Peter V. Rabins MD, MPH
ix
Preface
Dementia is one of the major challenges to face society
in the twenty-first century, numerically dwarfing many
other disorders which have caught the public’s imagina-
tion. There are, and will continue to be, many texts on
dementia. Our continued goal with this fifth edition is to
encompass, in a single comprehensive volume, all aspects
of all types of dementia. This is a highly ambitious task,
and however hard we have tried, we could obviously not
succeed completely, so someone, somewhere will rightly
complain that we have omitted something important. In
addition, and somewhat reassuringly in terms of progress,
this is a field that continues to expand rapidly. What we
have tried to do, therefore, is to concentrate on a solid
body of information which, although requiring some
updating in the future, is likely to remain the essential
core knowledge in the field for many years to come.
The book is divided into seven parts to reflect the
complex nature of the topic. Part 1 deals with gen-
eral aspects of dementia, including its history, diag-
nosis and assessment, and the use of investigations,
multi-­d isciplinary assessment and all aspects of its man-
agement. Part 2 focuses on mild cognitive impairment,
an increasingly important entity but one whose concep-
tual basis is changing as we discover more about early or
prodromal pre-dementia states. Part 3 concentrates on
Alzheimer’s disease and includes discussions about risk
factors, underlying neurobiology, biomarkers and both
pharmacological and non-pharmacological management
as well as prospects for prevention. The well recognized
but still poorly understood overlap between vascular and
degenerative pathologies and the interactions between
the two are covered in Part 4, whilst Part 5 deals with
vascular cognitive impairment and vascular dementia.
Part 6 contains chapters on Lewy body dementias, both
dementia with Lewy bodies and dementia that occurs in
established Parkinson’s disease, while Part 7 discusses
other dementias, such as fronto-temporal dementias and
less common causes of dementia like Creutzfeld–Jakob
disease (CJD), progressive supranuclear palsy (PSP) and
multi system atrophy (MSA). This final part also covers
the borderland between the dementias and functional
x
psychiatric disorders such as depression and schizophre-
nia, in which both subtle brain changes and cognitive
impairments occur, making the traditional organic versus
functional distinction look blurred.
Overlap between chapters is a difficult issue, and
although we have exercised the editorial Tippex to the best
of our ability, some duplication remains. However, much
of this is intentional, and some chapters would have been
denuded unnecessarily and could not have stood alone.
Areas where we have unashamedly fostered such overlap
include Chapters 41 through 43 on mild cognitive impair-
ment, Chapters 61 through 64 on the different ends of the
Lewy body dementias spectrum, and Chapters 65, 66 and
68 covering fronto-temporal dementia and its subtypes,
including semantic dementia. The general structure of this
book has been well honed over the four previous editions,
and we have stuck largely to what seemed a popular and
successful formula. However, we have ensured that nearly
all chapters have been updated; some established topics
have new authors taking an entirely fresh view, and we have
included new chapters on several key areas such as services,
managing co-morbidities, terminal care, the international
challenge of dementia, neuroinflammation in Alzheimer’s
disease and delirium.
We anticipate that target readership will be broad,
reflecting the breadth of the book. It was never designed as
a book to be read from cover to cover, and though we doubt
it will be, if it were it would probably be one of the quickest
ways of getting entirely up to speed with a complex and var-
ied field. However, it is designed as a reference guide, to be
dipped into as and when needed. We anticipate that at least
some sections will be relevant and of interest to just about
all health and social care professionals who have contact
with or an interest in people with dementia, including med-
ical specialists such as neurologists, psychiatrists and physi-
cians, nurses and allied health professionals, and trainees
within these groups. We hope that others will also find the
book of value. For example, pre-clinical scientists who work
in this area will be able to learn more about the clinical rel-
evance and underlying biology of those with ­disorders they
are studying.
 Preface xi

In choosing our authors, we have sought to achieve a renowned experts and those whom we consider to be the
balance between retaining sufficient authors from the pre- rising stars of the future.
vious editions to provide some continuity and including
some new contributors. We have also sought an authorship David Ames, Melbourne
to reflect a mixture of those who are already internationally Alistair Burns, Manchester
John T. O’Brien, Cambridge
Acknowledgements
We are grateful to our publishers for commissioning a fifth
edition of this book. The award of the best book of the year
in the area of psychiatry for the fourth edition of this book
by the British Medical Association in 2011 may have had a
lot to do with this recommission. As usual, some chapters
have been culled, some introduced, and virtually all have
been revised. We thank our patient and dedicated authors,
our secretaries and our publishing team for helping us put
together what we hope is a clear account of everything useful
known about dementia in 2016. If the sixth edition eventu-
ates, it may be edited by a different team, as one of us has now
retired from academic life and the other two are not getting
any younger, but we devoutly hope that this established text
will continue to be found useful by researchers and those
working with people with dementia for a long time to come.
David Ames, Alistair Burns, John T. O’Brien
Melbourne, Manchester, Newcastle-upon-Tyne
December 2015
ADDITIONAL ACKNOWLEDGMENTS
Chapter 24
Ian James thanks Angela Hope, who provided both
comments and assisted with the preparation of this
chapter.
Chapter 38
Cleusa P. Ferri, Maëlenn Guerchet and Martin Prince
acknowledge, in memoriam, the valuable contribution
made to the previous version of this chapter (4th edition)
by Jim Jackson.
xii
Chapter 42
Taryn Silber, Ron Petersen and Yonas E. Geda thank
Angelina Luti for her diligence in assembling the endnote
library on biomarkers and proofing the manuscript. The
authors would also like to thank Ezra Geda for proofing
the manuscript.
Chapter 46
This chapter was originally written by Peter Lantos and
Nigel Cairns and appeared as Chapter 37 in the second
edition of Dementia. It was updated by Colin Masters in all
subsequent editions.
Chapter 51
Harold Hampel and Simone Lista were supported by
the AXA Research Fund, the Foundation Université
Pierre et Marie Curie and the ‘Fondation pour la
Recherche sur Alzheimer’, Paris, France. The research
leading to these results has received funding from
the program ‘Investissements d’avenir’ ANR-10-IAIHU-06.
Chapter 59
Raj Kalaria’s work has been supported by the Medical
Research Council (United Kingdom), Alzheimer’s
Research, United Kingdom and the Dunhill Medical Trust,
United Kingdom.
Contributors

Dag Aarsland Newcastle University

Stavanger University Hospital Newcastle upon Tyne, United Kingdom
Stavanger, Norway
Martin M. Bednar
and Neuroscience and Pain Research Unit Pfizer Global
Division of Neurogeriatrics Research and Development
Department of Neurobiology Cambridge, Massachusetts
Care Sciences and Society, Karolinska Institute Alan Bensoussan
Stockholm, Sweden National Institute of Complementary Medicine
George S. Alexopoulos Western Sydney University
Weill Cornell Medical College Campbelltown, Australia
White Plains, New York Stephen Beres
Osvaldo P. Almeida Weill Cornell Medical College
Western Australian Centre for Health and Ageing White Plains, New York
School of Psychiatry and Clinical Neurosciences, Centre German Berrios
for Medical Research Emeritus Chair of the Epistemology of Psychiatry
University of Western Australia University of Cambridge
and Cambridge, United Kingdom
Department of Psychiatry
Royal Perth Hospital Betty S . Black
Perth, Australia Department of Psychiatry and Behavioral Sciences
Johns Hopkins Medical Institutions
June Andrews Baltimore, Maryland
Professor Emeritus
University of Stirling Kaj Blennow
Bridge of Allan, Scotland Clinical Neurochemistry Laboratory
Department of Psychiatry and Neurochemistry
Sylvaine Artero Institute of Neuroscience and Physiology
Institut National de la Santé et de la Recherche Médicale The Sahlgrenska Academy at the University of
(INSERM) Gothenburg
Neuropsychiatry, Epidemiological and Clinical Mölndal, Sweden
Research
and
Hôpital La Colombière
Montpellier, France The Torsten Söderberg Professorship in Medicine
Royal Swedish Academy of Sciences
Sube Banerjee
Stockholm, Sweden
Centre for Dementia Studies
Brighton and Sussex Medical School Stephen C. Bowden
University of Sussex Melbourne School of Psychological Sciences
Brighton, United Kingdom University of Melbourne
Melbourne, Australia
Robert Barber
Old Age Psychiatry Patricia A. Boyle
Institute of Neuroscience Department of Behavioral Science

xiii
xiv Contributors

Rush Alzheimer’s Disease Center Claudia Cooper

Rush University Medical Center Division of Psychiatry
Chicago, Illinois University College London
London, United Kingdom
Henry Brodaty
Dementia Collaborative Research Centre Jody Corey-Bloom
School of Psychiatry Department of Neurosciences
University of New South Wales University of California
Sydney, Australia San Diego, California

Kolbjørn Brønnick Sebastian J. Crutch

Psychiatric Division Dementia Research Centre
Stavanger University Hospital University College London
and London, United Kingdom
Network for Medical Sciences
Daniel Davis
University of Stavanger
Department of Public Health and Primary Care
Stavanger, Norway
University of Cambridge
Anna Burke Cambridge, United Kingdom
Banner Alzheimer’s Institute
Vari Drennan
University of Arizona College of Medicine
Health Services Research
Phoenix, Arizona
St. George’s University of London
William J. Burke and
Banner Alzheimer’s Institute Kingston University
University of Arizona College of Medicine London, United Kingdom
Phoenix, Arizona
Klaus P. Ebmeier
David Challis Department of Psychiatry
Personal Social Services Research Unit University of Oxford
University of Manchester and
Manchester, United Kingdom The Warneford Hospital
Oxford, United Kingdom
Dennis Chang
National Institute of Complementary Yonas E. Geda
Medicine Translational Neuroscience and Aging
Western Sydney University Program
Campbelltown, Australia Collaborative Research Building
Mayo Clinic
Edmond Chiu
Scottsdale, Arizona
Academic Unit for Psychiatry of Old Age
University of Melbourne Timo Erkinjuntti
Melbourne, Australia Clinical Neurosciences, Neurology
University of Helsinki
Phyllis Chua
and
Department of Psychiatry
Helsinki University Hospital
School of Clinical Sciences
Helsinki, Finland
Monash University
Clayton, Australia Aoife Fallon
Centre for Ageing, Neuroscience and the
and
Humanities
Statewide Progressive Neurological Disease Trinity College
Service Dublin, Ireland
Calvary Health Care Bethlehem
Cleusa P. Ferri
Caulfield South, Australia
Department of Psychobiology
David Conn Universidade Federal de São Paulo
Centre for Education and
Baycrest Health Sciences Hospital Alemao Oswaldo Cruz
University of Toronto Institute of Education and Health Sciences (IECS)
Toronto, Canada São Paulo, Brazil
 Contributors xv

Nicola Filippini Neuroscience Research Australia

Department of Psychiatry Sydney, Australia
University of Oxford
Harald Hampel
and
AXA Research Fund and UPMC Chair
The Warneford Hospital
and
Oxford, United Kingdom
Sorbonne Universités
Caroline A. Fisher Université Pierre et Marie Curie
The Melbourne Clinic and
The Royal Melbourne Hospital Institut de la Mémoire et de la Maladie d’Alzheimer
Melbourne, Australia (IM2A)
Leon Flicker Institut du Cerveau et de la Moelle Épinière (ICM)
Western Australian Centre for Health and Ageing Département de Neurologie
Centre for Medical Research, School of Medicine and Hôpital de la Pitié-Salpêtrière
Pharmacology Paris, France
University of Western Australia Rowan Harwood
Perth, Australia Nottingham University Hospitals NHS Trust
Andrew Ford and
Western Australian Centre for Health and Ageing University of Nottingham
School of Psychiatry and Clinical Neurosciences and Nottingham, United Kingdom
Centre for Medical Research John Hodges
University of Western Australia NeuRA and UNSW
and Randwick, Australia
Department of Psychiatry
Royal Perth Hospital Clive Holmes
Perth, Australia Clinical and Experimental Science
University of Southampton
Paul T. Francis Southampton, United Kingdom
Wolfson Centre for Age-Related Diseases
King’s College London, Guy’s Campus Jane Hughes
London, United Kingdom Personal Social Services Research Unit
University of Manchester
Serge Gauthier Manchester, United Kingdom
Alzheimer’s Disease Research Unit
McGill Centre for Studies in Aging Julian C. Hughes
McGill University Northumbria Healthcare NHS Foundation Trust
Montréal, Canada and
PEALS (Policy, Ethics and Life Sciences) Research Centre
Linda A. Gerdner Newcastle University
Stanford Geriatric Education Center Newcastle upon Tyne, United Kingdom
Center for Education in Family and Community Medicine
Stanford University School of Medicine Steve Iliffe
Stanford, California Primary Care for Older People
University College London
Dilip Ghosh London, United Kingdom
Soho Flordis International (SFI)
St Leonards, Australia Paul Ince
Department of Neuroscience
Maëlenn Guerchet Royal Hallamshire Hospital
King’s College London Sheffield, United Kingdom
and
Centre for Global Mental Health Louisa Jackman
Health Services and Population Research Department of Clinical Psychology
Institute of Psychiatry, Psychology and Neuroscience Newcastle University
London, United Kingdom Newcastle upon Tyne, United Kingdom

Glenda Halliday Robin Jacoby

University of New South Wales Department of Psychiatry
and University of Oxford
xvi Contributors

The Warneford Hospital Janina Krell-Roesch

Oxford, United Kingdom Translational Neuroscience and Aging Program
Collaborative Research Building
Ian James
Mayo Clinic
Older People’s Psychology and Challenging Behaviour
Scottsdale, Arizona
Teams
Northumberland, Tyne and Wear NHS Trust Alexander F. Kurz
and Department of Psychiatry and Psychotherapy
Campus for Ageing and Vitality Klinikum rechts der Isar
Newcastle upon Tyne, United Kingdom Technische Universität München
Munich, Germany
Mehran Javeed
Department of Old Age Psychiatry Nicola T. Lautenschlager
North Manchester General Hospital Academic Unit for Psychiatry of Old Age, Department of
and Psychiatry
Manchester Mental Health and Social Care Trust University of Melbourne
Manchester, United Kingdom NorthWestern Mental Health, Melbourne Health
Parkville, Australia
Matthew Jones
Cerebral Function Unit Iracema Leroi
Salford Royal NHS Foundation Trust Department of Psychiatry/Honorary Consultant
Salford, United Kingdom Institute of Brain, Behaviour and Mental Health
and and
Institute of Brain Behaviour and Mental Health Manchester Academic Health Sciences Centre
University of Manchester University of Manchester
Manchester, United Kingdom Manchester, United Kingdom

Linus Jönsson Simon Lewis

Division of Neurogeriatrics Brain & Mind Centre
NCS, Department of Neurobiology Care Sciences and Sydney Medical School
Society Sydney, Australia
Karolinska Institutet Evelyn A. Lindsay
Stockholm, Sweden Department of Medicine (Neuroscience)
and Monash University
H. Lundbeck A/S Melbourne, Australia
Valby, Denmark
Simone Lista
Raj N. Kalaria AXA Research Fund and UPMC Chair
Institute of Neuroscience and
Newcastle University Sorbonne Universités
Campus for Ageing and Vitality Université Pierre et Marie Curie
Newcastle upon Tyne, United Kingdom Institut de la Mémoire et de la Maladie d’Alzheimer (IM2A)
Institut du Cerveau et de la Moelle Épinière (ICM)
Joseph P.M. Kane
Département de Neurologie
Institute of Neuroscience
Hôpital de la Pitié-Salpêtrière
Newcastle University
Paris, France
Newcastle upon Tyne, United Kingdom
Gill Livingston
Milica G. Kramberger
Division of Psychiatry
Department of Neurology
University College London
University Medical Center Ljubljana
London, United Kingdom
Ljubljana, Slovenia
and Samantha Loi
Division of Neurogeriatrics Academic Unit for Psychiatry of Old Age
and Department of Psychiatry
Department of Neurobiology Care Sciences and Society University of Melbourne
Karolinska Institute Melbourne, Australia
Stockholm, Sweden and
 Contributors xvii

NorthWestern Mental Health Bronwyn Moorhouse

Melbourne Health Royal Talbot Rehabilitation Centre
Parkville, Australia Kew, Australia

Sue Lord Sarah Shizuko Morimoto

Institute for Neuroscience Weill Cornell Medical College
Newcastle University White Plains, New York
Newcastle upon Tyne, United Kingdom
David Neary
Constantine G. Lyketsos Cerebral Function Unit, Greater Manchester
Department of Psychiatry and Behavioral Sciences Neurosciences Centre
John Hopkins Bayview Medical Center Salford Royal NHS Foundation Trust
Baltimore, Maryland Salford, United Kingdom

Clare E. Mackay and

Department of Psychiatry Institute of Brain, Behaviour and Mental Health
University of Oxford University of Manchester
and Manchester, United Kingdom
The Warneford Hospital
Peter J. Nestor
Oxford, United Kingdom
German Center for Neurodegenerative Diseases
David M.A. Mann Magdeburg, Germany
Clinical and Cognitive Neuroscience Research Group
Shirley Nurock
Institute of Brain, Behaviour and Mental Health
Former Carer
University of Manchester
London Area Coordinator of the UK
and
Alzheimer’s Society Research in Dementia
Salford Royal NHS Foundation Trust
(QRD) Network
Salford, United Kingdom
Council of Relatives to Assist in the Care of
Jill Manthorpe Dementia
Social Care Workforce Research Unit London, United Kingdom
King’s College London
John T. O’Brien
London, United Kingdom
Department of Psychiatry
Colin L. Masters School of Clinical Medicine
Florey Institute of Neuroscience and Mental Health University of Cambridge
Parkville, Australia Cambridge Biomedical Campus
Cambridge, United Kingdom
Maree Mastwyk
Florey Institute of Neuroscience and Mental Health Sid E. O’Bryant
Parkville, Australia Institute for Aging and Alzheimer’s Disease Research
Department of Internal Medicine
Ian G. McKeith
University of North Texas Health Science Center
Biomedical Research Building
Fort Worth, Texas
Newcastle University Institute for Ageing
Campus for Ageing and Vitality Daniel W. O’Connor
Newcastle upon Tyne, United Kingdom Department of Psychiatry
Monash University
Susanna Melkas
Melbourne, Australia
Clinical Neurosciences, Neurology
University of Helsinki Desmond O’Neill
and Centre for Ageing, Neuroscience and the Humanities
Helsinki University Hospital Trinity College
Helsinki, Finland Dublin, Ireland

Kirsten Moore Leonardo Pantoni

Marie Curie Palliative Care Research Department NEUROFARBA Department
Division of Psychiatry Neuroscience Section
University College London University of Florence
London, United Kingdom Florence, Italy
xviii Contributors

Joana B. Pereira Craig W. Ritchie

Division of Clinical Geriatrics Centre for Dementia Prevention
Department of Neurobiology, Care Sciences and
and Society Centre for Clinical Brain Sciences
Karolinska Institute University of Edinburgh
Stockholm, Sweden Edinburgh, United Kingdom

Nilika Perera and

Department of Old Age Psychiatry Scottish Dementia Clinical Research Network
Stepping Hill Hospital NHS Scotland
and Perth, United Kingdom
Pennine Care NHS Foundation Trust
Karen Ritchie
Manchester, United Kingdom
Institut National de la Santé et de la Recherche Médicale
Nicole Pesa (INSERM)
Dementia Collaborative Research Centre Neuropsychiatry, Epidemiological and Clinical Research
and Hôpital La Colombière
Centre for Healthy Brain Ageing Montpellier, France
University of New South Wales
Lynn Rochester
Kensington, Australia
Institute for Neuroscience
Ronald C. Petersen Newcastle University
Alzheimer’s Disease Research Center Newcastle upon Tyne, United Kingdom
Mayo Clinic
Rochester, Minnesota Jonathan D. Rohrer
National Hospital for Neurology and Neurosurgery
Anna Pink University College London Hospitals
Translational Neuroscience and Aging Program NHS Foundation Trust
Collaborative Research Building London, United Kingdom
Mayo Clinic
Scottsdale, Arizona Gustavo C. Román
Department of Neurology
Martin Prince Weill Cornell Medical College
King’s College London Houston Methodist Neurological Institute
and Houston, Texas
Centre for Global Mental Health, Health Services and
Population Research Christopher C. Rowe
Institute of Psychiatry, Psychology and Austin Health, Department of Nuclear Medicine and
Neuroscience Centre for PET
London, United Kingdom Heidelberg, Australia

Nitin Purandare (deceased) Tom C. Russ

Exeter University Centre for Dementia Prevention
Exeter, United Kingdom and
Centre for Clinical Brain Sciences
Peter V. Rabins
and
Department of Psychiatry and Behavioral Sciences
Centre for Cognitive Ageing and Cognitive
John Hopkins Medical Institutions
Epidemiology
Baltimore, Maryland
and
Michael S. Rafii Alzheimer Scotland Dementia Research Centre
Department of Neurosciences University of Edinburgh
University of California Edinburgh, United Kingdom
San Diego, California and
Glenn Rees Scottish Dementia Clinical Research Network
Alzheimer’s Disease International NHS Scotland
London, United Kingdom Perth, United Kingdom

Ruth Remington Karim Saad

Framingham State University Consultant in Old Age Psychiatry
Framingham, Massachusetts Clinical Network for Dementia
 Contributors xix

NHS West Midlands Genevieve Z. Steiner

Coventry, United Kingdom National Institute of Complementary Medicine
Western Sydney University
Elizabeth Sampson
Campbelltown, Australia
Marie Curie Palliative Care Research Department
Division of Psychiatry Robert Stewart
University College London Department of Psychological Medicine
London, United Kingdom King’s College London
and
Greg Savage
Institute of Psychiatry, Psychology and Neuroscience
Department of Psychology
London, United Kingdom
ARC Centre of Excellence in Cognition and its
Disorders Elsdon Storey
Macquarie University Department of Medicine (Neuroscience)
Sydney, Australia Monash University
Melbourne, Australia
Simon J. Scalzo
Melbourne School of Psychological Sciences Joe Stratford
University of Melbourne Consultant Psychiatrist for Older People
Melbourne, Australia Stroud, United Kingdom

Katrin Seeher Daniel Strech

Dementia Collaborative Research Centre, School of Institute for History, Ethics and Philosophy of Medicine
Psychiatry Hannover Medical School
University of New South Wales Hannover, Germany.
Sydney, Australia
Sana Suri
Hugh Series Department of Psychiatry
Oxford Health NHS Foundation Trust University of Oxford
and and
University of Oxford Faculty of Law The Warneford Hospital
Oxford, United Kingdom Oxford, United Kingdom

Ajit Shah Caroline Sutcliffe

Department of Ageing, Ethnicity and Mental Health Personal Social Services Research Unit
University of Central Lancashire University of Manchester
Preston, United Kingdom Manchester, United Kingdom

Margie Smith Pierre N. Tariot

smartDNA Pty Ltd Banner Alzheimer’s Institute
MHTP Translational Research Facility University of Arizona College of Medicine
Clayton, Australia Phoenix, Arizona

John-Paul Taylor
Julie S. Snowden
Old Age Psychiatry, Institute of Neuroscience
Cerebral Function Unit
Newcastle University
Salford Royal NHS Foundation Trust
Newcastle upon Tyne, United Kingdom
Salford, United Kingdom
and Andrew Teodorczuk
Old Age Psychiatry, Institute of Neuroscience
Institute of Brain, Behaviour and Mental Health
Newcastle University
University of Manchester
and
Manchester, United Kingdom
Northumberland Tyne and Wear NHS Foundation
John Snowdon Trust
Sydney Medical School Newcastle upon Tyne, United Kingdom
University of Sydney
Alan Thomas
Sydney, Australia
Institute of Neuroscience
Kathleen A. Spangehl and
Translational Neuroscience and Aging Program Newcastle University Institute for Ageing
Mayo Clinic Newcastle University
Scottsdale, Arizona Newcastle upon Tyne, United Kingdom
xx Contributors

Jennifer Torr Robert S. Wilson

Department of Psychiatry Department of Behavioral Science and Department of
University of Melbourne Neurological Science
Melbourne, Australia Rush Alzheimer’s Disease Center
Rush University Medical Center
Anne Unkenstein
Chicago, Illinois
Department of Psychiatry
University of Melbourne Anders A. Wimo
Melbourne, Australia Division of Neurogeriatrics, NCS
Department of Neurobiology, Care Sciences and
Vyara Valkanova
Society
Department of Psychiatry
Karolinska Institutet
University of Oxford
Stockholm, Sweden
and
The Warneford Hospital Bengt Winblad
Oxford, United Kingdom Department of Neurobiology, Care Sciences and
Society
Jenny T. van der Steen
Karolinska Institutet
EMGO Institute for Health and Care Research
Stockholm, Sweden
VU University Medical Center
Amsterdam, the Netherlands Michael Woodward
Aged Care
Victor L. Villemagne
Austin Health
Department of Nuclear Medicine and Centre for PET
Victoria, Australia
Austin Health
and and
The Florey Institute of Neuroscience and Mental Health University of Melbourne
Heidelberg, Australia Melbourne, Australia
Jason D. Warren Paul Yates
Dementia Research Centre Department of Aged Care Services
Institute of Neurology Austin Health
University College London Heidelberg, Australia
London, United Kingdom
and
Flavie Waters University of Melbourne
School of Psychiatry and Clinical Neurosciences Melbourne, Australia
University of Western Australia
Crawley, Australia Genevieve S. Yuen
Weill Cornell Medical College
and
White Plains, New York
Clinical Research Centre
North Metropolitan Health Service Mental Health Henrik Zetterberg
Mt. Hawthorn, Australia Clinical Neurochemistry Laboratory
Department of Psychiatry and Neurochemistry
Alissa Westphal Institute of Neuroscience and Physiology
Department of Psychiatry The Sahlgrenska Academy at the University of
University of Melbourne Gothenburg
and Mölndal, Sweden
NorthWestern Mental Health, Melbourne Health
and
Victoria, Australia
Department of Molecular Neuroscience
Beverley Williams UCL Institute of Neurology
Aged Psychiatry Service London, United Kingdom
Caulfield Hospital
Caulfield, Australia
 Part     1
Dementia: General aspects

1 Dementia: Historical overview 3

German Berrios
2 The lived experience of dementia 19
Shirley Nurock
3 Prevalence and incidence of dementia 24
Daniel W. O’Connor
4 What is dementia, and how do you assess it? Definitions, diagnostic criteria and assessment 33
Joseph P.M. Kane and Alan Thomas
5 Screening and assessment instruments for the detection and measurement of cognitive impairment 44
Leon Flicker
6 Neuropsychological assessment of dementia 52
Greg Savage
7 Neuropsychiatric aspects of dementia 59
Nilika Perera, Mehran Javeed, Constantine G. Lyketsos and Iracema Leroi
8 Measurement of behaviour disturbance, non-cognitive symptoms and quality of life 67
Ajit Shah
9 Cross-cultural issues in the assessment of cognitive impairment 79
Ajit Shah
10 Structural brain imaging 92
Robert Barber and John T. O’Brien
11 Functional brain imaging and connectivity in dementia 107
Klaus P. Ebmeier, Nicola Filippini, Clare E. Mackay, Sana Suri and Vyara Valkanova
12 Molecular brain imaging in dementia 119
Victor L. Villemagne and Christopher C. Rowe
13 Services for people with dementia 135
Sube Banerjee
14 Family carers of people with dementia 142
Katrin Seeher and Henry Brodaty
15 Dementia care in the community: Challenges for primary health and social care 161
Steve Iliffe, Jill Manthorpe and Vari Drennan
16 Managing people with dementia in the general hospital 172
Andrew Teodorczuk, Rowan Harwood and Elizabeth Sampson
17 The role of nursing in the management of dementia 183
Maree Mastwyk and Beverley Williams
18 Social work and care/case management in dementia 192
David Challis, Jane Hughes and Caroline Sutcliffe
19 Occupational therapy in dementia care 199
Alissa Westphal
20 Speech and language therapy in dementia assessment and management 208
Bronwyn Moorhouse and Caroline A. Fisher
2 Dementia

21 Role of the physiotherapist in the management of dementia 220

Sue Lord and Lynn Rochester
22 Therapeutic effects of music in persons with dementia 229
Linda A. Gerdner and Ruth Remington
23 Psychological, behavioural and psychosocial interventions for neuropsychiatric symptoms in dementia:
What works, what does not and what needs more evidence? 235
Gill Livingston and Claudia Cooper
24 Treating problem behaviours in dementia by understanding their biological, social and psychological causes 244
Ian James and Louisa Jackman
25 Treatments for behavioural and psychological symptoms in Alzheimer’s disease and other dementias 257
Anna Burke, William J. Burke and Pierre N. Tariot
26 Psychological approaches for the practical management of cognitive impairment in dementia 279
Anne Unkenstein
27 Sexuality and dementia 285
Joe Stratford
28 Residential care for people with dementia 292
David Conn, John Snowdon and Nitin Purandare
29 Design and dementia 304
June Andrews
30 Legal issues and dementia 308
Hugh Series and Robin Jacoby
31 Driving and dementia 314
Aoife Fallon and Desmond O’Neill
32 Quality of life in dementia: Conceptual and practical issues 325
Betty S. Black and Peter V. Rabins
33 Ethical issues 339
Julian C. Hughes and Daniel Strech
34 End-of-life and palliative care in dementia 344
Julian C. Hughes and Jenny T. van der Steen
35 Advanced dementia and care at the end of life 349
Kirsten Moore and Elizabeth Sampson
36 Alzheimer’s associations and societies 359
Henry Brodaty, Nicole Pesa and Glenn Rees
37 Health economic aspects of dementia 371
Anders A. Wimo, Linus Jönsson and Bengt Winblad
38 Global challenge of dementia: What can be done? 388
Cleusa P. Ferri, Maëlenn Guerchet and Martin Prince
39 The international challenge of dementia 402
Karim Saad
40 The pharmaceutical industry and dementia: How can clinicians, researchers and industry work together for the
betterment of people with dementia and their families? Continuous vigilance and transparency is the answer 411
Martin M. Bednar and Leon Flicker

Dementia: Historical overview
GERMAN BERRIOS
1.1 MATTERS HISTORIOGRAPHICAL
Exploring why clinical textbooks often carry historical
chapters can be informative. One common reason for such
addition is fashion. Although for some time now such chap-
ters are almost de rigueur, editors vary in what they want.
Some just want lists of achievements as a celebration of
scientific progress and this task is best met by retired clini-
cians. Others go further and ask for a sort of meta-analysis
of historical papers; in practice, this leads to requesting
‘updated’ chapters for each new edition of the textbook.
Going further a third group of editors considers them a
necessity. Their view is correct because symptoms and dis-
orders are inherently historical; that is, objects constructed
in a semantic space and made temporarily stable by means
of specific social narratives networks neurobiological cor-
relations. In the case in hand, history has shown that all
narratives about dementia have been: (1) born in specific
historical convergences and (2) considered as ‘true’ during
the time they were socially predominant.
1.1.1 CONVERGENCES
Convergences are historical processes whereby words
(names, terms) and concepts (definitions, accounts, expla-
nations) are used to: (1) break up the complaints and
behaviour of certain individuals; and (2) select some of
the fragments on the basis that they constitute a mean-
ingful bundle (Berrios, 2011). Convergences tend to be
made explicit in writings: (1) inscribed in the predomi-
nant social media and (2) by authors who are seen as the
spokesmen of fashionable cliques. Hence, although social
usefulness tends to be the main determinant of the dura-
tion of convergences, they are rhetorically presented as a
scientific truth.
As this chapter will show, the word dementia has par-
ticipated in a number of convergences (i.e. has been used to
1
name different concepts and different behaviours); indeed,
currently it is part of yet another convergence. How long this
current bundle will last is unclear. Historians are only too
aware of the so-called presentistic fallacy (latest is b
­ estest)
and of how this distortion of reality tends to make research-
ers feel that the current narrative is (1) superior to all past
ones; and (2) the truth.
Since the fourth edition of this textbook, no ground-
breaking scholarly work has been published to challenge
the historical hypotheses put forward in earlier versions of
this chapter (e.g. Boller, 2008). If anything, developments
in the history and philosophy of science support its con-
structionist perspective (Golinski, 1998). As mentioned
above, clinical categories (whether symptoms or disorders)
result from the bundling up of selected morsels of behav-
iour, explanatory concepts and words. Complex social and
economic variables then determine whether the ensuing
bundle will last, and for how long. For reasons that have to
do with the rhetoric of science, these social acts are sold as
scientific acts. For example, it would be historically naive
to believe that the decision to consider a symptom-cluster,
such as Lewy Body dementia, as a ‘new disease’ is solely
based on the discovery of powerful, ineluctable and repli-
cable correlations (Perry et al., 1996). Given that there is no
clear theory linking firstly the symptoms to each other, and
secondly the symptom bundle to the Lewy bodies them-
selves, it is not unreasonable to believe that social variables
have also played a role in the acceptance of this new variant
of dementia.
This is not a new state of affairs and science has always
been made in the same way, for example, it was thus at
the time Kraepelin constructed the concept of Alzheimer’s
disease (Berrios, 1990a). In fact, there is nothing wrong
with accepting that social forces shape scientific facts,
­particularly in psychiatry. More to the point, accepting
such view would render neurobiologists less fundamen-
talist in their claims, and clinicians more useful to their
patients.
3
4 Dementia
Knowledge of the successive convergences that consti-
tute the history of dementia and of the current conver-
gence should be a precondition to do scientific research.
For the purposes of this chapter, it should suffice to map
these convergences since the eighteenth century, for
example, from that implied in the work of Boissier de
Sauvages (1771) to the one propounded by Marie (1906).
The former defined dementia as a generic term; the latter
saw in dementia a syndrome, which could be enacted in
a variety of diseases each with its recognisable phenom-
enology and putative neuropathology. Current research
on dementia remains inscribed in Marie’s epistemological
frame.
1.1.1.1 Words and concepts
In Roman times, the word dementia was used to mean
‘being out of one’s mind, insanity, madness, folly’ (Lewis
and Short, 1969). For example, in the first century bc,
Cicero (1969) (Tusculanan disputations, Book 3, para
10) and Lucretius (1975) (De Rerum Natura, Book 1, line
704) used dementia as a synonym of madness. Indeed,
up to the 1700s, states of cognitive and behavioural dete-
rioration of whatever origin that ended up in psychoso-
cial incompetence were still being called by a variety of
names: amentia, dementia, imbecility, morosis, fatuitas,
anoea, foolishness, stupidity, simplicity, carus, idiocy,
dotage and senility.
The term dementia first appears in the European ver-
naculars during the seventeenth century. In Blancard’s
English dictionary (1726) it is used as an equivalent of anoea
or ‘extinction of the imagination and judgment’ (p. 21).
By 1644, according to the Oxford English Dictionary, an
adjectival form demented entered the English language.
In his Spanish-French dictionary, Sobrino (1791) wrote:
‘­
demencia = démence, folie, extravagance, égarement,
alienation d’esprit’ (p. 300). Rey (1995), in turn, states that
démence appeared in French in 1381 to refer to ‘madness,
extravagancy’ but that the adjective dément only came into
currency by 1700. It would seem, therefore, that between
the seventeenth and eighteenth centuries derivatives of the
Latin stem demens (without mind) were becoming estab-
lished in most European vernaculars. As we shall see pres-
ently the full medicalisation of dementia started after the
1750s.
Evidence for an early medical usage of the term demen-
tia is found in the French Encyclopaedia (Diderot and
d’Alembert, 1765):
Dementia is a disease consisting in a paralysis of
the spirit characterized by abolition of the rea-
soning faculty. It differs from fatuitas, morosis,
stultitia and stoliditas in that in the latter there
is a weakening of understanding and memory;
and from delirium which is a temporary impair-
ment in the exercise of the said functions. Some
modern writers confuse dementia with mania,
which is a delusional state accompanied by dis-
turbed behaviour (audace); these symptoms
are not present in subject with dementia who
exhibit foolish behaviour and cannot under-
stand what they are told, cannot remember
anything, have no judgment, are sluggish and
retarded …
Physiology teaches that the vividness of
our understanding depends on the intensity
of external stimuli … in pathological states
these may be excessive, distorted or abolished;
dementia results from abolition of stimuli which
may follow: 1. damage to the brain caused by
excessive usage, congenital causes or old age,
2. failure of the spirit, 3. small volume of the
brain, 4. violent blows to the head causing brain
damage, 5. incurable diseases such as epilepsy,
or exposure to venoms (Charles Bonnet reports
of a girl who developed dementia after being
bitten by a bat) or other substances such as opi-
ates and mandragora.
Dementia is difficult to cure as it is related
to damage of brain fibres and nervous fluids; it
becomes incurable in cases of congenital defect
or old age … [otherwise] treatment must follow
the cause …
[The legal definition of dementia reads]:
‘Those in a state of dementia are incapable of
informed consent, cannot enter into contracts,
sign wills, or be members of a jury. This is why
they are declared incapable of managing their
own affairs. Actions carried out before the dec-
laration of incapacity are valid unless it is dem-
onstrated that dementia predated the action.
Ascertainment of dementia is based on
examination of handwriting, interviews by
magistrates and doctors, and testimony from
informants. Declarations made by notaries
that the individual was of sane mind whilst
signing a will are not always valid as they may
be deceived by appearances, or the subject
might have been in a lucid period. In regards
to matrimonial rights, démence is not a suf-
ficient cause for separation, unless it is accom-
panied by aggression (furour). It is, however,
sufficient for a separation of property, so that
the wife is no longer under the guardianship
of her husband. Those suffering from demen-
tia cannot be appointed to public positions or
receive privileges. If they became demented
after any has been granted, a coadjutor should
be appointed …’
Although modern-sounding, the above definition must
be read with caution: its clinical description depends
on contrasts and differences with delirium and a list of

disorders, which are no more; its legal meaning is based on
the old Roman accounts, and its mechanisms make use of
the camera obscura metaphor and assume the passive defi-
nition of the mind that Condillac (who inspired the author
of the article) had borrowed from John Locke.
1.1.1.2 Behaviours
There are two ways of conceiving diseases in the history
of medicine. According to the conventional view, medical
discoverers are like botanists exploring a new forest. Now
and again they discover a ‘new species’ of plant, name it
and offer it to the world. The plant has always been there,
only that undiscovered. The act of discovery does not add
anything to its essence. The second view is that discover-
ing a new disease is tantamount to constructing it out of an
opaque mass of symptoms and complaints. The languages of
description involved (whether phenomenological, anatomi-
cal or molecular) actually create the boundaries for the new
disease. These are called the ontological and constructionist
views, respectively.
Taken these views into account, we can say that asking
the frequent question ‘where were the patients with demen-
tia type a, b or c before the twenty-first century’? (when the
proper groupings have at long last been achieved!) reflects a
belief in the ontological view, in the view that twenty-first
century types of dementia have always existed except that
earlier medics were not clever enough to describe them
properly. The keen clinical-historian, wearing anachronistic
spectacles can indeed find in the literature of the seventeenth
and eighteenth century (and indeed of earlier periods) cases
that ‘sound as if’ they had dementia a, b or c. The thinking
here is similar to that seen in pathographic diagnosis: Did
St. Theresa of Jesus have epilepsy, Dr. Johnson Gilles de la
Tourette syndrome or Mozart Asperger’s?
For example, in relation to ‘Stupidity or Foolishness’,
Thomas Willis (1684) wrote ‘although it chiefly belongs to
the rational soul, and signifies a defect of the intellect and
judgement, yet it is not improperly reckoned among the
diseases of the head or brain; for as much as this eclipse of
the superior soul proceeds from the imagination and the
memory being hurt, and the failing of these depends upon
the faults of the animal spirits, and the brain itself’ (p. 209).
Willis suggested that stupidity might be genetic (original, as
when ‘fools beget fools’) or caused by ageing (‘some at first
crafty and ingenious, become by degrees dull, and at length
foolish, by the mere declining of age, without any great
errors in living;) (p. 211) or other causes such as ‘strokes or
bruising upon the head’, ‘drunkenness and surfeiting’, ‘vio-
lent and sudden passions’ and ‘cruel diseases of the head’
such as epilepsy.
The same is the case with Boissier de Sauvages (1771),
one of the great classificators of the eighteenth century.
Order three (eighth class) of his Nosographie Methodique
encompasses delirium, paraphrosyne, imbecility,
melancholia, demonomania and mania. Synonyms of
Dementia: Historical overview 5
‘Imbecility’ are bêtise (stupidity, foolishness), niaiserie
(silliness) and démence; in Greek paranoia, and demen-
tia, fatuitas and vecordia in Latin. The term is used to
refer to patients who are fools, (fous), imbeciles (imbécil-
les), mentally weak (foibles d’esprit), mad (insensés).’ (p.
723). Boissier lists 12 subtypes of imbecility of which the
first one is the imbecility of the elderly (l’imbécillite de
vieillard), also known as puerile state, drivelling or senile
madness, and which he explains thus: ‘Because of the
stiffness of their nervous fibres, old people are less sensi-
tive to external impressions …’ (p. 724).
In the Nosographie (1818; first edition 1798), Pinel dealt
with cognitive impairment under amentia and morosis,
which he explains as a failure in the association of ideas
leading to disordered activity, extravagant behaviour, super-
ficial emotions, memory loss, difficulty in the perception of
objects, obliteration of judgement, aimless activity, auto-
matic existence and forgetting of words or signs to convey
ideas. He also referred to démence sénile (para 116). Pinel
did not remark upon the difference between congenital and
acquired dementia (Pinel, 1806).
The above entries summarize well the views on
dementia before the nineteenth century. There was, first
of all, a legal meaning according to which dementia
was a state of non-imputability due to mental incompe-
tence (of whatever origin). In France, this was enshrine
in Article 10 of the Napoleonic Code: ‘There is no crime
when the accused is in a state of dementia at the time of
the alleged act’ (Code Napoléon, 1808). Secondly, there
was a clinical meaning. This could be very general (i.e.
a synonym of madness) or specific, that is a clinical con-
dition, which was differentiable from mania (which, at
the time, described as any state of acute excitement be
it schizophrenic, hypomanic or organic) and delirium
(which referred, more or less, to what goes on nowa-
days under the same name). Although chronic, demen-
tia could still be reversible, affect individuals of any age
and be a final common pathway, that is the end deficit for
many other mental disorders. This created a template for
the alienists of the nineteenth century.
1.2 THE NINETEENTH CENTURY
1.2.1 BRAIN CHANGES AND AGEING
Since the beginning of the nineteenth century, cases had
been described of brain softening followed by cognitive fail-
ure. For example, Rostan (1823) divided 98 subjects with
brain softening due to scurvy into three groups: simple,
abnormal and complicated, the latter two showing mental
symptoms. These occurred before, during and after the soft-
ening itself; thus, senile dementia and insanity might pre-
cede the brain changes. Related to stroke, Rostan described
cognitive failure and attacks of insanity suggesting that
these symptoms were ‘a general feature … not a positive
6 Dementia
sign of localisation’ (pp. 214–215). Durand-Fardel (1843)
provided an account of the relationship between softening
and insanity, warning that softening was used to refer both
to a disease (stroke) and to a state of the brain. Psychiatric
complications were acute and long term, the former includ-
ing confusion, depression, irritability, acute insanity and
loss of mental faculties (p. 139); the latter, of gradual onset,
included impairment of memory, poverty of thinking and a
regression to infantile forms of behaviour, features that led
to ‘true dementia’ (pp. 327–328).
Although J.H. Jackson (1875) wrote ‘softening … as a
category for a rude clinical grouping was to be deprecated’
(p. 335), he proceeded to follow Durand-Fardel’s classifica-
tion suggesting that mental symptoms might follow stroke
immediately or wait for days and even months. Jackson
recognized that major cognitive failure may ensue, and saw
this as an instance of dissolution, according to which emo-
tional symptoms were considered as release phenomena (for
an analysis of dissolution see Berrios, 1991). Lastly, Jackson
suggested that anxiety, stress and irritability might be har-
bingers of stroke.
A major difference can be noticed between the eigh-
teenth century views of dementia and those set down a cen-
tury later when this category was divided up into subtypes
with the so-called ‘senile type’ referring to irreversible states
of cognitive impairment affecting the elderly. Amentia,
until then used as a synonym of dementia was redefined as
a ‘psychosis with sudden onset following severe, often acute
physical illness or trauma’ (Meynert, 1890). This does not
mean that the syndromatic view of the dementias had been
abandoned, indeed, the so-called vesanic dementias (i.e. ter-
minal states for all manner of mental disorders) continued
well into the beginning of the twentieth century.
1.2.2 DEMENTIA IN SOME COUNTRIES
1.2.2.1 France
In his doctoral thesis, Esquirol (1805) used the word
dementia to refer to loss of reason, as in démence acciden-
tal, démence mélancolique; and proceeded to distinguished
between acute, chronic and senile dementia. Acute demen-
tia was short-lived, reversible and followed fever, haemor-
rhage and metastasis; chronic dementia was irreversible
and caused by masturbation, melancholia, mania, hypo-
chondria, epilepsy, paralysis and apoplexy; lastly, senile
dementia resulted from ageing, and consisted in a loss of the
faculties of understanding (Esquirol, 1814). Esquirol’s final
thoughts on dementia were influenced by his controversy
with Bayle (1822) who via his notion of chronic arachnoidi-
tis propounded an anatomical (organic) view of all forms of
insanity and scorned Pinel’s views that some vesanias might
develop in a psychological space (Bayle, 1826).
Together with his student Georget, Esquirol supported
a descriptivist approach, at least in relation to some forms
of mental disorder. He reported 15 cases of ‘dementia’
(seven males and eight females) with a mean age of 34 years
(standard deviation = 10.9); seven being, in fact, cases of
general paralysis of the insane showing grandiosity, disin-
hibition, motor symptoms, dysarthria and terminal cog-
nitive failure. There also was included a 20-year-old girl
who in modern terms might have suffered from a catatonic
syndrome; and a 40-year-old woman with pica, cognitive
impairment and space-occupying lesions in her left hemi-
sphere and cerebellum (Esquirol, 1838). Although the mean
age of this sample and the absence of cases of senile demen-
tia may simply reflect a selection bias or the much shorter
life expectancy operating in Esquirol’s day, it is more likely
to reflect the view that age was not an important variable for
the definition of dementia. Together with irreversibility, age
only became a defining criterion by the second half of the
nineteenth century (only in some forms of dementia).
Aware of the importance of clinical description like his
teacher Esquirol, Calmeil wrote: ‘It is not easy to describe
dementia, its varieties and nuances; because its complica-
tions are numerous … it is difficult to choose its distinctive
symptoms’ (p. 71). Dementia followed chronic insanity and
brain disease, and was partial or general. Calmeil was less
convinced than his co-student Georget that all dementias
were associated with alterations in the brain.
In regard to senile dementia, Calmeil remarked: ‘There
is a constant involvement of the senses, elderly people can
be deaf, and show disorders of taste, smell and touch; exter-
nal stimuli are therefore less clear to them, they have little
memory of recent events, live in the past, and repeat the
same tale; their affect gradually wanes away …’ (p. 77). A
keen neuropathologist, Calmeil concluded that there was no
sufficient information on the nature and range of anomalies
found in the skull or brain to decide on the cause of demen-
tia (pp. 82–83) (Calmeil, 1835).
A Ghent alienist, thinking in Flemish and writing in
French, Guislain (1852) reported that in dementia: ‘All
intellectual functions show a reduction in energy, exter-
nal stimuli cause only minor impression on the intel-
lect, imagination is weak and uncreative, memory absent
and reasoning pathological … There are two varieties of
dementia … one affecting the elderly (senile dementia of
Cullen) the other younger people. Although confused with
dementia, idiocy must be considered as a separate group’
(p. 10). In dementia, ‘the patient has no memory, or at
least is unable to retain anything … impressions evapo-
rate from his mind. He may remember names of people
but cannot say whether he has seen them before. He does
not know what time or day of the week it is, cannot tell
morning from evening, or say what 2 and 2 add to … he
has lost the instinct of preservation, cannot avoid fire or
water and is unable to recognize dangers; has also lost
spontaneity, is incontinent of urine and faeces and does
not ask for ­a nything, he cannot even recognize his wife or
children …’ (p. 311) (Guislain, 1852).
Because in the past the mentally ill: ‘Had been catego-
rized only in terms of a [putative] impairment of their men-
tal faculties …’ (p. 2), Morel (1860) endeavoured to develop
a taxonomy that distinguished between occasional and

determinant causes of mental disorder (p. 251) and sug-
gested six clinical groups: hereditary, toxic, associated with
the neuroses, idiopathic, sympathetic and dementia.
In regards to the latter, Morel (1860) believed that:
… if we examine dementia (amentia, progres-
sive weakening of the faculties) we must accept
that it constitutes a terminal state. There will, of
course, be exceptional insane individuals who,
until the end, preserve their intellectual facul-
ties; the majority, however, are subject to the
law of decline. This results from a loss of vital-
ity in the brain … Comparison of brain weights
in the various forms of insanity shows that the
heavier weights are found in cases of recent
onset. Chronic cases show more often a gen-
eral impairment of intelligence (dementia). Loss
in brain weight – a constant feature of dementia
– is also present in ageing, and is an expression
of decadence in the human species. [There are]
natural dementia and that dementia resulting
from a pathological state of the brain … some
forms of insanity are more prone to end up in
dementia (idiopathic) than others … it could
be argued that because dementia is a terminal
state it should not be classified as a sixth form
of mental illness … I must confess I sympathise
with this view, and it is one of the reasons why I
have not described the dementias in any detail
… on the other hand from the legal and patho-
logical viewpoints, dementia warrants separate
treatment … (pp. 837–38).
Morel’s view was in keeping with his own theory of
‘degeneration’ (Morel, 1857; Pick, 1989), that is, in tainted
pedigrees, successive generation show worse forms of men-
tal disorder, ending up in dementia. Morel believed that
there were no specific brain alterations in dementia. This
was challenged by L.F. Marcé (1863) in a series of articles on
the neuropathology of senile dementia.
1.2.2.2 Great Britain
There is no space in this chapter to analyse with the same
level of detail the evolution of the concept of dementia in
other European countries although it can be said that it
followed similar lines. Views in England, for example, were
mainly derivative from French ones. In a popular textbook,
and following Pinel, Esquirol and Calmeil, Prichard included
a category, which he called ‘incoherence or dementia’:
[It] is a very peculiar and well-marked form
of mental disorder. The mind in this state is
occupied, without ceasing, by unconnected
thoughts and evanescent emotions; it is incapa-
ble of continued attention and reflection, and at
length loses the faculty of distinct perception or
Dementia: Historical overview 7
apprehension. Numerous examples of this dis-
ease, or decay of the mental powers are to be
met within every receptacle containing a con-
siderable assemblage of deranged persons …
incoherence is either a primary disease, arising
immediately from the agency of exciting causes
on a constitution previously health, or it is a sec-
ondary affection, the result of other disorders
of the brain and nervous system which, by their
long duration or severity, give rise to disease in
the structure of those organs … secondary inco-
herence or dementia follows long-protracted
mania, attacks of apoplexy, epilepsy or paraly-
sis, or fevers attended with severe delirium. This
decay of the faculties has been termed fatuity
or imbecility, and it has been confounded with
idiotism, which in all its degrees and modifica-
tions is a very different state … (Prichard, 1835,
pp. 83–85).
The same can be said of the views expressed by Bucknill
and Tuke in their popular textbook:
Dementia may be either primary or consecu-
tive; acute or chronic. It may also be simple or
complicated; it is occasionally remittent but
rarely intermittent. It is primary when it is the
first stage of the mental disease of the patient;
and when this occurs, it is, perhaps, one of
the most painful forms of insanity; the patient
often being acutely sensible of a gradual loss
of memory, power of attention and executive
ability. At this period, the distinction is often
well marked between the strictly intellectual
and affective disorder … dementia is much
more frequently consecutive, that is the conse-
quence of other diseases of the mind. Thus dur-
ing 44 years, while 277 cases of mania and 215
of melancholia were admitted at the Retreat,
only 48 of dementia were admitted during the
same period; yet, at the end of that term, there
were remaining in the institution, 20 patients in
a state of dementia out of 91 inmates. Mania
very often degenerates into dementia; as also
do melancholia and monomania … it should be
observed, that the term dementia may be, and
sometimes is, too indiscriminately employed.
All writers of authority agree in representing
impairment of the memory as one of the earli-
est symptoms of dementia; but we believe cases
are occasionally classed under incipient demen-
tia, in which close observation would show that
the memory is unimpaired. … It is often rather
a torpid condition of the mind, falling under the
division ‘apathetic insanity, which ought not to
be confounded with dementia …’ (Bucknill and
Tuke, 1858, pp. 117–119).
8 Dementia
1.2.2.3 Germany
Similar concepts are found in German-speaking nations
and the views of Heinroth, Feuchtersleben, Griesinger and
Kahlbaum were influential until the beginning of the sec-
ond half of the nineteenth century. Heinroth (1975) used the
term dementia in a very broad sense to refer to a state of
mind, which might accompany or follow other mental dis-
orders, that is, as vesanic dementia, a term which late in the
century was to become very popular, particularly in France.
This concept, which is not related to age, is redolent of the
later notion of secondary dementia, that is the state of psy-
chosocial and cognitive incompetence that might follow a
functional psychosis.
Feuchtersleben’s (1847) usage is even more general. He
uses dementia as a synonym of madness and may refer to
forms of acute madness with and without accompanying
idiocy. There is only one form of dementia, which he refers
as moria and considered as more or less chronic and more
or less cognitive. Although the patient may end up in a state
of idiocy he can also show lucid intervals. Once again, age is
of no relevance to moria and hence one must conclude that
Feuchtersleben is referring to a form of vesanic dementia.
Griesinger’s nosology is not altogether clear and has
often been interpreted as being based on the belief that there
is only one form of madness (unitary psychoses concept),
which may go through at least three stages: depression (as
in melancholia), exaltation (as in mania) and weakness (as
in chronic madness and dementia). In the second edition
of his great work, Griesinger (1861/1867) insists that the
states of mental weakness ‘do not constitute primary but
consecutive forms of insanity’ (p. 319). This suggests that he
is also referring to a form of vesanic dementia although he
includes under this large class all the forms of mental handi-
cap where no preliminary primary forms of madness can
be recognized. Under the heading ‘dementia’, Griesinger
includes mental disorders fundamentally caused by a ‘gen-
eral weakness of the mental faculties’ including loss of emo-
tions. Age is not a factor in the development of dementia or
apathetic dementia and hence it must also be concluded that
Griesinger is referring to vesanic dementia.
The work of Kahlbaum, particularly his important book
of 1863 on the definition and classification of mental dis-
orders marks the beginning of a new era in psychiatry. His
incorporation of time as a variable in the analysis of mad-
ness (longitudinal definition) and his view that period of life
is relevant to the form of the disease remain the pillars of
psychiatric nosology to this day. The concept of dementia
is dealt with in the third section of Kahlbaum’s book (1863)
under the name of aphrenia. This clinical category refers
to states of mental impotence (Zustand geistiger Impotenz)
(p. 153), which Kahlbaum equates to the old German notion
of Blödsinn. After complaining that neither the Greeks nor
Latin writers managed to specify a term for this condition,
he insists that a word is needed to refer to states of cognitive
and behavioural incompetence such as those seen in demen-
tia terminalis (Berrios, 1996).
1.2.3 THE FRAGMENTATION OF
DEMENTIA
During the second half of the nineteenth century, and
based on the clinical observations and reconceptualiza-
tion carried out by the French, German and English writ-
ers mentioned above, dementia starts to be considered as a
syndrome and hence could be attached to a variety of disor-
ders. The primary classification was to be between primary
and secondary, the latter including all the vesanic demen-
tias, that is states of defect that could follow any severe form
of insanity. An increased use of light microscopy during
the second half of the century led to the view that primary
forms of dementia could be caused by degenerations of
cerebral parenchyma or by arteriosclerosis. By 1900, senile,
arteriosclerotic, infectious and traumatic forms of demen-
tia had been reported (Berrios and Freeman, 1991). Mixed
forms, such as dementia praecox were also suggested reflect-
ing Kahlbaum’s view that mental disorders appeared dur-
ing specific biological transitions. The list of parenchymal
forms became longer after the inclusion of states of degen-
eration due to alcoholism, epilepsy, myxoedema and lead
poisoning. The history of some of these forms will be dis-
cussed presently.
1.2.3.1 Vesanic dementias
The term vesanic dementia began to be used after the 1840s
to refer to the clinical states of cognitive disorganisation fol-
lowing insanity (Berrios, 1987); its meaning, has changed
pari passu with psychiatric theory. According to the uni-
tary insanity notion, vesanic dementia was a terminal stage
(after mania and melancholia); according to degeneration
theory, it was the final expression of a corrupted pedigree;
and according to post-1880s nosology, a final common
pathway to some insanities. Vesanic dementias were revers-
ible, and could occur at any age; risk factors such as old age,
lack of education, low social class, bad nutrition, etc., accel-
erated the progression of the dementia or impeded recovery
(p. 597) (Ball and Chambard, 1881).
The vesanic dementias included cases of melancho-
lia with marked cognitive impairment. Under the term
démence mélancolique Mairet (1883) reported cases of
depressed patients with cognitive impairment who on post-
mortem showed alterations in the temporal lobe; this led
Mairet to hypothesize that the affected sites were related to
feelings, and to suggest that nihilistic delusions appeared
when the lesion spread to the cortex (Berrios, 1985a).
Mairet’s cases, some of which would now be called Cotard’s
syndrome showed psychomotor retardation, refused food
and died in stupor (Cotard, 1882; Berrios and Luque, 1995).
Other cases got better and are redolent of what later on was
called depressive pseudodementia.
Another contributor to the understanding of cogni-
tive impairment in the affective disorders was George
Dumas (1894) who suggested that it was ‘mental fatigue
that explained the psychological poverty and monotony

of melancholic depressions’ and that the problem was
not ‘an absence but a stagnation of ideas’; i.e. he was,
therefore, the first to explain the disorder as a failure in
performance.
The word pseudodementia, however, had originated
in a different clinical tradition and was first used by Carl
Wernicke to refer to ‘a chronic hysterical state mimicking
mental weakness’ (Bulbena and Berrios, 1986). In the 1950s
it was given a lease of life by writers such as Madden et al.
(1952), Anderson et al. (1959) and Kiloh (1961). Current
usage remains ambiguous as it relates to three clinical
situations: a real (albeit reversible) cognitive impairment
accompanying some psychoses, a parody of such impair-
ment and the cognitive deficit of delirium (Bulbena and
Berrios, 1986).
1.2.3.2 General paralysis of the insane
Bayle (1822) described under the name arachnitis chro-
nique cases of what later was to be called ‘general paraly-
sis of the insane’. Whether this ‘new phenomenon’ resulted
from ‘a mutation in the syphilitic virus towards the end
of the eighteenth century’ is unclear (p. 623) (Hare, 1959).
Equally dubious is the claim that its discovery reinforced
the belief of alienists in the anatomo-clinical view of men-
tal disease (Zilboorg, 1941). In fact, it took more than 30
years for general paralysis to gain acceptance as a ‘separate’
disease. Bayle’s ‘discovery’ was more important in other
way, namely, in that it challenged the cross-sectional view of
­disease; in the words of Bercherie (1980): ‘For the first time
in the history of psychiatry there was a morbid entity which
presented itself as a sequential process unfolding itself into
successive clinical syndromes’ (p. 75).
By the 1850s, no agreement had yet been reached as to
how symptoms were caused by the periencephalite chro-
nique diffuse (as general paralysis was known at the time).
Three clinical types were recognized: manic-ambitious,
melancholic-hypochondriac and dementia; according to the
unitary view, all three constituted stages of a single disease,
the order of their appearance depending on the progress of
the cerebral lesions. Baillarger (1883), however, sponsored
a dualist view: ‘Paralytic insanity and paralytic dementia
are different conditions’. It is clear that the debate had less
to do with the nature of the brain lesions than with how
mental symptoms and their contents were produced in gen-
eral: How could the ‘typical’ content of paralytic delusions
(grandiosity) be explained? Since the same mental symp-
toms could be seen in all manner of conditions, Baillarger
(1883) believed that chronic periencephalitis could only
account for the motor signs—mental symptoms ‘there-
fore, having a different origin’ (p. 389). The absence of a
link between lesion and symptom also explained why some
patients recovered.
The view that general paralysis might be related to syphi-
lis (put forward by Fournier, 1875) was resisted. Indeed, the
term pseudo-general paralysis was coined to refer to cases
of infections causing psychotic symptoms (Baillarger, 1889).
Dementia: Historical overview 9
In general, there is little evidence that alienists considered
general paralysis as a paradigm disease, i.e. a model for all
other mental diseases. It can even be said that the new ‘dis-
ease’ created more problems than it solved (for a discussion
of this issue see Berrios, 1985a).
1.2.3.3 Arteriosclerotic dementia
Old age was considered as an important factor in the devel-
opment of arteriosclerosis (Berrios, 1994) and a risk factor
in diseases such as melancholia (Berrios, 1991). By 1910,
there was a trend to include all dementias under ‘men-
tal disorders of cerebral arteriosclerosis’ (Barrett, 1913).
Arteriosclerosis, might be generalized or cerebral, inherited
or acquired and caused by syphilis, alcohol, nicotine, high
blood pressure and ageing. In those genetically predisposed,
cerebral arteries were considered as thinner and less elas-
tic. Arteriosclerosis caused mental changes by narrowing of
arteries and/or reactive inflammation. The view that arte-
riosclerotic dementia resulted from a gradual strangulation
of blood supply to the brain was also formed during this
period; consequently, emphasis was given to prodromal
symptoms and strokes were but the culmination of a pro-
cess started years before.
Some opposed this view from the beginning. For
example, Marie (1906) claimed that such explanation was
a vicious circle as alienists claimed both that: ‘Ageing was
caused by arteriosclerosis and the latter by ageing’ (p. 358),
and Walton (1912) expressed serious doubts from the his-
topathological point of view. The frequent presence in
­post-mortem of such changes also concerned pathologists
who worried that they could not ‘safely exclude cerebral
arteriosclerosis of greater or less degree in any single case’ of
senile dementia (p. 677) (Southard, 1910). Based on a review
of these arguments, Olah (1910) concluded that there was no
such a thing as ‘arteriosclerotic psychoses’. But the ‘chronic
global ischaemia’ hypothesis won the day, and it was to
continue well into the second half of the twentieth century.
For some it became a general explanation; for example,
North and Bostock (1925) reported a series of 568 general
psychiatric cases in which around 40% suffered from arte-
rial disease, which—according to the authors—was even
responsible for schizophrenia. The old idea of an apoplectic
form of dementia, however, never disappeared.
1.2.3.4 Apoplectic dementia
Apoplectic dementia achieved its clearest enunciation in the
work of Benjamin Ball (Ball and Chambard, 1881). Organic
apoplexy resulted from bleeding, softening or tumour and
might be ‘followed by a notable decline in cognition, and
by a state of dementia which was progressive and incur-
able … of the three, localized softening (ramollissement en
foyer) caused the more severe states of cognitive impair-
ment’ (p. 581). Ball believed that prodromal lapses of cog-
nition (e.g. episodes of somnolence and confusion with
automatic behaviour, for which there was no memory after
10 Dementia
the event) and sensory symptoms were caused by athero-
matous lesions. Visual hallucinations, occasionally of a
pleasant nature, were also common. After the stroke, per-
sistent cognitive impairment was frequent. Post-mortem
studies showed in these cases softening of ideational areas
of cortex and white matter. Ball also suggested a laterality
effect (p. 582) in that right hemisphere strokes led more
often to dementia whereas left hemisphere ones caused per-
plexity, apathy, unresponsiveness and a tendency to talk to
oneself (p. 583). Following Luys, he believed that some of
these symptoms resulted from damage to corpus striatum,
insular sulci and temporal lobe. During Ball’s time atten-
tion also shifted from white to red softening. Charcot (1881)
wrote on cerebral haemorrhage (the new name for red soft-
ening): ‘Having eliminated all these cases, we find ourselves
in the presence of a homogeneous group corresponding to
the commonest form of cerebral haemorrhage. This is, par
excellence, sanguineous apoplexy … as it attacks a great
number of old people, I might call it senile haemorrhage’
(p. 267).
1.2.3.5 Presbyophrenia and confabulation
The word presbyophrenia was coined by Kahlbaum (1863)
to name a subtype of the paraphrenias (insanities occurring
during periods of biological change). Presbyophrenia was a
form of paraphrenia senilis characterized by amnesia, dis-
orientation, delusional misidentification and confabulation.
Ignored for more than 30 years, the term reappeared in the
work of Wernicke, Fischer and Kraepelin.
Wernicke’s classification of mental disorders was based
on his theory of the three-partite relational structure con-
sciousness (outside world, body and self) (Lanczik, 1988).
Impairment of the link between consciousness and outside
world led to presbyophrenia, delirium tremens, Korsakoff’s
psychosis and hallucinosis. Amongst the features of pres-
byophrenia, Wernicke included confabulations, disorienta-
tion, hyperactivity, euphoria and a fluctuating course; acute
forms resolved without trace, chronic ones merged with
senile dementia (Berrios, 1986).
In France, Rouby (1911) suggested that presbyophre-
nia was a final common pathway for cases suffering from
Korsakoff’s psychosis, senile dementia or acute confusion.
Truelle and Bessière (1911) proposed, in turn, that it might
result from a toxic state caused by liver or kidney failure.
Kraepelin (1910) lumped presbyophrenia together with the
senile and presenile insanities, and after comparing them
with Korsakoff’s patients reported that presbyophrenic
patients were older, free from polyneuritis and history of
alcoholism, and showed hyperactivity and elevated mood.
Ziehen (1911) wrote that ‘their marked memory impair-
ment contrasts with the relative sparing of thinking’. Oskar
Fischer (1912) suggested that disseminated cerebral lesions
were the essential anatomical substratum of presbyophrenia.
During the 1930s, two new hypotheses emerged.
Bostroem (1933) concluded that in clinical terms presbyo-
phrenia resembled mania, suggesting an interplay between
two factors: cerebral arteriosclerosis and cyclothymic pre-
morbid personality. Lafora (1935) emphasized the role of
cerebrovascular pathology, and claimed that disinhibition
and presbyophrenic behaviour were caused by a combina-
tion of senile and atherosclerotic changes. Burger-Prinz and
Jacob (1938), however, questioned the view that cyclothy-
mic features were a necessary precondition. Bessière (1948)
claimed that presbyophrenia was a syndrome found in con-
ditions such as senile dementia, brain tumours, traumatic
psychoses and confusional states. More recently, it was sug-
gested that presbyophrenia was a subform of Alzheimer’s
disease characterized by a severe atrophy of locus caeruleus
(Berrios, 1985b).
One of the features of presbyophrenia was confabula-
tion. This complex symptom has not quite found a place
in psychopathology (Berrios, 2000a). Two phenomena are
included under the name confabulation. The first type
concerns ‘untrue’ utterances of subjects with memory
impairment; often provoked or elicited by the interviewer,
these confabulations are accompanied by little conviction
and are believed by most clinicians to be caused by the
(conscious or unconscious) need to ‘cover up’ for some
memory deficit. Researchers wanting to escape the ‘inten-
tionality’ dilemma have made use of additional factors
such as presence of frontal lobe pathology, dysexecutive
syndrome, difficulty with the temporal dating of memo-
ries leading to an inability temporally to string out mem-
ory data etc.
The second type concerns confabulations with fantastic
content and great conviction as seen in subjects with func-
tional psychoses and little or no memory deficit. Less is
said in the neuropsychological literature about this group
although (at least in the case of schizophrenics) it has been
correlated with a bad performance on frontal lobe tests. It
is our belief that this group remains of crucial importance
to psychiatrists. Little is known about the epidemiology of
either type of confabulation.
In clinical practice, these two ‘types’ can be found in
combination. It remains unclear why so many patients with
Korsakoff’s psychosis or frontal lobe disorder, in spite of the
fact that they do meet the putative conditions for confabula-
tion (amnesia, frontal lobe damage, difficulty with the dating
of memories etc.) do not confabulate. Furthermore, confab-
ulations have also been reported in subjects with lesions in
the non-dominant hemisphere and in the thalamus.
Under different disguises, the covering up or gap ­filling
hypothesis is still going strong. Although superficially
­plausible, it poses a serious conceptual problem in regards
to the issue of awareness of purpose: If full awareness is pre-
sumed, then it is difficult to differentiate confabulations
from lying; if no awareness is presumed then the semantics
of the concept of purpose is severely stretched and confabu-
lations cannot be differentiated from delusions.
The received view of confabulations also neglects the
clinical observation that confabulations (particularly pro-
voked ones!) do occur in dialogical situations: For exam-
ple, the way in which the patient is asked questions may

increases the probability of his producing a confabulation.
This suggests that the view that confabulations are a disor-
der of a putative narrative function found in normal human
subjects must be taken seriously. It is hypothesized here that
this trait is normally distributed in the population. In the
absence of adequate epidemiological information, research
efforts should be directed at mapping the distribution of
this narrative (or confabulatory) capacity in the community
at large. Only then it will be possible to understand the sig-
nificance of its disorders. In the long term, this approach
will prove more heuristic than unwarranted speculation
based on few anecdotal cases.
Reported in relation to clinical conditions other than
memory deficit, confabulation-like behaviours can already
be found in the clinical literature of the second half of the
nineteenth century. Sully (1895) suggested that such behav-
iours might be related to a psychological function whose
role was filling gaps in the flow of our lives and explained
why ‘our image of the past is essentially one of an unbro-
ken series of conscious experiences’. Sully believed that
this function also intervened when memory failed: ‘Just as
the eye sees no gap in its field of vision ­corresponding to
the ‘blind’ spot of the retina, but carries the impression
over this area, so memory sees no lacuna in the past, but
carries its image of conscious life over each of the forgot-
ten spaces’ (p. 282).
Kraepelin (1886–1887) reported typical cases of con-
fabulation associated with inter alia general paraly-
sis of the insane, melancholia and dementia; and later
on suggested that pseudomemories could be a symptom
of paraphrenia (without cognitive impairment), and
described a clinical variety called paraphrenia confabu-
lans (Kraepelin, 1919). Under schizophrenic akzessorischen
Gedachtnisstörungen, Bleuler (1911) discussed three related
phenomena: Gedächnisillusionen (illusions or distortions
of memory), identifizierenden Erinnerungstäuschungen
(memory falsifications based on identification), and
Erinnerungshalluzinationen (memory hallucinations). Of
the former he wrote: ‘Memory illusions often constitute the
main material for the construction of delusions in para-
noids. The entire previous life of the patient may be changed
in his memory in terms of this complex’ (p. 115). On this
definition, it is difficult, on the basis of their intrinsic fea-
tures, to distinguish illusion of memory from confabula-
tion. Indeed, symptom-naming is determined by whether
schizophrenia or ‘organic disorder’ is the associated disease.
Unsuccessfully, Bleuler (1911) tried to establish a differenti-
ation on the basis of mechanism: ‘Until now, and in contrast
to the views of some authors, I have not observed confabu-
lation as it appears in organic cases; e.g. memory halluci-
nations that fill in memory gaps, which at first appear at a
(usually external) given moment and mostly adapt them-
selves to such an occasion (p. 117). Kleist (1960) described
patients with ‘progressive confabulosis’ as ‘cheerful, expan-
sive and with little in the way of thought or speech disorder’
(p. 211); and Leonhard (1957) redescribed the condition as
‘confabulatory euphoria’.
Dementia: Historical overview 11
1.3 THE TWENTEITH CENTURY
1.3.1 ALZHEIMER’S DISEASE
Alzheimer’s disease has become a prototypical form of
dementia. From this point of view, a study of its origins
should throw light on the evolution of the concept of
dementia in general. The writings of Alzheimer, Fischer,
Fuller, Lafora, Bonfiglio, Perusini, Ziveri, Kraepelin and
others feel deceptively fresh, and this makes anachronis-
tic reading inevitable. However, the psychiatry of the late
nineteenth century is a foreign country: Concepts such as
dementia, neurone, neurofibril and plaque were then still in
process of construction and meant different things to differ-
ent people. A discussion of these issues is beyond the scope
of this chapter (for this see Berrios, 1990a).
1.3.1.1 The neuropathology of dementia
before Alzheimer
Enquiries into the brain changes accompanying demen-
tia started during the 1830s but consisted in descriptions
of external appearance (Wilks, 1865). The first important
microscopic study was that of Marcé (1863) who described
cortical atrophy, enlarged ventricles and softening. The
vascular origin of softening was soon ascertained (Parrot,
1873), but the distinction between vascular and parenchy-
mal factors had to await until the 1880s. From then on,
microscopic studies concentrated on cellular death, plaques
and neurofibrils.
1.3.1.2 Alzheimer and his disease
Alzheimer (1907) reported the case of a 51-year-old woman,
with cognitive impairment, delusions, hallucinations, focal
symptoms, and whose brain showed plaques, tangles and
arteriosclerotic changes. The existence of neurofibrils had
been known for some time (DeFelipe and Jones, 1988; Barret,
1913); for example, that in senile dementia ‘the destruction
of the neurofibrillae appears to be more extensive than
in the brain of a paralytic subject’ (Bianchi 1906, p. 846).
Fuller (1907) had remarked in June 1906 (i.e. 5 months
before Alzheimer’s report) on the presence of neurofibrillar
bundles in senile dementia (p. 450). Likewise, the associa-
tion of plaques with dementia was not a novelty: Beljahow
(1889) had reported them in 1887, and so had Redlich and
Leri few years later (Simchowicz, 1924); in Prague, Fischer
(1907) gave an important paper in June 1907 pointing out
that miliary necrosis could be considered as a marker of
senile dementia.
Nor was the syndrome described by Alzheimer new:
States of persistent cognitive impairment affecting the
elderly, accompanied by delusions and hallucinations were
well known (Marcé, 1863; Krafft-Ebing, 1873; Crichton-
Brown, 1874; Marie, 1906). As a leading neuropathologist,
12 Dementia
Alzheimer was aware of this work. Did he then mean to
describe a new disease? The answer is that it is most unlikely
he did, his only intention having been to point out that such
a syndrome could occur in younger people (Alzheimer,
1911). This is confirmed by commentaries from those who
worked for him: Perusini (1911) wrote that for Alzheimer
‘these morbid forms do not represent anything but atypical
form of senile dementia’ (p. 143).
1.3.1.3 Naming the disease
Kraepelin (1910) coined the term in the eighth edition of
his handbook: At end of the section on ‘senile dementia’
he wrote: ‘The autopsy reveals, according to Alzheimer’s
description, changes that represent the most serious form
of senile dementia … the Drusen were numerous and
almost one third of the cortical cells had died off. In their
place instead we found peculiar deeply stained fibrillary
bundles that were closely packed to one another, and
seemed to be remnants of degenerated cell bodies … The
clinical interpretation of this Alzheimer’s disease is still
confused. Whilst the anatomical findings suggest that
we are dealing with a particularly serious form of senile
dementia, the fact that this disease sometimes starts
already around the age of 40 does not allow this supposi-
tion. In such cases we should at least assume a “senium
praecox” if not perhaps a more or less age-independent
unique disease process’. He went on to call it Alzheimersche
Krankheit (p. 356).
1.3.1.4 Reception of the disease
Alzheimer (1911) showed surprise at Kraepelin’s interpreta-
tion, and always referred to his ‘disease’ as Erkrankungen
(in the medical language of the 1900’s a term softer than
Krankheit, term used by Kraepelin). Others also expressed
doubts. Fuller (1912), whose contribution to this field
has been sadly neglected, asked ‘why a special clinical
­designation—Alzheimer’s disease—since, after all, they are
but part of a general disorder’ (p. 26). Hakkboutsch and
Geier (1913), in Russia, saw it as a variety of the involu-
tion psychosis. Simchowicz (1911) considered ‘Alzheimer’s
disease’ as only a severe form of senile dementia. Ziehen
(1911) did not mention the disease in his major review of
senile dementia. In a meeting of the New York Neurological
Society, Ramsay Hunt (Lambert, 1916) asked Lambert, the
presenter of a case of ‘Alzheimer’s disease’ that ‘he would
like to understand clearly whether he made any distinction
between the so-called Alzheimer’s disease and senile demen-
tia other than … in degree and point of age’. Lambert agreed
suggesting that, as far as he was concerned, the underlying
pathological mechanisms were the same (Lambert, 1916).
Lugaro (1916) wrote: ‘For a while it was believed that a cer-
tain agglutinative disorder of the neurofibril could be con-
sidered as the main “marker” (contrassegno) of a presenile
form [of senile dementia], which was “hurriedly baptized”
(fretta battezzate) as “Alzheimer’s disease”’ (p. 378). He went
on to say that this state is only a variety of senile dementia.
Simchowicz (1924), who had worked with Alzheimer, wrote
‘Alzheimer and Perusini did not know at the time that the
plaques were typical of senile dementia [in general] and
believed that they might have discovered a new disease’
(p. 221). These views, from men who lived in Alzheimer’s
and Kraepelin’s time, must be taken seriously (for a detail
discussion of these issues see Berrios 1990a).
Of late there has been an attempt to rewrite the history
of Alzheimer’s disease. After having been lost for years, the
case notes of Auguste D., the first patient with Alzheimer’s
disease were found in the late 1990s (Maurer and Maurer,
1998). As mentioned above the original report by Alzheimer
(1907) clearly stated that Auguste suffered from severe con-
fusion, delusions, hallucinations, focal symptoms and on
post-mortem her brain showed plaques, tangles and most
importantly arteriosclerotic changes. As if to confirm
the ontology of Alzheimer’s disease, Graeber et al. (1998)
reported that in tissue sections belonging to this case they
confirmed the presence of neurofibrillary tangles and amy-
loid plaques. Most interestingly, and given that vascular
changes are currently not supposed to be a diagnostic crite-
rion, these authors decided to correct Alzheimer’s own his-
topathological study and state that Auguste’s brain showed
no arteriosclerotic lesions. Furthermore, they report that
the apolipoprotein E (ApoE) genotype of Auguste was ε3/
ε3, ‘indicating that mutational screening of the tissue is
feasible’.
On the basis of these findings, can one say that back in
1910 Kraepelin was after all right in claiming that Alzheimer
had ‘discovered’ a new disease? The answer has to be that
one must judge his decision in terms of what Kraepelin
knew at the time and of the academic pressure he was under.
He knew what the Alzheimer’s report stated in 1907, what
the latter might have verbally added, and upon Kraepelin’s
perusal of Auguste’s case notes, which were requested by
him from Frankfurt (indeed this is the reason why they
were lost for such a long time). In clinical terms, Auguste
was not a ‘typical’ case. At 51 she had delusions, halluci-
nations and Alzheimer’s reported arteriosclerotic changes.
None of these features is mentioned in Kraepelin’s original
claim. The question is, why?
It is also interesting that the so-called ‘second case’ of
Alzheimer’s (Graeber et al., 1997), Johann F., reported
in 1911 is now considered to have suffered a plaques-only
form of Alzheimer’s disease. The same authors suggest that
knowledge of this case may have encouraged Kraepelin
to report the discovery by Alzheimer’s of a new disease.
Unfortunately, there is no evidence that Kraepelin knew of
this case when he was writing the relevant section of the
eighth edition of his Lehrbuch. More to the point is that he
knew of Perusini’s review (1909) as he himself had asked the
young Italian assistant to collect four cases. In addition to
Auguste D (which includes more information than that pro-
vided by Alzheimer in 1907), Perusini reviewed the cases
of Mr. R.M., a 45-year-old basket maker who had epileptic

seizures, Mrs. B.A. a 65-year-old who had marked clinical
features of myxoedema and Schl. L, a 63-year-old who had
suffered from syphilis since 1870, and was Romberg-positive
and had a pupillary syndrome and heard voices. Since these
are likely to have been the cases on which Kraepelin based
his decision to construct the new disease, it would be inter-
esting that the neuropathology and neurogenetics of the
other three cases (Auguste’s has already been done) is also
investigated.
1.3.2 PICK’S DISEASE AND THE FRONTAL
DEMENTIAS
Dementias believed to be related to frontal lobe pathol-
ogy have once again become fashionable, and authors
often invoke the name of Arnold Pick (Niery et al.,
1988). However, when the great Prague neuropsychiatrist
described the syndrome named after him, all he wanted
was to draw attention to a form of localized (as opposed
to diffuse) atrophy of the temporal lobe (Pick, 1892). This
alteration was to give rise to a dysfunction of language and
praxis, and be susceptible to diagnosis during life. Pick
believed that lobar atrophies constituted a stage in the evo-
lution of the senile dementias.
The story starts, as it should, before Pick. Louis Pierre
Gratiolet (1854) renamed the cerebral lobes after the respec-
tive sections of overlying skull: Thus anterior became frontal
lobe. He made no assumption as to the function of the ‘ante-
rior extremity of the cerebral hemisphere’. Phrenologists,
however, did and related reflective and perceptive functions
(qualitatively defined) to the forehead (Anonymous, 1832)
(on the science of Phrenology: See Combe, 1873; Lanteri-
Laura, 1970). Modular assumptions (i.e. a one-to-one cor-
relation between mental function and brain site) involving
the frontal lobes started only during the 1860s, following
reports on dysfunction of language in lesions of the fron-
tal lobes (Broca, 1861; Henderson, 1986). These claims ran
parallel to those of Jackson’s that the cerebral cortex was
the general seat of personality and mind (Jackson, 1894).
Meynert (1885) believed that ‘the frontal lobes reach a high
state of development in man’ but still defined mental disor-
ders as diseases of the forebrain (by which he meant ‘pros-
encephalon’ or human brain as a whole).
Neither in the first (case of focal senile atrophy and
aphasia in a man of 71; Pick, 1892) nor in the second case
report (a woman of 59 with generalized cortical atrophy,
particularly of the left hemisphere; Pick, 1901) did Pick
actually inculpate the frontal lobes as responsible for the
symptomatology. A link with the frontal lobes was only
made in his fourth case report (a 60-year-old man with
‘bilateral frontal atrophy’; Pick, 1906). Which of these
cases should, therefore, be considered as the first with
Pick’s disease? At the time, in fact, no one thought that
Pick had described a new disease; Barrett (1913) con-
sidered the two first cases of Pick’s as atypical forms of
Alzheimer’s disease, and Ziehen (1911) did not see any-
thing special in them.
Dementia: Historical overview 13
During the same period, Liepmann, Stransky and
Spielmeyer had described similar cases with aphasia
and circumscribed cerebral atrophy (Mansvelt, 1954); so
much so that Urechia and Mihalescu felt tempted to name
the syndrome Spielmeyer’s disease (Caron, 1934). This did
not catch on, however, and in two classical papers on what
he coined the term Pick’s disease, Carl Schneider (1927,
1929) constructed a new profile for this condition by sug-
gesting that it evolved in three stages – the first with a
disturbance of judgement and behaviour, the second with
localized symptoms (e.g. speech) and the third with gen-
eralized dementia. He recognized rapid and slow forms,
the former with an akinetic and aphasic subtypes and a
malignant course, and the latter with a predominance
of plaques (probably indistinguishable from Alzheimer’s
disease).
1.3.3 DEMENTIA SINCE WORLD WAR I
By the 1920s, the description and classification of the
dementias had notably changed. This is well illustrated
by comparing the first (1869) and fifth (1918) editions
of the Official Nomenclature of Diseases of the Royal
College of Physicians. In 1869, dementia (Condition 107)
is classified as acute and chronic and is grouped with
paralysis of the insane (Condition 108), amentia (idiocy)
(Condition 109) and insipientia (imbecility) (Condition
110). In 1918, dementia is grouped with dementia prae-
cox (also called schizophrenia) and divided into primary
and secondary (the latter originating from organic cere-
bral disease other than syphilis, arterial disease, senile,
epilepsy and injury).
Continental views are well illustrated by the popular
Lehrbuch der Psychiatrie written by Eugen Bleuler whose
English, French and Spanish translations did a great deal
to uniformize psychiatric nomenclature and classifica-
tion in both Europe and the United States. Bleuler (1920)
listed four main categories: dementia paralytica, prese-
nile and senile dementia, arteriosclerotic dementia and
presbyophrenia. ‘Vesanic dementia’, the category used to
name a final common pathway for all chronic psychoses
was all but abandoned. By the end of the Second World
War, Presbyophrenia also was sounded its dead knell.
Lastly, Bini (1948) published his great book on Le Demenze
Presenili where he reported 37 cases studied in detail and
offered the classificatory scheme for the dementias that has
lasted until today.
The stage was being prepared for Roth’s (1955) classi-
cal paper on The Natural History of Mental Disorder in Old
Age where he explored the clinical context in which the
dementias occurred and concluded that the results: ‘Suggest
that affective psychosis, late paraphrenia and acute confu-
sion are distinct from the two main causes of progressive
dementia in old age; senile and arteriosclerotic psychosis.
They also provide some support for the validity of the clini-
cal distinction drawn between senile and arteriosclerotic
psychosis’ (p. 295). This paper offered not only a working
14 Dementia
classification of the mental disorders of all age but also a
vindication of the real place of the vesanic dementias and in
doing so set the basis for a new professional specialism, the
psychiatry of old age.
1.4 CONCLUSIONS
The history of the word dementia must not be confused
with that of the concepts or behaviours involved. By the
year 1800, two definitions of dementia were recognized
and both had psychosocial incompetence as their central
concept: In addition to cognitive impairment, the clinical
definition included other symptoms such as delusions and
hallucinations. Irreversibility and old age were not features
of the condition, and in general dementia was considered to
be a terminal state to all sorts of mental, neurological and
physical conditions.
The adoption of the anatomo-clinical model of disease by
nineteenth-century alienists changed this. Questions were
asked then as to the neuropathological basis of dementia
and this, in turn, led to readjustments in its clinical descrip-
tion. The history of dementia during the nineteenth century
is, therefore, the history of its gradual attrition. Stuporous
states (then called acute dementia), vesanic dementias and
localized memory impairments, were gradually reclassified,
and by 1900 the cognitive paradigm, i.e. the view that the
essential feature of dementia was intellectual impairment,
was established (Berrios, 1989).
From then on, efforts were made to explain other symp-
toms such as hallucinations, delusions and mood and
behavioural disorders as epiphenomena, and as unrelated
to whatever the central mechanism of dementia was. There
has also been a fluctuating acceptance of the parenchymal
and vascular hypotheses, the latter leading to the descrip-
tion of arteriosclerotic dementia. The separation of the ves-
anic dementias and of the amnestic syndromes led to the
realisation that age and ageing mechanisms were impor-
tant, and by 1900 senile dementia became the prototype of
the dementias; by 1970, Alzheimer’s disease had become the
flagship of the new approach. During the last few years, the
cognitive paradigm has become an obstacle, and a gradual
re-expansion of the symptomatology of dementia is fortu-
nately taking place (Berrios, 1989; 1990b).
It is against this clinical and classificatory context that
the mental disorders in old age in general, and the demen-
tias in particular have continued their development. The
latter were different disorders, had a different outcome
and hence had a different aetiology. As the neuroscien-
tific narratives became predominant, classifications of the
dementias based on biological markers gradually replaced
older ones based on clinical phenomenology. This process
is going on and from the perspective of the history and
epistemology of dementia it is difficult to predict where it
will go.
Thus far, biological therapies based on the neuroscien-
tific narrative of dementia have been less successful than
expected. This has led to some broadening of therapeutic
approach, and the earlier emphasis on a pure cognitive par-
adigm has given way to interest in behavioural failures such
as self and personality deterioration, and emotional and
volitional involution.
As a collateral issue, promises of finding a ‘cure’ for
dementia have generated some speculation on the eventual
finding of an elixir of eternal youth. This has unavoidably
led to asking the deontological question about the duties of
the generation that has discovered such elixir to the follow-
ing ones.
So far, the most hopeful response to the crisis created by
the need to care for the growing number of persons affected
with dementia has been the positive and creative attitude of
carers, both professional and lay, and the search for solutions
in fields beyond neuroscience. Their good will, patience and
creativity needs to be encouraged and supported by all, and
mostly by the body politics.
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The lived experience of dementia
SHIRLEY NUROCK
2.1 OUR STORY
‘What do you mean, Alzheimer’s disease? Surely
he’s too young!’
Apparently not. With these words (over the telephone) our
lives were turned upside-down. My handsome, caring hus-
band Leonard, a GP here in London, in his fifties, had been
diagnosed with Alzheimer’s disease (AD), our three chil-
dren then in their early teens.
Yes, he had been more than usually forgetful over the last
couple of years, infuriating me sometimes by mislaying keys
or turning up at the wrong time or wrong place, but onset was
insidious and I was pre-occupied with my work, our hectic
lifestyle, the children and their decisions about schools, uni-
versities, and choice of subjects and unthinkingly accepted
his explanation of merely being stressed at work. This was
the late l980s and a new GP contract was coming into place
that involved computerization and appointment of practice
managers; not concepts he was familiar with.
The neurologist advised he stop work immediately, stop
driving, just stay at home and keep as healthy as possible
and don’t move house, that would be the worst thing to do;
‘Oh, and join the Alzheimer’s Society. That was it. He did.
Or rather we did. Although aware that this was not good
news, I was unfamiliar with the diagnosis and he seemed
not to grasp its wider implications.
Given that his practice list was over 12,000, his assertion
that only one or two of his patients may had AD seemed an
underestimate. We lived in a five-storey narrow town house
and the advice about not moving ultimately turned out to be
one of the factors that led to earlier institutionalization than
should have been the case.
I laid hands on as many books as I could (this was before
the age of universal Internet access) and slowly the full hor-
ror of the prognosis began to sink in; that this was a termi-
nal illness, possibly I was going to be looking after him for
years, our happy and charmed life with our loving family
2
was not going to turn out as we had envisaged. I felt desper-
ately sad for him and initially wondered if it could be a mis-
take, that he was being forgetful on purpose and would soon
revert to his usual charming, distracted self. Denial soon
turned to alarm as his memory deteriorated noticeably,
then, selfishly, to anger. Never voiced, but I was angry with
him for abandoning us in this way. What would become of
us? What would become of me? In my forties, my life now
on hold.
As we cried ourselves to sleep I embarked on that roll-
ercoaster of emotions that was to last over 15 years. I think
he felt humiliated and, aware that his mental faculties were
failing, became increasingly frustrated and would mutter
about throwing himself off the bridge. I genuinely believed
he had a period of good quality life and love ahead and could
always reassure him that he had much to live for and three
affectionate children nearing adulthood. I had no choice but
to give up my part-time work painting children’s pictures,
just at a time when numbers of commissions were soaring.
Subsequently I recall panicking and frantically rushing
round reorganizing our finances, signing new Wills, Powers
of Attorney and arguing with the Pensions Department
about entitlement.
Imparting the news to friends and family was a relief, no
more making excuses for Leonard’s lapses of memory and
increasing forgetfulness over names and faces. Most just
looked bewildered and sadly many of our medical friends
just vanished. Were they afraid it was contagious, sorry they
couldn’t make him better, or what? When effusive letters of
condolence came from them some 15 years later, I was not in
forgiving mood. A brave few turned out to be true friends,
visiting no matter how distressing they found our situation.
The children accepted what I told them and although
always gentle with their father, I was aware that they
retreated more into their own lives and friends. It was
particularly hard for the two youngest, still at school and
living at home. The youngest, our son, shy at the best of
times, was consumed with embarrassment when I would
19
20 Dementia
turn up at school concerts or parents’ evenings, husband-
in-tow because there was nowhere else to leave him. If we
were out as a family in public places our son had to help
his father to the toilet. I appreciate how hard it was for him.
Embarrassment became a feature of our lives and as one
by one the children left home for pastures new and friends
deserted us, loneliness became another. Even my husband
noticed the latter and one day, not having spoken for weeks,
clearly asked ‘Where they all gone?’ I knew but hadn’t the
heart to tell him.
Still active, he sought the outdoors and would spend
hours pacing the nearby park. Within a year or two he was
becoming a danger crossing roads so I would accompany
him; in fact I have never walked so much in my life as those
years. Often I would drive to the river and we would walk
along the towpath to look at boats seeking a tranquillity not
possible in the city centre.
At home he invariably followed me round the house,
sat next to me when I was speaking on the telephone and
accompanied me to the bathroom, unwilling to let me out of
his sight. Touching, and I understood why, but desperately
lonely and starved of company and good conversation, I felt
I was going crazy and remember on occasion pushing him
away from my side.
He never saw a doctor, he was never ill in the way of
having colds or flu. No one seemed to think I could be
finding life hard, it was as if I didn’t exist, I had no status.
Even as a doctor’s wife, I was unaware that there should be
help available and that someone other than the none-too-
helpful GP should know of our situation. That no expres-
sion of sympathy, concern or encouragement ever came
from the medical profession was something I found hard
to bear.
In desperation I tried to access drug trials, enquired
at centres of research in the London area and followed up
every relevant journal article, but to no avail. When eventu-
ally he was invited to an assessment his Mini-Mental State
Examination score was below the criteria for eligibility.
Failed again, although of course that trial came to nothing.
All those years ago an eminent neurologist assured me not
to worry about the remote possibility of the children inher-
iting the condition since within 20 years there would be a
cure. Where is it?
During the early years we took some holidays abroad.
He loved the sun and I discovered that cruises were ideal;
we had our own cabin, he couldn’t get lost – well he could,
we both did, but couldn’t go far – he could pace the deck,
visit new places, watch films. The motion of the ship and
the wide sea proved almost hypnotic. I never knew what
our fellow passengers made of us. I recall him asking the
captain of the ship whether he was going to Leningrad
too! These holidays were hard work mentally, but, on bal-
ance, worthwhile, a last attempt to lead as normal a life as
possible.
A couple of years later agitation was added to the equa-
tion and I was forced on alert 24-hours a day. I still man-
aged to lose him once and those three hours until he was
found by the police were traumatic. For two years I slept on
a mattress on the floor by his side of our bed so that when
he got up to wander in the middle of the night he tripped
and woke me. Thus I could prevent him walking out of the
bedroom door and falling down the stairs. Locking doors,
removing electric plugs, hiding basin plugs, turning off light
switches, night-lights everywhere, flushing the toilet every
time I went past, all became routine.
Eventually our GP, fed up with seeing me asking for more
sleeping pills (for myself) said he would refer us to a private
psychiatrist. Great, I thought, perhaps something could be
done about my husband’s agitation. It was only after two
sessions that I realized I was the patient, that he thought I
was depressed. I was furious. Yes, I probably was depressed
but could not coping with my husband’s illness be one rea-
son why?
From the outset, being under 65 years of age, Leonard
was not eligible to be seen by a geriatrician, but this psychia-
trist did refer us to social services and an appointment was
made for an assessment at the mental health day hospital
and in turn this led to some helpful visits from an occupa-
tional therapist.
Anti-depressants helped me, but I was aware he was
depressed too. The psychiatrist’s suggestion that I try him
on my pills was a disaster – he became totally disoriented.
I took matters into my own hands and in a convoluted way
found a retired psychologist from the neuro-rehabilitation
unit at The National Hospital and subsequently my husband
attended regularly for over a year – again privately. When I
collected him he was different, happier, it was worth any-
thing to see him like that even if the effects lasted only a few
hours. Helpfully I was given feedback on what he seemed
unable to express to me, as the time he knew I was going
away for a week and had found a private respite home for
him just outside London. Evidently he thought I would leave
him there and never come back.
Local day-centres were totally unsuitable. How could I
leave him sitting in front of a TV with a rug over his knees
in the company of 80-year-olds? It took months to track
down a private centre run by a charity that had received
a good review in an Alzheimer’s Society magazine. When
a place became available I was relieved to discover two
other younger men attending. I had to convince my pro-
testing husband that he was going there to help, he was
a ­doctor after all. The three became good friends and
although by this stage none could read, I am told some
amusing c­onversations ensued on the subject of cur-
rent affairs, but it didn’t matter, it gave them a sense of
companionship.
The downside was that it was on the other side of
London, so Tuesdays and Thursdays I had a frantic rush
to get him up and dressed for the hour’s drive through
the rush-hour traffic. I then ended up the opposite side
of London with insufficient time easily to drive home and
back to collect him.
By then I had decided I needed to know why I felt the
way I did (dreadful) and enrolled on a part-time external

Diploma in Psychology at London University. Lectures were
in the evenings so I had to leave our son to give my husband
supper and see him into bed. Subsequently I found a good
public library near the day centre and would spend those
days struggling with essays.
When he was in long-term care I went on to gain an MSc
in Gerontology. At the back of my mind was the thought
that when all this was over I could have years ahead and
would have to do something with my life. Sadly, going back
to my former occupation was out of the question. During
my years as a carer I have completely lost any creative ability
and although I still paint as a hobby can no longer produce
imaginative children’s designs.
At first I didn’t even realize I was a so-called ‘carer’. I
was using occasional sitters from a local private agency – in
fact we went straight from hiring baby-sitters to husband-
sitters, sometimes they were the same girls. Eventually, after
much form-filling, social services allocated us home respite
for three hours a week. This only worked well during a six
month ‘pilot’ when a carer with specific dementia train-
ing looked after him and I could go out with an easy mind.
Usually it was a different carer each week and I spent the
time away from home fretting and worrying.
In time a voluntary organization in the Borough offered
a 2-hour free sitting service once a week. The first after-
noon a lovely Jamaican nurse arrived and I went off to
the dentist. When I returned my husband was wander-
ing about the house causing havoc and no sign of her.
Evidently he had told her to go and, not being obliged to
stay, she left. She had dreadlocks and beads in her hair and
I think he was scared of her. When I tactfully tried to ask
the office whether they had someone else, we were accused
of being racist – no good telling them that my husband
was not racist, that you cannot rationalize with someone
with dementia and, if he was scared, no amount of talking
would convince him otherwise. We went to the bottom of
the waiting list.
Two years later we must have reached the top again and
for a few blissful months a kindly lady would arrive at 8 p.m.
alternate Tuesdays and beg me to enjoy an evening out with
friends. Night out, you’re kidding! Friends! What friends? I
would take a large glass of wine and a sleeping pill and shut
myself in a bedroom until 8 o’clock next morning when she
would knock on my door with my husband showered and
dressed.
Those carers who say they find their role rewarding and
spiritually uplifting fill me with disbelief. I could never see
it like that, only as an appalling tragedy with catastrophic
consequences for him and all who loved him and in the
absence of any pastoral concern from within our commu-
nity I turned away from religion altogether. Laughter was
conspicuously absent; obviously my fault that unlike other
carers I was unable to find amusing any of the incidents in
our day-to-day life, it was just unremitting hard work laced
with utter despair.
The agitation became worse and worse over the next
couple of years. Eventually the unsympathetic geriatrician
The lived experience of dementia 21
suggested something to calm him down. It was haloperidol.
When we returned a month later I said he seemed worse,
could barely talk or walk now and was showing signs of
incontinence. The dose was doubled.
If only I had known then what I know now. In my igno-
rance I was unaware for whom haloperidol was meant or
what the side-effects were, and to this day I blame myself
for his rapid descent into severe dementia. After only a few
weeks he became a bent, drooling, shuffling shell of his for-
mer self, without facial expression and with involuntary foot
jerking movements that were to stay with him for the rest of
his days. I was distraught, no one seemed to listen to me and
I felt powerless to help my poor husband. I had become a
bystander watching horror after horror being heaped upon
him as he hurtled down the dark tunnel of AD. It was heart-
breaking, it was obscene, haloperidol yet another trigger to
institutionalization.
One day as I collected Leonard from the day centre the
manager took me aside and said sorry they couldn’t have
him back if he carried on like this, he hadn’t sat down all
day, refused to eat, was falling and disrupting the oth-
ers. When we arrived home I phoned the GP and for the
first and only time asked for a home visit. A young locum
doctor arrived, took one look at him shuffling round the
living-room in tight circles, leaning sideways at an alarm-
ing angle and foaming at the mouth and said ‘Take him
to A & E.’
Midsummer’s Eve and, if I had but known it, this was
to be his Last Journey. He never came home again to live.
The taxi driver surveyed us suspiciously as I spread a plas-
tic sheet on the seat. It wasn’t a heart attack or another fit
as the locum suspected and after a few days on an acute
medical ward he was transferred to the chaotic in-patient
assessment ward at the Mental Health unit from where,
despite my protests, it was eventually recommended he go
into long-term care.
The last years of his life in first a home for the elderly
mentally ill, where within a few weeks, he broke a hip, and
a few months later the other hip (no one saw these incidents
happen) were a nightmare. I had been told I would feel only
relief when he went into care. In fact it was harder. I was
not in control of his life, how understanding staff were, how
they handled him, what he was given to eat and I hated to
see him wearing someone else’s clothes. AD had robbed him
of his dignity and he had always been an immensely digni-
fied man.
I spent hours with him each day trying to provide some
quality of life and the sort of interaction never given in the
Home. After breaking the second hip he never got back on
his feet again so when he broke a femur – apparently due
to staff’s poor skills with the hoist – I refused to let him
return there and he was eventually found a bed in continu-
ing National Health Service care in a private nursing home
not too far from where we lived.
I had to accept that nowhere would be perfect or pro-
vide the standard of care I wished for him, but I found
it impossible to forgive the poor quality of his and the
22 Dementia
other residents’ lives. To the Home Manager’s annoyance
I employed some private carers; a strong man able to push
the wheelchair up the hill to the park weather permitting; a
delightful Irish lady to sit with him occasionally – and sing;
a caring Russian girl to give him tea on Saturdays so that
I could see my children outside the care home setting and
visit my parents.
And my parents are still alive now, my father 98. They
loved their son-in-law, their honorary doctor they called
him, and couldn’t accept what was happening to him, so out
of turn. Neither could bear to visit him in the Home, so con-
sequently saw little of me during those years as my time was
spent beside Leonard.
I doubt being GP to a care home with so many frail
elderly people is every doctor’s dream, but the ability to
diagnose concomitant illnesses of old age in non-verbal
patients is key to their quality of life. On one occasion I had
been insisting to the GP for over two weeks that something
was very wrong, that it couldn’t ‘still be an allergy’. It was
for me to telephone a former dermatologist colleague of
my husband’s who that same day diagnosed bullous pem-
phigoid and started him on steroids. I had always believed
nature should be allowed to take its course, but in another
24 hours, undiagnosed, he would have died the most appall-
ing death as those massive blisters spread down his throat
and other orifices.
How could I feel other than anger and helplessness?
Interestingly that year on steroids he reverted to something
resembling his old self; smiles and occasional laughter not
heard for years. When I suggested he stay on a low-dose
given the feelings of wellbeing they promoted, I was told
this wasn’t ethical. What about all those ethical issues ill-
prepared family carers are forced to confront at all stages of
the disease? What is ethical about the way some care homes
treat people with dementia?
Much as I disliked the Home and literally had to
grit my teeth as I rang the entry bell each day, I always
longed to see my husband, to touch him and prattle on
with my usual monologue, my mental state so closely tied
with how he was. If he was unwell, in pain, or looking
­d istressed I would go home in the evening feeling dis-
traught. If he was alert and calm I felt lighter and slept
better. The wording on the birthday cake one year said
Happy 88th Birthday; he was 68. Numbed and aghast in
equal measure, I couldn’t protest. Sadness was ever pres-
ent, but now it was weariness, wondering what disaster
would befall him next and an overriding sense of fear that
engulfed me.
‘What do you mean, MRSA? How?’ The Home man-
ager had no idea how or where, and gradually over the
next few months with a series of chest infections, sores,
and endless courses of antibiotics, Leonard went down-
hill. He looked so unhappy and anguished, painfully thin,
just bones really, and had a greatly diminished quality
of life. I had always worried how I would know when the
end was approaching. Suddenly I knew. I had to force the
nurse out of the room as I pleaded with the GP ‘please no
more antibiotics, just let him go in peace.’ Ten days later he
died, with myself, our son and son-in-law by his side. His
journey through a living hell was over, a farewell that had
lasted nearly 16 years. Watching him being wheeled out to
the waiting ambulance on a cold drizzly February Friday
was the bleakest day of my life.
Leonard, these you have missed: watching our children
embarking on their paths to adulthood, through univer-
sity, their careers, celebrating their successes. You were
there, but not there. You saw both the girls on their wed-
ding days wearing their beautiful white dresses because
we stopped by the Home on our way to the ceremony, but
I don’t know if you recognized them or understood the
momentousness of the day. You never had the pleasure
of walking your daughters up the aisle or knowing your
delightful sons-in-law and daughter-in-law. Our son grew
up not knowing you for the brilliant, kind and caring man
you had once been.
You would have adored the grandchildren, five of them
now and, incredibly, twins on the way. You always doted
on our children, how much more time you would have
had in retirement to enjoy the next generation. I trea-
sure the photograph of our first grandchild Sam on your
lap just a few weeks before you died. You were staring
­w ide-eyed at this little baby; I so hope you knew it was
yours.
And our children … I still cannot fathom the extent
to which their lives have been affected. The day after he
graduated from Cambridge our son started his first job – in
Scotland – as far away from home as possible. Now they are
all married, all back in London and seem happy, although
the spectre of AD, unspoken, must linger on occasion.
Rightly or wrongly, I tried to shield them from the caring
role, feeling that it should not be allowed to dominate their
lives and I would never ever wish or expect them to look
after me should I succumb in the future. I tried so hard
to be a good wife and carer, mother and father, daughter
and eventually grandmother, but in the end was so over-
whelmed, so torn in a myriad directions, I am not sure I
have succeeded as any of these.
Current research is trying to emphasize the positive
aspects of caring. Few coping 24/7 with challenging behav-
iour, incontinence, social services and unhelpful carers
are going to accept being told it is a positive and satisfac-
tory experience. However if carers survive the physical and
emotional turmoil of a ‘caring career’ there is evidence that
we emerge more confident, more empowered to deal with
statutory authorities. Literally, we have fought a battle and
come through it.
In my case the positive legacy includes teaching medi-
cal students, postgraduate clinical psychologists and nurses
about the impact of dementia on families, active involve-
ment on many major dementia research projects and the first
carer to be awarded a research grant by the UK Alzheimer’s
Society. I continue my interest because our children are
nearing middle age and, who knows, potentially at risk in
the next decade or two.

The mental and physical costs are long-lasting: for me,
anxiety, chronic insomnia and backache from all those years
of ‘lifting’. The year before he died I spent weeks in hospital
and recuperating from legionella and have never felt com-
pletely well since. Feeling totally knocked out, I remember
sobbing by his side, convinced he would outlive me yet. The
toll on family relationships; with my parents (who in some
obscure way I think blame him for ruining their daughter’s
life); and wider family members who all had their own views
on how I was looking after him and what I should, or should
not, be doing for the best. The social legacy is immense in
terms of work, lifestyle, relationships and, of course, finances.
However, Life goes on: new friends, new hobbies, some
amazing fellow carers, travel, a degree of contentment I
never believed possible to achieve again. But tears are never
far away and I would do anything to wind the clock back 25
years and be sharing happy memories with my beloved hus-
band as we grow old together, rather than rushing around
the country telling how it was.
The lived experience of dementia 23
2.2 POSTSCRIPT
My caring career started over twenty years ago. Awareness
of dementia has increased exponentially with the predicted
explosion of numbers likely to be affected in the future.
Research inches forward and more is known about the
benefits of psychological interventions. We already have
evidence on what optimum care looks like and the special
needs of younger people with dementia. We family carers
believe there needs to be a change of attitude, more effort
and the necessary funding to translate that evidence into
delivering better quality care and training as the main route
to improving life for those suffering now and until such
time as effective symptom relief or a cure becomes available.
The latter of course remains the ultimate goal.
Our turbulent journey, just one of millions being acted
out across the globe, may serve as a caution to all those pro-
fessionals involved in caring for this group.

Prevalence and incidence of dementia
DANIEL W. O’CONNOR
3.1 SCOPE OF EPIDEMIOLOGY
Epidemiology is the study of the distribution and determinants
of disease in human populations. It maps the frequency of dis-
ease and identifies people at higher or lower risk of contracting
particular conditions. Once risk factors are confirmed, their
impact can be reduced. Studies linking cigarette smoking
with lung cancer, and hypertension with stroke, sparked suc-
cessful campaigns to limit smoking and lower blood pressure.
Ideally, epidemiological studies will identify reversible trig-
gers to Alzheimer’s disease (AD) and other dementias.
Links between life experience and disease are identi-
fied by means of observational, analytic and experimental
approaches. Observational studies entail large-scale sur-
veys to measure the frequency of dementia and to note cor-
relations with sociodemographic, biometric and lifestyle
variables. Surveys, while costly and time-consuming, are
essential in conditions like dementia. Many cases go unrec-
ognized by primary and specialist health services, even
in high-income countries, and clinical registers are there-
fore not reliable sources of data (Iliffe and Robinson, 2009;
Knopman et al., 2011).
Analytic studies contrast the backgrounds of people with
dementia (drawn from community surveys or clinical prac-
tice) with those of matched controls to identify points of dif-
ference that might, on further study, prove to be risk factors.
Case–control studies are economical but accurate matching
is problematic and associations will emerge by chance if
questions cover hundreds of putative causes. To complicate
matters, people with dementia cannot report accurately on
exposure. Information must therefore be sought from rela-
tives whose knowledge is imperfect and subject to bias.
Both types of study, observational and analytic, gener-
ate hypotheses to be tested in experimental trials, some-
times with unexpected results. The finding in some (but
not all) case–control studies that hormone replacement
therapy (HRT) conferred protection against dementia was
24
3
not confirmed by a large controlled trial of HRT as a treat-
ment of dementia, perhaps because women taking HRT
were healthier and at lower risk (Almeida and Flicker,
2005). Apart from selection bias, reasons for discrepancies
between analytic and experimental studies include con-
founding by pre-existing cognitive impairment, insufficient
treatment dosing and limited follow-up (Coley et al., 2008).
Since dementia develops over many decades, interventions
might need to be deployed decades earlier to be effective.
Particular risk factors for AD and vascular dementia
(VaD) are addressed in Chapter 44 and Chapters 57 through
60. This chapter focuses instead on the starting point of
epidemiological knowledge, namely studies of the preva-
lence and incidence of dementia and its various subtypes.
Wherever possible, information comes from community
surveys rather than clinical settings.
3.2 METHODOLOGICAL ISSUES
The prevalence of dementia measures the proportion of peo-
ple within a population who meet diagnostic specifications.
Incidence measures the numbers of new cases of dementia
within a defined period. Prevalence studies are simpler: people
are divided into ‘cases’ of dementia and ‘non-cases’ at a single
point in time. Some will have developed dementia recently:
others have had it for many years. A community might there-
fore have a higher than usual prevalence because its residents
with dementia survive longer. Incidence studies entail two
surveys, a year or more apart, to determine the annual con-
version of former ‘non-cases’ to ‘cases’. They have greater sci-
entific value since rates are not confounded by survival.
The first surveys of mental disorder date from the
1950s. Lin (1953), who supplemented brief evaluations of
Taiwanese residents with information from relatives and
hospitals, concluded that only 0.5% of people aged over 60
years had ‘senile dementia’. By contrast, Essen-Moller (1956)
 Prevalence and incidence of dementia 25

diagnosed 28% of Swedes aged over 70 years with ‘mild or
severe dementia’ based on detailed personal assessments by
skilled clinicians. This 60-fold discrepancy might reflect
genuine differences in dementia prevalence, but method-
ological factors were almost certainly to blame.
Even today, there is no commonly agreed protocol to
screen, assess and diagnose dementia in community popu-
lations. As a result, prevalence rates can rarely be compared
directly. There is little disagreement in advanced cases of
dementia: discrepancies arise more commonly in mild or
borderline cases. Since early dementia merges impercepti-
bly with the normal age-related cognitive decline, the divid-
ing line will vary depending on investigators’ definitions
and assessment tools.
By way of illustration, Table 3.1 summarizes the meth-
ods employed in three large, well-documented reports from
a regional South Indian city (Mathuranath et al., 2010), a
regional centre in Western Turkey (Arslantaş et al., 2009)
and a representative sample of older South Koreans (Kim et
al., 2011). The studies varied in important respects (research
personnel, participants’ education, screening tests, screen-
ing cut-points and special assessments) making it difficult to
compare one with another. Diagnostic criteria, while appar-
ently identical, might also be operationalized quite differ-
ently (Seshadri et al., 2011). Reported dementia prevalence
rates in age group 70–74 years varied from 2.6% in India to
5.2% in South Korea and 9.8% in Turkey (albeit with wide
confidence intervals). If true, further investigation is war-
ranted to determine what genetic or lifestyle factors are
responsible. In reality, differences might stem largely or
solely from methodological discrepancies. The few studies
in which identical research protocols were applied to dispa-
rate populations are discussed in Section 3.7.
3.2.1 SCREENING
Population surveys are so expensive that most researchers
use a brief cognitive test to select respondents for detailed
evaluation. Of the many tests available, the 30-point Mini-
Mental State Examination (MMSE) (Folstein et al., 1975),
which takes only 10 minutes or so to administer and requires
no specialist equipment, is used most commonly in high-
income countries (Ismail et al., 2010). In a meta-analysis
of 21 community and primary studies, 83% of people with
dementia scored at or below the selected cut-point (usually
23 points) while 87% of ‘normals’ scored above it (Mitchell,
2009). However, only a third of those ‘failing’ the MMSE met
criteria for dementia so further investigation is mandatory.
Since the MMSE tests reading, writing and arithmetic,
performance is shaped by education. In the United Kingdom,
11% of ‘normal’ older people who left school before their fif-
teenth birthday scored 23 points or less compared with only
3% of those with higher education. Conversely, the same
cut-point missed 27% of dementias in better educated people
compared with only 12% in those with limited education
(O’Connor et al., 1989c). Adjusting cut-points to reflect age-
and education-specific norms seems not to improve validity
in literate communities (Cullen et al., 2005). A better strategy

Table 3.1 Comparison of methods and results in three dementia prevalence studies
Place India South Korea Turkey
First author (year) Mathuranath (2010) Kim (2011) Arslantaş (2009)
Respondents (N) 2466 6141 3100
Sampling frame Census Census Census
Sample, age (years) Aged over 55 Aged over 65 Aged over 55
Institutions Not applicable Included Included
Education 21% ≤ 4 years education 16% no education 18% illiterate
Screening test Addenbrooke’s Cognitive MMSE MMSE
Examination
Informant interviews Some Yes Yes
Investigations Clinical interview, Clinical interview, Clinical interview,
neuropsychology, neuropsychology, neuropsychology,
physical examination, laboratory tests, imaging laboratory tests, imaging
laboratory tests, imaging
Diagnostic criteria DSM-IV, NINCDS-ADRDA, DSM-IV, NINCDS-ADRDA, DSM-IV, NINCDS-ADRDA,
Hachinski Ischemia Scale NINCDS-AIREN, other NINCDS-AIREN, other
Dementia types AD, VaD AD, VaD, LBD AD, VaD, other
Research personnel Interviewers, psychologists, Interviewers, nurses, Clinicians
neurologists psychologists, psychiatrists
Dementia prevalence, 70–74 2.6% 5.2% 9.8%
years
Abbreviations: MMSE, Mini-Mental State Examination; DSM-IV, Diagnostic and Statistical Manual of Mental Disorders, 4th Edition;
AD, Alzheimer’s disease; LBD, Lewy bodies dementia; VaD, vascular dementia.
26 Dementia
in two-phase studies is to evaluate all who score below the
chosen cut-point together with a proportion of high scorers
to reduce the risk of missing early or atypical dementias.
The MMSE is not an appropriate screening tool in coun-
tries where older people are often illiterate and innumer-
ate. An alternative instrument, the Community Screening
Instrument for Dementia which combines culturally sensi-
tive cognitive test items with an informant interview, has
performed well in epidemiological surveys in India, China,
Latin America and Africa and is available in a shortened
form (Prince et al., 2011).
In high-income countries, up to half of all people with
moderate and severe dementia will be missed if residents
of long-stay hospitals and aged care facilities are excluded
(O’Connor et al., 1989b). With respect to geographic scope,
some investigators approach all eligible residents of a suburb
or town. Others employ complex strategies to select represen-
tative residents of entire cities, states or countries. A smaller
locale promotes cooperation, reduces costs and makes
­follow-up easier. Larger scale studies ensure that findings can
be generalized to the whole of a region or nation. The choice
of approach is driven by study resources and objectives.
Survey response rates are an issue if participants dif-
fer significantly from non-participants. Very active older
people can be difficult to contact while, conversely, people
with dementia are sometimes shielded by carers. In one U.S.
study, older people who declined to participate in a survey
were twice as likely to have been diagnosed with dementia
as participants (Knopman et al., 2014).
3.2.2 DIAGNOSIS
Ideally, clinical assessment comprises a mental status exami-
nation, cognitive battery, informant interview, neurological
examination, laboratory tests and neuroimaging with inputs
from physicians, psychiatrists and neuropsychologists, but
not all studies meet this standard (Prince et al., 2013).
Informant interviews are essential. Since dementia
impairs memory and insight, information must be sought
from a relative or carer about the subjects’ personal details,
cognition, functional status, medical and psychiatric his-
tory and medications. These details help to confirm the
diagnosis of dementia, especially in its early stages, and to
distinguish AD from other disorders. Informants’ reports
correlate highly with other markers of cognitive and func-
tional capacity: under-reporting and over-reporting are
remarkably uncommon (O’Connor et al., 1989a). Small num-
bers of respondents forbid contact with informants or have
no surviving relatives. One stand-alone, structured infor-
mant interview, the Informant Questionnaire on Cognitive
Decline in the Elderly (IQCODE), has sound psychometric
properties barely affected by education (Jorm, 2004).
If research findings are to carry weight, diagnostic criteria
must be interpreted similarly in different centres. In a study
of five research centres in Australia, Europe and the United
states in which clinicians were asked to apply Diagnostic
and Statistical Manual of Mental Disorders – 3rd Edition,
Revised (DSM-III-R) and Clinical Dementia Rating criteria
to vignettes of older people identified in clinics and com-
munity surveys, between-centre agreement was generally
high. As expected, agreement rates were lower at the border
of ‘normal ageing’ and ‘mild dementia’ and for frail, deaf or
depressed participants (O’Connor et al., 1996).
The critical role of diagnostic glossaries was shown by
Erkinjuntti et al. (1997) who used data from a multistage sur-
vey of 10,000 older Canadians to illustrate how criteria (and
also assessment procedures) shape prevalence rates. Only
3% of those surveyed met the International Classification of
Diseases, 10th Edition (ICD-10) criteria for dementia com-
pared with 29% on DSM-III-R. Similar anomalies emerged
in studies in middle-income countries where prevalence
rates based on 10/66 dementia specifications were roughly
double those based on inferred Diagnostic and Statistical
Manual of Mental Disorders, 4th Edition (DSM-IV) criteria
(Prince et al., 2012).
Community diagnoses based on thorough clinical
evaluations and informant histories have acceptable clini-
cal validity. In a large British survey, only 3 of 56 people
diagnosed with mild dementia by the Cambridge Mental
Disorders of the Elderly Examination (CAMDEX) were
judged not to have dementia 2 years later (O’Connor et al.,
1991). Factors contributing to premature diagnoses included
deafness, depression and unstable diabetes mellitus.
Validity is best confirmed by neuropathological exami-
nation but gathering post-mortem material in community
populations is challenging. In a comparison of well-assessed
community and clinic research participants, community-
based subjects were less likely to have pure AD but more
likely to have cortical infarctions and mixed pathologies
(Schneider et al., 2009).
Given all these issues, it is desirable to apply identical
assessment and diagnostic procedures when comparing
dementia rates in setting with another. This occurs infre-
quently. Only the geriatric mental status schedule (Copeland
et al., 1991) and the 10/66 Dementia Research Group proto-
col (Prince et al., 2007) have been deployed across multiple
communities and countries.
3.3 DEMENTIA
3.3.1 PREVALENCE
If dementia is truly more common in one part of the world
or in people from a particular background, knowledge of
the responsible social or environmental triggers might lead
to preventative or mitigating interventions.
In the first of several meta-analyses, Jorm et al. (1987)
took findings from 22 reports to construct a mathemati-
cal model relating dementia prevalence to age and study
characteristics. Rates varied widely but there was a con-
sistent trend for prevalence to rise exponentially with age
with a doubling every 5.1 years (Table 3.2). This was con-
firmed by Hofman et al. (1991) who reanalysed data from

Table 3.2 Prevalence rates (%) for dementia by age
derived from 22 studies
Age (Years)
65–69 1.4
70–74 2.8
75–79 5.6
80–84 10.5
85–89 20.8
90–94 38.6
95–99 144.3
Source: Data from Jorm, A.F. et al., Acta Psychiatrica Scandinavica,
76, 465–479, 1987.
12 European studies conducted between 1977 and 1989 in
which dementia was defined using DSM-III or equivalent
criteria. No major differences emerged between countries.
More recently, a meta-analysis of data from 147 studies
across most parts of the world found a prevalence of 5%–7%
over age 60 in most regions. There were pointers to higher
than average rates in Latin America and lower ones in West
sub-Saharan Africa but the similarities between regions
were more striking than any differences (Prince et al., 2013).
Two studies with strikingly high prevalence rates hint at
an association between dementia and social deprivation. In
the first, aged residents of three Arab–Israeli villages were
assessed using modified cognitive tests and informant inter-
views. A quarter met DSM-IV criteria for dementia, three
times more than in comparable Jewish–Israeli communi-
ties. Risk increased with age, female gender and illiteracy
(Bowirrat et al., 2001). In Australia, where many indigenous
people have limited education and multiple medical co-
morbidities, the prevalence of dementia above age 65 was
27% based on detailed, culturally appropriate assessments
(Smith et al., 2008). By contrast, rates were very low in Cree
Indian settlements in northern Canada where older people
remain actively engaged in fishing, trapping and crafts
(Hendrie et al., 1993).
Three groups of investigators tracked dementia preva-
lence rates over time using identical (or at least very similar)
methods within a defined geographic area. Rates were sig-
nificantly lower in the UK study, pointing to improvements
in cognitive health over a 20-year period (Matthews et al.,
2013). However, prevalence remained stable with time in
a 10-year study of an African-American community (Hall
et al., 2009) and a 20-year Swedish study (Qiu et al., 2013).
3.3.2 INCIDENCE
If it is true that prevalence increases exponentially with age,
varying only in its time of onset, everyone will be affected
at some point in their life. This hypothesis, which has major
public health implications, was tested by Ritchie and Kildea
(1995) who analysed findings from 12 studies with data over
age 80, adequate sampling procedures and clear diagnostic
methods. Their logistic model showed a flattening of growth
at age 95, suggesting that dementia is not inevitable. Further
Prevalence and incidence of dementia 27
evidence came from the Bronx Aging Study in which the
risk of dementia grew steadily with age, but with a slowed
rate of growth from age 80 (Hall et al., 2005). The matter
is not completely settled though. In a study of Californian
nonagenarians, dementia incidence rates climbed steadily
over the 4-year follow-up period with very high rates among
centenarians (Corrada et al., 2010).
In the few studies to date that tracked changes in demen-
tia incidence rates using consistent assessment and diagnos-
tic methods over periods of one to two decades, there were
no significant changes in rates in China (Li et al., 2007) and
the Netherlands (Schrijvers et al., 2012).
3.3.3 SURVIVAL
The best estimates of survival come from follow-up of newly
diagnosed cases since prevalence surveys capture only sur-
vivors. In the Leipzig Longitudinal Study that followed new
cases of dementia for 3 years, 51% of participants died com-
pared with 19% of non-impaired controls. Male sex, age,
frailty and dementia severity increased mortality risk fur-
ther (Gühne et al., 2006). In the Cache County study, the
risk of death was 3.5 times higher than normal for people
with dementia aged 75–84 and 7.3 times higher for those
aged 65–74 (Tschanz et al., 2004).
3.4 ALZHEIMER’S DISEASE
3.4.1 PREVALENCE
Table 3.3 presents findings from a meta-analysis of AD rates
using data from 11 European studies conducted in the 1990s
(Lobo et al., 2000). As before, rates rise sharply with age.
Corrada et al. (1995) applied logistic regression to iden-
tify methodological factors associated with variability in
15 published papers from Europe, United States, Japan and
China. After adjusting for age, higher rates tended to be
reported in studies that included mild cases and used labo-
ratory tests to aid in diagnosis. Lower rates emerged from
studies that used brain scans and cerebral ischaemia scores.
This is not surprising. Studies that can afford laboratory
tests are likely to be more thorough in other respects too
and studies using brain scans might attribute cases, rightly
or wrongly, to visible evidence of vascular pathology.
3.4.2 INCIDENCE
In a refinement of an earlier meta-analysis, Ziegler-Graham
et al. (2008) found that incidence rates doubled every
5.5 years quite consistently in 27 studies from Asia, Europe
and the Americas. Base rates varied somewhat between
regions but not to a statistically significant degree. Findings
from three recent incidence surveys in the United States
(Miech et al., 2002), Brazil (Nitrini et al., 2004) and Canada
(Tyas et al., 2006) lay within the bounds identified in the
meta-analyses.
28 Dementia
Table 3.3 Prevalence rates (%) of Alzheimer’s disease in a
meta-analysis of 11 European studies
Age (Years) Males Females
65–69 0.6 0.7
70–74 1.5 2.3
75–79 1.8 4.3
80–84 6.3 8.4
85–89 8.8 14.2
90+ 17.6 23.6
Source: Data from Lobo, A. et al., Neurology, 54 (Suppl. 5), S4–S9,
2000.
3.4.3 SURVIVAL
Younger onset adds to the lethality of AD. In a follow-up study
of 108 incident cases identified in the Baltimore Longitudinal
Study of Aging, diagnosis was associated with a 39% reduc-
tion in median life span for people aged 90 years compared
with 67% for those aged 65 years (Brookmeyer et al., 2002).
3.5 VASCULAR DEMENTIA
3.5.1 PREVALENCE
Estimating the prevalence of VaD is difficult: definitions
and assessment methods vary too widely to give confidence
in study findings. In a review by Rocca and Kokmen (1999),
for example, prevalence rates were higher in studies that
combined ‘mixed dementia’ with VaD and based diagnoses
on radiologists’ reports of brain scans.
In a meta-analysis by Lobo et al. (2000), rates were lower
than those for AD (Table 3.4). This fits with findings from
community autopsy series in the United Kingdom and
United States showing a preponderance of AD pathol-
ogy, though with high admixtures of vascular abnormali-
ties (Neuropathology Group of the MRCCFA Study, 2001;
Schneider et al., 2009).
Rates of VaD look to be higher in Asia. When Fratiglioni
et al. (1999) compared findings from 25 European studies
with five from Japan, Korea, India and China, the propor-
tions of cases ascribed to VaD were 28% in Europe and
38% in Asia. It was diagnosed twice more often than AD
in a series of Japanese studies but ratios were similar in two
Chinese studies (Graves et al., 1996).
Caucasian–Asian differences might be real, not artifac-
tual. In one rigorous, 7-year Japanese study in which diag-
noses were confirmed whenever possible by post-mortem
examination, 61% of dementias in men were attributed
to vascular disease, a much higher rate than observed
in equivalent studies in Europe and the United States
(Yoshitake et al., 1995). Similar findings were reported in
a more recent study by Ikeda et al. (2001). Lifestyle is prob-
ably more influential than genes: rates of VaD in elderly
Japanese-Americans were similar to those of other North
Table 3.4 Prevalence rates (%) of vascular dementia in a
meta-analysis of 11 European studies
Age (Years) Males Females
65–69 0.5 0.1
70–74 0.8 0.6
75–79 1.9 0.9
80–84 2.4 2.3
85–89 2.4 3.5
90+ 3.6 5.8
Source: Data from Lobo, A. et al., Neurology, 54 (Suppl. 5), S4–S9,
2000.
Americans (Borenstein et al., 2014). By contrast, Japanese
men in Hawaii, whose lifestyle is more authentically Asian,
had VaD rates similar to those in Japan (White et al, 1996).
3.5.2 INCIDENCE
Incidence rates vary widely from study to study for the rea-
sons outlined earlier but are generally much lower than for
AD. Rates look to be higher in Asian populations than North
American ones (Fratiglioni et al., 1999), more in older stud-
ies than recent ones (Homma and Hasegawa, 2000).
3.6 OTHER DEMENTIAS
While most attention has been paid to AD and VaD, demen-
tia due to other causes accounted for 11% of cases in the
25 European prevalence surveys summarized by Fratiglioni
et al. (1999).
In a meta-analysis of 18 community surveys, there was
a wide variation in prevalence rates of Lewy body demen-
tia, depending on the investigators’ diagnostic criteria and
thresholds. Prevalence rates ranged from 0% to 5% (mean
0.52%) at age 65 years and over, with Lewy body demen-
tia accounting for between 0% and 20% (mean 4.6%) of
all identified dementias (Vann Jones and O’Brien, 2014).
Frontotemporal dementia is discussed in the following.
Dementias due to potentially reversible causes are rare. In
a U.S. case file review of 560 new cases of dementia identified
in the Rochester Epidemiology Project, non-­degenerative
causes were identified in 30% of young-onset patients but
only 5% in the older-onset group. The most common causes
were chronic mental illness, brain tumours, alcoholism and
cerebral anoxia (Knopman et al., 2006). No cases were iden-
tified of dementia due to normal pressure hydrocephalus,
subdural haematoma, hypothyroidism, vitamin B12 defi-
ciency or neurosyphilis.
3.6.1 EARLY-ONSET DEMENTIA
Dementia before 65 years of age is too rare to warrant a
door-to-door survey. Instead, frequency estimates are
­
derived from checks of memory clinics, hospital records and
diagnostic registers. Given the gravity of these conditions

for carers and service providers, many cases are likely to be
captured in this way though socially marginalized people
can evade detection for lengthy periods. In a London study
in which 227 cases nominated by general practitioners
(GPs), specialists and community services were reviewed
in detail, diagnoses in age group 45–64 years were as fol-
lows: AD (35%), VaD (18%), frontotemporal dementia (15%),
alcohol-related dementia (14%) and other conditions (18%)
including Lewy body dementia, Huntingdon’s disease, mul-
tiple sclerosis, corticobasal degeneration, Down’s syndrome
and unspecified conditions (Harvey et al., 2003).
The 80 cases identified in the same age group in a Sydney
linkage study had a different spread of conditions: alcohol-
related dementia (25%), AD (15%), frontotemporal dementia
(9%), VaD (11%) and other or unspecified conditions (40%)
(Withall et al., 2014).
Frontotemporal dementia appears to be more common
than previously thought. In a sustained community-based
search, Dutch neurologists and nursing home physicians
identified 245 cases of whom 40 came to autopsy. The
median age of onset was 58 years with a range of 33–80
years. The prevalence rose from 3.6 per 100,000 at age 50–59
to 9.4 at age 60–69 years and then fell to 3.8 at 70–79 years
(Rosso et al., 2003). Incidence rates have since been reported
in the United Kingdom, with numbers similar to those for
early-onset AD (Mercy et al., 2008).
Irrespective of cause, early-onset dementia resulted in
much increased mortality in a Dutch memory clinic cohort.
Over a short follow-up period (mean 2 years), the risk of
death was 43 times higher than for controls of the same age.
For dementia with later onset, by contrast, the risk was only
three times higher (Keodam et al., 2008).
3.7 COMPARATIVE STUDIES
Putative socio-environmental risk factors will be identified
more confidently if identical case-finding tools are applied
to groups with vastly different social, educational, dietary,
occupational and medical exposures.
Revealing findings emerged from a direct comparison
of dementia in elderly Nigerian-Africans and African-
Americans. This decade-long study applied identical
screening tests and diagnostic evaluations comprising neu-
ropsychology, informant interviews, personal evaluations
and CT brain scans to residents of Ibadan, Nigeria and
Indianapolis, United States (Hendrie et al., 1995). Contrary
to expectation, the age-standardized prevalence rate of AD
was lower in Nigerians aged over 65 years than African
Americans (1.4% versus 6.2%). Rates for dementia of all
causes were lower too (2.3% versus 8.2%). This disparity
was not due to greater life expectancy in the United States.
In a 5-year follow-up, age-standardized annual incidence
rates of AD were still lower in Ibadan, perhaps because of
lower weight, blood pressure, glucose and cholesterol levels
(Hendrie et al., 2001).
Prevalence and incidence of dementia 29
In a rural community in northern India, only 1% of peo-
ple aged over 65 met DSM-IV criteria for dementia despite
low literacy levels when assessed in detail using tools modi-
fied from an earlier U.S. survey. Gender and literacy made
no difference (Chandra et al., 1998). In a 2-year follow-up,
incidence rates were about a third those found in the United
States (Chandra et al., 2001) suggesting that northern Indian
lifestyles are protective.
3.8 FUTURE TRENDS
According to burden of disease estimates, dementia con-
tributes to more years lived with disability in later life than
stroke, musculoskeletal disorders, cardiovascular disease
and cancer (WHO, 2003). Given population ageing, the rap-
idly growing numbers of people with dementia will therefore
impose great demands on families and social, residential and
medical services throughout the world. To map this global
impact, Brookmeyer et al. (2007) applied a complex math-
ematical model of incidence, progression and survival in AD
to projected world populations. These very rough estimates
suggest that the numbers of AD will quadruple between 2006
and 2050 from 27 to 106 million. Numbers in world areas
might conceivably be as follows: 6 million in Africa, 9 million
in North America, 11 million in Latin America, 16 million
in Europe and 63 million in Asia. Modelling suggests that if
interventions could delay both disease onset and progression
by just 1 year, there would be nine million fewer cases over-
all. Prevention is therefore of paramount importance.
3.9 CONCLUSIONS
Surveys of dementia prevalence and incidence provide
varying rates, most probably because of differences in study
methodology. Future studies will be easier to interpret now
that many investigators are using similar, and sometimes
identical, approaches to assessment and diagnosis.
Alzheimer, vascular and other pathologies often coex-
ist in advanced old age. Seemingly clear-cut diagnoses in
prevalence, incidence and survival studies must therefore
be interpreted cautiously.
Dementia might be more common in certain places and
cultures. It is important to compare incidence (not preva-
lence) rates of AD, VaD and so on in aged people from
widely differing backgrounds. Observations of very low
rates of dementia in Nigeria and northern India might
prove to be of great significance.
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What is dementia, and how do you assess it?
Definitions, diagnostic criteria and assessment
JOSEPH P.M. KANE AND ALAN THOMAS
4.1 INTRODUCTION
While many of the defining characteristics of the dementia
concept have been recognized for over 100 years, develop-
ments in recent decades have both influenced, and been
influenced by, the way we think about dementia. The discov-
ery of biomarkers and the development of individual ­criteria
for aetiologies like Alzheimer’s disease (AD) (Dubois et al.,
2007), frontotemporal dementia (FTD) (Rascovsky et al.,
2011) and dementia with Lewy bodies (DLB) (McKeith
et al., 2005) have sought to refine the diagnosis, but they
also present pressures on clinicians to go beyond dementia
to its causal subtypes. There are also additional challenges
from an ageing population, the emergence of mild cognitive
impairment (MCI) as a diagnostic entity and its relation-
ship to ageing-related change, and wider social, political
and economic pressures.
This chapter discusses dementia as both a concept and
a diagnostic label, exploring the main characteristics of
recently published diagnostic criteria. It discusses some of
the challenges faced in translating these criteria from the
research environment into clinical practice, before outlin-
ing the process of clinical assessment. For detailed informa-
tion about the history of the concept of dementia, the reader
is referred to Chapter 1.
4.2 HISTORICAL BACKGROUND
Alzheimer’s observation of plaques and neurofibrillary tan-
gles in the brain of Auguste D (Alzheimer, 1907), a 51-year-
old woman, and the subsequent baptism of his eponymous
disorder by Emil Kraepelin (1910) effectively saw the cre-
ation of two conceptual entities: presenile dementia, or AD,
4
and senile dementia (Reisberg, 2006). Kraepelin (1899), who
had referred to presenile dementia 8 years before Alzheimer’s
findings, considered presenile dementia to represent a rare
illness occurring exclusively in patients under 65 years old,
and senile dementia to be the expression of cerebral arte-
riosclerosis in patients over 65 (Reisberg, 2006). Alzheimer
had reservations over whether his findings represented a
distinct clinicopathological entity, not least because of sub-
sequent identification of neurofibrillary tangles in patients
with senile dementia, but this perception of a dichotomy
persisted until 1965 when Corsellis and Evans (1965) failed
to find a marked association between arteriosclerosis and
senile dementia, and continued to be reflected as separate
entities in modern classification until 1980 (Reisberg, 2006).
Arguably, Kraepelin’s writings have contributed more to
the modern conception of dementia than any other single
body of work. In addition to recognizing dementia’s psycho-
pathological heterogeneity, he placed senile dementia at the
extreme of a continuum of age-associated mental weakness
that included impaired comprehension and mental flex-
ibility, memory lapses (particularly for recent events) and
disturbed attention. Critically, he recognized senile demen-
tia as a disorder that had a significant impact on everyday
living and independence, and which continues to form a
cornerstone of both classification and diagnosis (Kurz and
Lautenschlager, 2013).
4.3 THE ADVENT OF CLASSIFICATION
Changing conceptualizations of dementia since the lat-
ter half of the twentieth century are illustrated and influ-
enced most clearly by the criteria listed in the Diagnostic
and Statistical Manual of Mental Disorders (DSM) and the
International Classification of Diseases (ICD).
33
34 Dementia
The first two editions of DSM, together with ICD-8 and
-9 (American Psychiatric Association, 1952, 1968; World
Health Organization, 1974, 1978), provided only a brief
generalized description of ‘organic brain syndrome’ (OBS),
leaving considerable scope for interpretation by clinicians.
‘A mental disorder caused by diffuse impairment of brain
function and manifested by impaired cognitive functions’,
OBS encompassed both delirium (acute brain syndrome)
and dementia (chronic brain syndrome), distinguishing
them primarily on the basis of reversibility, but it excluded
focal impairment and failed to acknowledge the existence
of reversible dementias. Impairment in functioning of suf-
ficient severity to ‘interfere grossly with the capacity to meet
the ordinary demands of life’ was employed as a means of
severity rather than a requisite for the diagnosis itself.
While DSM-III (American Psychiatric Association,
1980) retained the concept of an OBS, it was the first of
the systems to introduce dementia as a unitary concept,
describing it as one of 10 OBS subtypes that also included
intoxication, withdrawal, organic personality syndrome
and organic hallucinosis (Fox, 1983). DSM-III was a land-
mark text, selling 500,000 copies in the United States in
14 languages; use for the first time extended far beyond that
of psychiatry into legal practice, government agencies, the
insurance industry and social services (George et al., 2011).
It ushered in a ‘diagnostic revolution’ that transformed the
clinical conception of all psychiatric disorders from a broad
dimensional one to a more categorical approach, bringing
its authors, the American Psychiatric Association, to the
forefront of the field of psychiatric nosology (George et al.,
2011). DSM-III provoked unprecedented debate and con-
troversy that has, perhaps, escalated with the publication of
each subsequent edition.
DSM-III marked a more defined, operationalized
approach to diagnosis, evident in changes to criteria for
dementia. It specified memory impairment as a necessary
criterion and required impairment in multiple domains,
with deficits in ‘higher cortical functions’ (aphasia, apraxia,
or agnosia), impairment of judgement or a change in per-
sonality required in addition to amnesia. It sought to dif-
ferentiate dementia from delirium by including clouding of
consciousness and the presence of specific organic factors
as exclusion criteria. The threshold for functional impair-
ment appeared to diminish with inclusion of the require-
ment for impairment of sufficient severity ‘to interfere with
social or occupational functioning’. ICD-10 (World Health
Organization, 1992), although less circumspect in defining
functional changes, required the presence of a disturbance
in multiple higher cortical functions; memory was included,
but not necessary.
Neither DSM-I nor II had referred to AD, but by describ-
ing primary degenerative dementia and multi-infarct
dementia, DSM-III reintroduced these terms to the scien-
tific and clinical lexicon (Boller and Forbes, 1998; George
et al., 2011). Boller and Forbes (1998) note the paucity
of AD in research literature during the 1970s, with only
42 papers published using ‘Alzheimer’ as a keyword in 1975,
but increasing recognition of common neuropathological
features of presenile and senile dementia, together with
its classification in DSM-III provoked exponential growth
in research into the disorder and wider recognition as an
aetiology.
DSM-IV (American Psychiatric Organization, 1994) dis-
posed of OBS entirely as the term was felt to imply incor-
rectly that ‘non-organic’ mental disorders do not have a
biological basis.
It retained the conceptual framework laid out by DSM-
III in necessitating multiple cognitive deficits, including
memory impairment, but brought about an important
conceptual change in lowering the functional diagnostic
threshold of impairment from ‘sufficient to interfere with
social or occupational functioning’ to ‘sufficient to cause
limitations in complex activities’; limitation of activities
such as work and managing finances were now considered
as sufficient evidence of a functional impact on functioning,
and therefore dementia diagnosis. Rather than excluding
cases where symptoms arose in the context of clouding of
consciousness, DSM-IV specified that symptoms must arise
in the absence of delirium itself, not least as it had been rec-
ognized that clouding of consciousness could occur in DLB.
Thus, successive criteria have defined dementia through
specification of a number of core criteria, many of which can
be traced back to the work of Kraepelin and his predeces-
sors: cognitive impairment, representing a decline in previ-
ous abilities, adversely affecting everyday functioning, and
differentiated from acute and transient cognitive impair-
ment (delirium). Although subsequent classification systems
have expanded their descriptions of cognitive impairment
beyond that of Kraepelin, amnesia, accompanied by impair-
ment in at least one other cognitive domain, has remained
the hallmark of the cognitive decline of dementia, and the
focus of attention for clinicians and researchers. Revision
and refinement of the boundaries representing functional
impairment, however, has led to a successive lowering of
thresholds for dementia, recognizing impairment in com-
plex tasks, rather than in more basic activities of living, as
being sufficient for a diagnosis. Clarification of both cogni-
tive and functional parameters has remained a key objective
of recent dementia diagnostic criteria, such as DSM-5 and
the National Institute on Aging-Alzheimer’s Association
(NIA-AA) criteria.
4.4 DSM-5 AND NIA-AA CRITERIA
An ageing global population has led to an increasing preva-
lence of dementia, and to a growing recognition of cogni-
tive decline and dementia as a continuum that encompasses
pre-dementia syndromes, their diagnosis and treatment.
Historically common underlying causes of cognitive impair-
ment, such as B12 deficiency, hypothyroidism and neuro-
syphillis, have disappeared with easy identification and
effective treatment, while some new, but rare causes, such as
 What is dementia, and how do you assess it? Definitions, diagnostic criteria and assessment 35
human immunodeficiency virus (HIV) and its related cog-
nitive impairment have produced new challenges to clinical
and research communities. A greater understanding of the
aetiologies underpinning dementia, aided by advances in
diagnostic techniques, together with disease-specific treat-
ments targeting these aetiologies, have led to greater efforts
to define pathological disorders. While in the past, the
fierce competition between Kraepelin’s Munich and Arnold
Pick’s Prague laboratories was said to be amongst the for-
mer’s motivation to classify and name AD, the international
research community today is characterized by a more col-
laborative spirit, aided by advances in communications and
transport, and exemplified by the revised internationally
agreed consensus criteria for AD, DLB, Parkinson’s disease
dementia (PDD) and FTD, all published in recent years.
Although consensus groups continue to develop crite-
ria, there remains a need for operationalized criteria for
the overarching diagnosis of dementia itself, particularly
as the legal and social implications remain as pertinent as
they were in antiquity. There is also increasing recognition
that in the oldest-old, multiple pathologies are the norm,
not the exception, and that clinically distinguishing a sin-
gle aetiology in such people is very difficult (Savva et al.,
2009; Jellinger and Attems, 2010). Both the recent DSM-5
(American Psychiatric Organization, 2013) and NIA-AA
(McKhann et al., 2011) criteria have attempted to address
this, seeking to define dementia first, before considering
underlying subtypes, a method expected to be mirrored
in ICD-11, scheduled for 2017. Both classification systems
demonstrate an effort to clarify functional impairment
and neurocognitive domains better, and in doing so, the
boundaries of normal ageing, MCI and dementia. Although
some disagreement exists between the two systems over the
importance of impairment in a single cognitive domain,
the diminishing significance of memory impairment in
each represents a move away from the Alzheimerization of
dementia as an entity.
The NIA-AA work groups, who updated the National
Institute of Neurological Disorders and Stroke–Alzheimer
Disease and Related Disorders (NINCDS–ADRDA) criteria
in 2011 (McKhann et al., 2011), have retained in their cri-
teria the nomenclature and basic framework of its prede-
cessors; cognitive or behavioural symptoms must interfere
with the ability to function at work or at usual activities,
representing a decline from previous levels of function-
ing, and not be explained by delirium or major psychiatric
disorder. The NIA-AA self-consciously tried to maintain
continuity with its previous criteria, while DSM-5 intro-
duced not only changes to the diagnostic criteria but also
changes to the nomenclature itself, coining the term ‘major
neurocognitive disorder’ (major NCD) in place of ‘demen-
tia’. The latter was considered not only to be pejorative and
stigmatizing but also believed to be synonymous with AD
in the eyes of many patients, policymakers and clinicians.
It also represents an explicit intent of the part of its authors
(the Neurocognitive Disorders Work Group) to ‘reopen the
global debate on the terminology and conceptualization of
dementia’ (Ganguli et al., 2011) and to propose a uniform
framework for defining all dementing disorders. These DSM
criteria recognize that although categorization is necessary
and helpful, a continuum exists between normal cognitive
function and dementia, with MCI (or mild neurocognitive
disorder in DSM language) lying between these categories.
The creation of the broad category of ‘neurocognitive dis-
order’ reflects this, with subcategories of mild and major
neurocognitive disorders comparable to MCI and dementia,
respectively, albeit with important differences between the
DSM categories and their NIA-AA counterparts. Here, we
focus on definitional differences in dementia between the
two.
4.4.1 COGNITIVE IMPAIRMENT
Although DSM-5’s major NCD definition retains many
of the characteristics of NIA-AA’s description, changes to
both cognitive and functional aspects of the criteria repre-
sent a significant broadening of the scope of the diagnosis.
Where DSM-IV, and indeed most conceptualizations of
dementia since Kraepelin, required the presence of cogni-
tive decline in more than one domain, one of which must be
memory impairment, neither NIA-AA nor DSM-5 require
the presence of amnesia as part of their evidence of cogni-
tive decline. This demonstrates a common shift away from
memory impairment as the central feature for diagnosis,
and perhaps a move away from the use of AD as the blue-
print for conceptualization of dementia, a criticism which
has long been levelled at dementia diagnostic criteria.
However, while NIA-AA criteria still require the pres-
ence of cognitive impairment in at least two of five listed
domains, in keeping with DSM-IV conceptualization, a
DSM-5 diagnosis of major NCD requires impairment in
one cognitive domain only. In making this change, DSM-5
has created a category much broader than that of NIA-AA’s
dementia, including patients who previously would have
been diagnosed with DSM-IV’s amnestic disorder and
those with severe aphasia. DSM-5 cites that this evidence
of decline in a single domain must be accompanied by ‘con-
cerns’, rather than complaints, on the part of the patient,
informant or clinician that there has been a significant
decline in cognitive performance; this reflects that actual
impairment may not have been reported, rather elicited by
questioning. This may be viewed as a purely academic point,
given the unlikelihood that assessment will occur in the
absence of expressed concerns by at least one of the patient,
informant or clinician.
DSM-5’s decision to specify a single cognitive domain,
rather that multiple domains, represents a greater concep-
tual change than the new nomenclature itself; perhaps the
most significant since the abandonment of OBS and is not
without significant controversy. The DSM work group cite
this change as a conscious effort to classify ‘neurocognitive
disorder’ as an entity spanning a broad range of age groups
and aetiologies, many of which have in recent years moved
away from the use of ‘dementia’, such as frontotemporal
36 Dementia
lobar degeneration or cognitive impairment due to trau-
matic brain injury (TBI) or HIV infection (Ganguli et al.,
2011). While the group is at pains to point out the distinc-
tion between major NCD and NIA-AA’s more conventional
conception of dementia (Ganguli et al., 2011), the DSM’s
significant role in the history of psychiatric nosology,
and the public and media spotlight shone on the manual,
prompts one to wonder whether the two overlapping defi-
nitions could become confused outside the specialist envi-
ronment. In the opinion of many clinicians and researchers,
dementia is an inherently broad construct with the under-
lying pathologies necessarily involving multiple cognitive
domains. By broadening the scope of the criteria to be more
inclusive of rarer and earlier forms of cognitive damage,
DSM-5 has muddied the waters, grouping those with static
single-domain deficits together with the major degenerative
causes of dementia. The majority population of people with
dementia are those who have degenerative and widespread
vascular brain disease, a different patient group from typi-
cally younger TBI and HIV patients.
Both classifications go further than previous proposals in
detailing parameters of cognitive impairment, in an effort
to gain consensus in a poorly defined area. DSM-5 defines
and illustrates six domains (complex attention, executive
ability, learning and memory, language, visuoconstruc-
tional and perceptual motor ability, social cognition), over
three pages of text, while NIA-AA specify five (impaired
ability to acquire and remember new information; impaired
reasoning and handling of complex tasks; poor judgement;
impaired visuospatial abilities; impaired language function
and changes in personality, behaviour or comportment).
Although these categories are broadly comparable, NIA-AA
has no domain analogous to DSM-5’s ‘complex attention’,
characterized by ‘sustained attention, divided attention,
selective attention and processing speed’. As well as defin-
ing the domains, DSM-5 attempts to quantify the degree of
impairment necessary for diagnosis, specifying a threshold
for cognitive performance as two standard deviations below
appropriate norms (or below the third percentile).
4.4.2 FUNCTIONAL IMPAIRMENT
Despite the changes intended to clarify and sharpen the
cognitive components of dementia diagnosis, both catego-
rization systems remain necessarily vague regarding the
functional aspect of the dementia assessment process, and
are broadly comparable with recent predecessors. Critically,
however, functional impairment remains a crucial part of
the boundary separating MCI from dementia and MCI’s
DSM-5 counterpart (mild NCD) from major NCD. It should
be noted that this boundary is not without controversy; the
World Health Organization (WHO) recommend that the
classification of functioning should be kept entirely separate
from diagnosis, with impaired functioning and disability
being considered as a consequence of disease, rather than a
diagnostic feature (World Health Organization, 2001). The
organization suggests that one cannot infer participation
in everyday life from a diagnosis, and therefore categorizes
functioning on a complementary, but separate, scale to its
diagnostic ICD-10 manual; the International Classification
of Functioning, Disability and Health (ICF) conceptualizes
functioning as a dynamic interaction between an individu-
al’s medical condition, their environment and personal fac-
tors. Understandable concerns regarding both discontinuity
with preceding criteria and a potential for an overemphasis
on cognitive measures, precluded removal of functioning
from the DSM-5 criteria (Ganguli et al., 2011), but its role as
a key criterion of dementia diagnosis is likely to remain the
subject of debate; ICD-11, scheduled for publication in 2015,
aims to harmonize ICF with all diagnostic criteria while
continuing to recognize functioning as separate conceptual
entity from disease (Escorpizo et al., 2013).
DSM-5 and NIA-AA nonetheless retain functional
impairment as an important component of their diag-
nostic criteria, recognizing the varied complex functional
tasks that often comprise patients’ and carers’ presenting
complaints, and the significance of these features in demar-
cating entities like MCI and dementia in the cognitive
impairment spectrum. At first glance, DSM-5’s requirement
of impairment ‘sufficient to interfere with independence’
for a diagnosis of major NCD might not appear to repre-
sent a significant change from that of DSM-IV’s ‘sufficient to
interfere with social or occupational functioning’, but this
is broadly comparable with NIA-AA’s description of suffi-
cient functional impairment (significant interference in the
ability to function at work or in usual daily activities) and
helps to offer a clearer description of the boundary between
dementia and MCI. DSM-5 and NIA-AA’s respective criteria
for Mild NCD and MCI recognize that a degree of impair-
ment of complex functional tasks, such as paying bills or
shopping, may exist without the impairment necessarily
meeting the functional threshold for dementia diagnosis.
A patient’s performance of a complex task may, for exam-
ple, involve a greater number of errors, or a longer period
of time than that previously required, yet remain within
the boundaries of MCI or normal ageing; the patient may
use tools like pill boxes or calendars as aids in maintain-
ing tasks like medication management. In such cases, while
the patient’s functioning has been impaired, independence
has been maintained. Only once assistance is required (e.g.
supervision of medicine use or financial management), is
independence compromised and functional impairment
deemed sufficient for a diagnosis of dementia.
4.4.3 SUBCATEGORIZATION
Having outlined the criteria of a mild or major NCD,
DSM-5 then further subcategorizes by aetiology, the pres-
ence or absence of behavioural disturbance, and disease
severity (mild/moderate/severe). The aetiology subcategory
represents a considerable expansion on pathologies listed
in DSM-IV, including criteria for AD, cerebrovascular dis-
ease, FTD, DLB, PDD, Huntington’s disease, TBI, prion
disease and substance use-associated disease. These criteria
 What is dementia, and how do you assess it? Definitions, diagnostic criteria and assessment 37
are deliberately consistent with those of respective expert
groups on each subtype, which is important, given devel-
opments in AD, DLB and FTD criteria since the last edi-
tion. Biomarkers supportive of each aetiology, although
listed alongside respective criteria, are generally omitted
from the criteria themselves, having been eschewed by the
DSM-5 working group. A notable exception to this trend is
the inclusion of evidence of a causative AD genetic mutation
from family history or genetic testing. It is hoped that reflec-
tion on the increasing body of evidence indicating the pres-
ence of pathology prior to presentation will lead to inclusion
of relevant biomarkers in future DSM criteria, something
which is likely to improve early identification and diagnosis
of dementia subtypes. The behavioural disturbance subcat-
egory reflects the prevalence of depression, psychosis and
agitation in neurocognitive disorders, and their frequent
role as the primary cause for presentation to services.
DSM-5’s categorization of aetiology after identification
of major NCD is outside of the remit of NIA-AA criteria,
which after defining the dementia syndrome, goes on to list
AD groups, stratified by likelihood of AD diagnosis and
evidence of the AD pathological process. Examination of
NIA-AA’s dementia and probable AD categories provides
an insight into how the working group perceives the rela-
tionship between the two entities, especially when con-
trasted with DSM-5’s description of the syndromes. Of the
five cognitive domains listed by NIA-AA, at least two of
which are required for a diagnosis of ‘all-cause dementia’,
four correspond to probable AD dementia subtypes: amnes-
tic presentation, the most common, and three non-amnestic
presentations (language, visuospatial and executive dys-
function presentations). Only cognitive impairment involv-
ing changes in personality, behaviour or comportment, in
addition to impairment in at least one other domain, direct
the clinician away from an AD diagnosis once NIA-AA
dementia criteria are met, broadening the range of clini-
cal syndromes recognized as AD, perhaps consistent with
the provenance of these criteria. This is compounded by
well-defined exclusion criteria for probable AD in demen-
tia patients that create a high threshold for consideration of
non-AD pathological causes of dementia: only ­substantial
concomitant cerebrovascular disease with multiple or
extensive infarcts or severe white matter hyperintensity bur-
den is deemed sufficient to exclude patients with features of
vascular dementia (VaD), thus including all-cause demen-
tia patients with, for example, single infarcts and insidious
onset. While DLB consensus criteria require only one core
feature of fluctuating cognition, recurrent visual hallucina-
tions and spontaneous features of parkinsonism, for a diag-
nosis of possible DLB, and two for probable DLB (McKeith
et al., 2005), NIA-AA criteria require no fewer than two
core features to exclude a diagnosis of probable AD, and so
the same person can meet possible consensus DLB criteria
and probable NIA-AA AD criteria. Similar thresholds are
illustrated by requirements for prominent features of behav-
ioural variant FTD or prominent features of primary pro-
gressive aphasia.
These requirements, while not representing diagnostic
criteria for these other diseases, rather instances in which a
diagnosis of probable AD is not applicable, set a high thresh-
old that continues to recognize AD as the default entity to
be considered following dementia diagnosis. For NIA-AA,
only if there is very good reason to think of a non-AD cause,
should another aetiology be considered. This position
would appear to be contrary to evidence suggesting that
DLB and FTD are often unrecognized in clinical practice
in favour of AD (Knopman et al., 2004; Knapp et al., 2007),
and can be contrasted with DSM-5’s explicit intention to
move away from the Alzheimerization of the dementia con-
cept. In contrast, DSM-5’s criteria for NCD due to probable
AD, requires decline in at least two domains, one of which
must be memory and learning, a steadily progressive course
without extended plateaus, and no evidence of mixed aetiol-
ogy, representing a higher threshold for probable AD, and a
much lower one for consideration of other pathologies.
In summary, the major conceptual difference between
the NIA-AA and DSM-5 criteria is in the latter’s widen-
ing of the threshold of cognitive impairment from multi-
ple domains to that of a single domain, creating a broader
category, major NCD. However, both NIA-AA and DSM-5
criteria abandon the requirement of amnesia and so rep-
resent a conceptual move away from the AD blueprint of
dementia evident in their predecessors. Despite NIA-AA
retaining the broader traditional characteristics of demen-
tia, it has a different approach to categorization of demen-
tia subtypes, creating a high threshold for consideration of
non-AD pathologies, in contrast to DSM-5, which pushes
in the opposite direction in encouraging consideration of
other potential causes of the dementia syndrome.
4.5 COMPARING CLASSIFICATION
SYSTEMS
At first glance, differences between classification systems
and their successive revisions might appear modest, retain-
ing Kraepelin’s core concepts throughout and reflecting
gradual changes in the language employed in discussing
thresholds of functional and cognitive impairment. Closer
consideration of these criteria, however, particularly in the
research setting, demonstrates that they reflect significant
differences in the understanding of dementia, with impor-
tant implications for practice. This has been demonstrated
with previous criteria. Erkinjuntti et al. (1997) found that
the prevalence of dementia in a large Canadian population
cohort varied dramatically – almost tenfold – depending
on which of the diagnostic criteria were applied; DSM-III
(29.1%), DSM-III-R (17.3%), DSM-IV (13.7%), ICD-9 (5.0%),
the Cambridge Mental Disorders of the Elderly Examination
(CAMDEX; 4.9%) and ICD-10 (3.1%). Furthermore, the six
classification systems agreed a dementia diagnosis in only
20 of over 450 patients, suggesting not that some criteria
are more restrictive than others, but that different systems
38 Dementia
reflect different meanings of the dementia syndrome itself.
While the criteria probably have clinical utility when applied
flexibly, their application in a research setting requires more
standardization. In particular, alleged objective assessment
of functional impairment actually requires considerable
subjectivity on the part of the assessor, leaving broad scope
for differences in practice. Functioning is subject to a num-
ber of social and cultural factors, as well as patients’ and
carers’ circumstances and expectations; an individual, for
example, living with a high degree of social support and low
level of expectation will only meet functional criteria at a
much more advanced level of impairment. Consideration
of the multifaceted nature of factors like functional impair-
ments, and their significance in diagnosis and other clini-
cal decisions, are entirely acceptable in clinical practice,
but are likely to contribute towards the significant variation
observed in prevalence studies.
4.6 TRANSLATING DIAGNOSTIC
CRITERIA INTO THE CLINICAL
ENVIRONMENT
A number of factors make effective transfer of the concep-
tual and biological knowledge underpinning the dementia
criteria into the clinical environment difficult. Research
studies, including those contributing to diagnostic criteria,
maintain internal validity through application of exclusion
criteria and strict standardization of assessment, sometimes
conducted by lay interviewers using structured interviews.
However, this reduces their generalizability to typical clini-
cal settings. Patients with dementia may be excluded from
studies due to comorbidities or diagnostic uncertainty, as
might patients with very mild or very severe symptoms.
Such exclusion criteria are seldom applicable in clinical
practice, with clinicians expected to diagnose a wider, older
and more heterogeneous population, often with acute pre-
sentations of behavioural, medical or psychiatric symptoms.
Thus, the role of the clinician may extend far beyond that
of diagnostician alone, and he or she will be aware of the
expectations and concerns of both patient and carer. The
focus of the clinical interaction is usually much more than
making a diagnosis, and involves engaging the patient and
fostering a rapport with a view to further assessment and
investigation. In the case of primary care assessment, the
relationship between the practitioner and patient and carer
may extend back several decades, providing an invaluable
insight into premorbid functioning and cognitive ability
seldom available to researchers, but may also come with
prejudice and perceived collusion with family members or
carers in some cases.
Subcategorization itself can introduce problems into
clinical diagnosis. While biological findings have acted as
the main driver for the evolution of dementia-diagnostic
criteria recently, a relative lack of scrutiny has been applied
to the qualitative and environmental factors that influence
individual cases. Dementia has moved from a broad concept
to a tightly defined cognitive syndrome due to one of sev-
eral specific aetiologies, each with increasingly explicit and
detailed criteria that now often include biomarkers or com-
plex investigations. Invariably, clinical practice will include
patients who fail to fulfil these criteria, or indeed, those who
fulfil more than one set of criteria. Multiple disease contri-
butions to dementia are increasingly likely with ageing, with
the oldest patients highly unlikely to have pure single dis-
ease causes (Savva et al., 2009; Jellinger and Attems, 2010).
Mixed aetiologies, sensory or motor functional impairment
and psychiatric or physical comorbidities further cloud the
diagnostic process, particularly when applied to an ageing
population.
Diagnostic criteria like DSM-5 and NIA-AA have sought
to include a degree of judgement of the skilled clinician
translating research findings to the assessment. The term
‘impairment’, used with respect to cognitive and functional
abilities, is necessarily vague, taking into account the broad
range of patients that professionals engage with in clinical
practice; indeed NIA-AA criteria explicitly state that ‘sig-
nificant interference’ in functioning is inherently a ‘clini-
cal judgment made by a skilled clinician on the basis of the
individual circumstances of the patient’.
Current diagnostic criteria neither suggest suitable cog-
nitive rating scales, nor ‘cut-off’ scores for diagnosis. While
DSM-5 does cite cognitive scores of less than 1.5 or 2 stan-
dard deviations below the mean, this figure must represent
ability when compared against populations of a similar age,
sex, education and background. It is implicit in this caveat
that normative data will not always be available, particu-
larly for those at either very low or very high levels of intel-
lectual ability, and that when assessing a patient who falls
outside ‘normal’ values for such parameters, clinicians must
employ their clinical judgment in consideration of cogni-
tive impairment. Clearly, where previously collected data
are available for comparison, decline can be demonstrated,
but accurate information may not be at the clinician’s dis-
posal, even with the availability of a collateral history.
Furthermore, in many parts of the world, everyday clinical
assessments will not be able to utilize such standardized cri-
teria and will always depend on clinician judgement. While
formal neuropsychological testing is preferable in demon-
strating cognitive deficits, the availability of such services,
even in developed countries, can be limited. Accordingly,
NIA-AA is more realistic in stating that neuropsychologi-
cal testing need only be employed when bedside testing and
mental state examination is unable to provide a confident
diagnosis.
Judgement of a decline in functional ability presents cli-
nicians with similar scope for judgement. While research
studies usually describe functional decline through scores
in Bristol Activities of Daily Living Scale (Bucks et al., 1996)
or the Instrumental Activities of Daily Living Scale (Lawton
and Brody, 1969), neither of these scales might reflect decline
in more complex tasks perceived by patients and their car-
ers. Similarly, use of these scales might fail to take into
 What is dementia, and how do you assess it? Definitions, diagnostic criteria and assessment 39
account sociocultural nuances, like gender-assigned house-
hold tasks; it is common for tasks like cooking and cleaning
to have been performed by a patient’s spouse throughout his
adult life, and an inability to perform such tasks could sim-
ply reflect a longstanding pattern rather than a manifesta-
tion of cognitive decline. Some activities may be impaired
due to physical disability, like visual impairment in the use
of telephone or electronic equipment. Where a patient no
longer performs activities that were previously executed
with ease, external factors must also be considered; is non-
compliance with medication related to cognitive decline or
unreported side effects? Might concerns over safety be influ-
encing the use of public transportation? Such instances may
require exploration of subtle decline in other functional
parameters, such as the patient’s ability to pursue hobbies
and interests to a similar standard as before; the voracious
reader no longer completing books at the same rate, the
amateur musician who struggles to learn a new piece, or
the casual gambler unable to complete their betting coupon
may all be demonstrating evidence of functional impair-
ment that assessment scales fail to reflect.
4.7 CLINICAL ASSESSMENT OF A
PATIENT PRESENTING WITH
POSSIBLE DEMENTIA
The clinician conducting the assessment aims to achieve
much more than a diagnosis; the assessment serves as a
means of engaging the patient and their family to facilitate
further investigation, treatment and monitoring. The impor-
tance of establishing a rapport with both the patient and
carer is further underlined by the clinician’s role in discuss-
ing the sensitive topic of dementia diagnosis, prognosis and
management. Discussions will persist for years to come over
the topic of dementia as a conceptual entity, but the demen-
tia diagnosis is unquestionably important in clinical prac-
tice; not only does diagnosis lead to access to treatments and
services but also it encourages individuals to make impor-
tant decisions and plans at a stage in the disease process at
which this is still feasible (National Institute for Clinical
Excellence, 2006), and the clinician’s ability to impart such
information is assisted by a warm rapport with the parties
involved (Bamford et al., 2004). If the ongoing evolution
of the dementia concept has taught us anything, it is that
exceptions to criteria exist, and that the application of core
concepts to individual patients is a nuanced clinical skill
best conducted by an experienced practitioner, rather than a
series of items on a checklist or administration of diagnostic
criteria. Thus, an accurate and detailed clinical history and
mental state examination, made by an experienced special-
ist, clarified by physical examination and special investiga-
tions, remains the cornerstone of the diagnostic process.
Although one main problem may have been cited as the
reason for referral, assessment may uncover a constellation
of interrelated issues, each requiring characterization of
its relationship with the clinical presentation. These may
include non-cognitive symptoms that, while not contrib-
uting to dementia diagnosis itself, may help point toward
subtype and serve as a focus for symptomatic treatment.
Nevertheless, the central diagnostic tenets of cognitive
decline associated with functional impairment are crucial
aspects of the interview, not only in relation to dementia
diagnosis but also in areas of monitoring and intervention.
Determining the course of symptoms can be invaluable
in making subtype diagnosis but the insidious pattern of
amnesia associated with AD can also be shared by DLB and
subcortical VaD. The classical VaD presentation of sudden
onset dementia with stepwise deterioration is unusual in old
age psychiatry services, as such patients more often present
to acute stroke services. A more rapid onset, over days or
weeks, is consistent with delirium or depression and should
prompt further questioning to identify the presence of these
syndromes. The presence of cognitive symptoms, although
likely to be determined by cognitive testing, should also
be inquired into. It is important to ask questions about
the behavioural and psychological symptoms of dementia
because these frequently cause greater distress and more
problems than cognitive symptoms. Furthermore, symp-
toms like visual hallucinations and sleep changes may be
suggestive of DLB (McKeith et al., 2005), or changes in
social interactions and eating behaviour indicative of FTD
(Rascovsky et al., 2011), in turn indicating different man-
agement strategies.
Identifying the presence of a decline in instrumental and
basic functioning that accompanies cognitive impairment
is not only an important component of diagnosis but also
a means of recognizing areas for further multidisciplinary
assessment and intervention. Structured assessment tools
such as Bristol Activities of Daily Living (Bucks et al., 1996)
can be helpful here, but assessment can be complicated by
varying levels of assistance, expectation and premorbid
functioning and it is wise to consider these factors when
appraising functioning.
A detailed account of both medical and psychiatric his-
tory should be compiled, including recent operations and
other procedures. Particular attention should be paid to
illnesses occurring shortly before, and since, the apparent
onset of symptoms suggestive of dementia. Evidence or risk
of vascular disease (stroke, transient ischaemic attacks, dia-
betes, hypertension, falls) should be explored. It is wise to
corroborate any list of medical or psychiatric conditions
provided in the referral with the patient and/or their infor-
mant. Similarly, reconciling the medication list provided
with the patient’s reported prescriptions can help determine
compliance, the presence of non-prescribed and alternative
treatments, and recent medication changes; in particular,
practitioners should seek to identify the presence of recently
commenced medications that might precipitate or exacer-
bate cognitive impairment, such as anticholinergic agents.
Recording aspects of patients’ personal history at the
beginning of the interview can be helpful, as cognitively
40 Dementia
impaired patients often talk happily about their earlier life
without being distressed by difficulties remembering recent
events. A detailed personal history can be of considerable
use in determining the presence and severity of amnesia
without the aid of cognitive testing, and identifying difficul-
ties such as remembering the names of children and grand-
children can give an approximate indication of the point
at which the their memory began to fragment. Crucially, it
also helps understanding of the patient as a person.
In the absence of major childhood events, an account
of patients’ happiness and friendships at school, and con-
tentedness at home, provide sufficient insight into early life.
It is inadvisable to infer intelligence from the age at which
an older patient left full-time education, given how socially
determined this was historically; indeed, it still is in many
places. An account of their further training and occupa-
tional history, focusing on positions maintained for the
longest duration, or holding particular significance for the
patient, can more accurately reflect premorbid intellectual
ability. Clarifying the degree of responsibility or autonomy
held by the patient in these jobs may provide additional
insight. Marital history, focusing on the nature of the rela-
tionship with both the spouse, children and grandchildren,
as well as any other marriages and sexual relationships, can
both give an insight into an individual’s personality as well
as the potential degree of familial support that the patient
and carer may be able to access. Similarly, discussing the
patient’s response to stressors such as bereavements, illness
or role transitions, allow information to be gathered about
the past that may help anticipate and address future chal-
lenges, such as placement in residential care. While many of
these stressors are often managed very well, recognized by
many as a part of growing old, they can precipitate affective
illness and impact on other areas of the patient’s life; diffi-
cultly adapting to retirement, for example, can create stress
at home and consequent marital disharmony in addition
to being a role transition and a life milestone. While direct
questioning regarding personality traits is unlikely to be
of significant use, the information derived throughout the
history-taking process provides an insight into a patient’s
enduring pattern of relationships, activity and behaviours.
This may be difficult to distinguish from the effects of ill-
ness in patients with chronic disease, but in those with a
more recent diagnosis, premorbid personality may mould
the presentation of the illness; thus, the fiercely independent
patient may find adaptation at a ward or residential home
more challenging than one more accustomed to seeking and
receiving assistance.
The patient’s social history should represent a detailed
account of their pattern of everyday life, activities and rela-
tionships, with the quality and quantity of care provided by
relatives, friends and formal carers explored in detail. This
may be supplemented by a written care plan giving insight
into day-to-day issues as well as the programme of care,
which can be invaluable in identifying issues such as apa-
thy or resistiveness. Having identified the pattern of living
and support, the more direct questions that comprise social
history in younger patients, such as the issue of substance
misuse, can be administered. The subject of driving motor
vehicles has become increasingly prominent in recent years;
it is necessary to ask carers if concerns regarding driving
have arisen or if incidents have occurred, and the clinician
may need to consider asking the patient to stop altogether
if concerns exist (see Chapter 31). Questions regarding the
patient’s property and financial arrangements are impor-
tant in establishing his or her risk of exploitation and in
identifying future choices that they might face.
4.8 MENTAL STATE EXAMINATION
It is important to remember that symptoms reported in
history may not be reflected in the patient’s current men-
tal state. The mental state assessment begins on arrival and
continues throughout the consultation, adopting the same
structure as that used in examination of younger adults.
While cognitive assessment is the most essential component
of the mental state examination in the context of dementia
diagnosis, other clinical features both help refine differen-
tial diagnosis and point toward aetiological subtype.
4.8.1 APPEARANCE AND BEHAVIOUR
Observation of the patient’s appearance can provide insight
into the level of self-care and hygiene, general health, nutri-
tional status and alertness. The clinician also should be alert
to the range of the behavioural signs, such as suspicious-
ness, paranoia and poor eye contact. Psychomotor retar-
dation, especially prominent in depressed older people,
should also be considered in the context of the bradykine-
sia characteristic of Parkinson’s disease. The significance
of parkinsonian symptoms in DLB diagnosis necessitates
careful consideration of these features throughout history
and examination. It is prudent for every new patient to be
assessed for bradykinesia, rigidity and gait changes, as well
as for the presence of focal neurological signs suggestive of
stroke disease.
Apathy is prevalent in even early dementia (Mega et al.,
1996), and is difficult but important to distinguish from
depression (Levy et al., 1998). The apathetic patient, though
seemingly listless and disengaged when being discussed
with an informant, will ‘warm up’ when addressed directly,
in contrast to the depressed patient. When reporting a move
away from previously enjoyed activities, apathetic patients
may describe this as a consequence of diminishing drive
to pursue affairs rather than a lack of enjoyment of them.
As well as apathy, disinhibition, such as overfamiliarity, is
a feature of frontal dementias, and can be somewhat diffi-
cult to distinguish from the normal range of social interac-
tion; watching the patient’s relatives’ reactions to his or her
behaviour, together with their collateral history can provide
insight into whether such interactions represent a patholog-
ical change, or the patient’s normal behaviour.
 What is dementia, and how do you assess it? Definitions, diagnostic criteria and assessment 41
4.8.2 SPEECH
Dysphasia, a key feature of early dementing illness, can
be a helpful clinical sign in distinguishing dementia from
depression, particularly as poverty of speech can be char-
acteristic of both syndromes. However, receptive dyspha-
sia can be difficult to discriminate from deafness when an
apparent difficulty in understanding is reported or observed.
Similarly, the subtle difficulties in speech structure, such as
in name-finding ability, while often present in mild demen-
tia, can be challenging to determine due to patients’ use of
circumlocutions to disguise them.
4.8.3 MOOD
The clinician should be vigilant for affective symptoms.
Spontaneous, short-lived episodes of weeping or elevated
mood should alert the practitioner to the possibility of the
emotional lability associated with cerebrovascular disease
(House et al., 1989). Elevated mood can be indicative of
frontal dementias, and where present may be suggestive of
a more severe illness. Depressive illness, often accompanied
by more anxiety than is observed in younger adults, should
be considered both amongst the differential diagnoses for
the cognitively impaired patient, and as a comorbid feature
of dementia.
4.8.4 THOUGHT
Paranoid delusions, particularly those of theft, and sev-
eral variants of misidentification delusions are common
in dementia; Capgras syndrome (where a close relative
is believed to have been replaced by an exact double), the
‘mirror sign’ (where patients fail to recognize their image
in a mirror, engaging with or becoming angry at the other
party), the ‘TV sign’ (where the patient believes people seen
on television are present in the room) and phantom boarder
syndrome (in which the patient believes extra people to be
living in the house), are all related to failure to recognize
or correctly identify an image. Incoherence of thought is
common in dementing illnesses, particularly in their later
stages, but formal thought disorder is much rarer than in
younger patients with mental illnesses.
4.8.5 PERCEPTION
The organic nature of illnesses that present to old age psy-
chiatry services can result in prominent and persistent hal-
lucinations in other sensory modalities to the auditory and
olfactory hallucinations associated with schizophrenia,
such as the visual and tactile hallucinations frequently seen
in patients with delirium. Complex and enduring visual
hallucinations, characteristically of people and animals, are
a core feature of DLB (McKeith et al., 2005), but delirium
must also be considered. Effort should be made to distin-
guish whether the visual hallucinations occur in the absence
of a real stimulus or whether they represent misperception
resulting from poor eyesight; however, since such problems
in visual processing commonly occur in DLB, the diagnosis
should be strongly considered, even when frank hallucina-
tions cannot be identified. Where a patient’s complex visual
hallucinations are present as the sole phenomenological fea-
ture, with no apparent cognitive impairment or alteration
in consciousness, a diagnosis of Charles Bonnet syndrome
may be appropriate. Although many such patients will
decline cognitively, developing dementia and other features
of DLB, not all do so. The similar phenomenon of auditory
hallucinosis in the absence of cognitive decline, sometimes
called auditory Charles Bonnet syndrome, is often associ-
ated with sensorineural deafness.
4.8.6 COGNITION
Cognitive assessment is discussed in Chapters 5 and 6. A
structured assessment tool can provide both an estimation
of the severity of cognitive impairment and enable monitor-
ing of progression or treatment response. However, effective
cognitive assessment goes beyond assessment tools alone,
considering inconsistencies and gaps in the patient’s history
as possible evidence of amnesia, and detecting deficits in
orientation, cognition, spatial or executive dysfunction in
reported symptoms and observed signs.
4.8.7 INSIGHT
Little formal insight is retained in moderate-to-severe
dementia, but awareness that something is not right, and
that help is required, may be present; however, patients may
have a greater awareness of their symptoms and illness than
they are capable of verbalizing. While greater insight may
be retained in mild dementia, the degree to which this is
acknowledged varies greatly. Insight into amnesia appears
greater than that into the impact of both functioning, and
the impact of the disease on others.
4.9 PHYSICAL INVESTIGATIONS
The characteristic physical signs in dementia aetiologies such
as DLB and FTD, together with those identified in reversible
dementias, underline the importance of the physical exami-
nation in the diagnostic process. Brief observation itself may
identify the presence of tremors, choreoathetoid movements
or focal neurological deficits, as well as skin signs sugges-
tive of anaemia or jaundice. Cardiovascular and respiratory
examination may ascertain the presence of pathology or
risk factors for pathology such as hypertension, murmurs,
rhythm disturbances, heart failure or orthostatic hypoten-
sion. Abdominal examination can determine the presence
of liver stigmata or aortic aneurysm, while discomfort on
bladder palpation may identify pathology frequently associ-
ated with delirium, such as faecal loading, often precipitated
by anticholinergic or opiate agents.
42 Dementia
Abnormalities in posture, gait and movement should
also be formally assessed, keeping in mind cerebellar ataxia,
the shuffling gait classically associated with parkinsonism
and the broad-based gait of normal pressure hydrocephalus.
Tremors should be examined and characterized in an effort
to determine aetiology, considering the intention and static
tremors present in cerebellar disorders, the pill-rolling
tremor characteristic of parkinsonism and the action trem-
ors exaggerated in thyrotoxicosis, uraemia and liver disease.
The presence of facial weakness, abnormal eye movements,
nystagmus, and visual field defects should be scrutinized as
a part of routine cranial nerve examination, as should oph-
thalmoscopy, which may identify the evidence of systemic
disease like diabetes, hypertensive retinopathy or papilloe-
dema secondary to raised intracranial pressure.
Abnormalities in the pyramidal and the extra-pyramidal
motor systems may help confirm a diagnosis of VaD, DLB,
Parkinson’s disease or amyotrophic lateral sclerosis; myoc-
lonus may be associated with epilepsy or Creutzfeldt–Jakob
disease. Sensory examination, though often difficult in
patients with cognitive impairment, may reveal abnormali-
ties suggestive of cerebrovascular lesions, peripheral dia-
betic neuropathy or vitamin B12 deficiency, as well as the
rarer, subacute combined degeneration of the spinal cord.
Reflexes can be similarly challenging to assess but the char-
acteristic acquisition of the primitive reflexes (grasp, suck-
ing and snout reflexes) in frontal dementias can be a helpful
diagnostic sign, otherwise occurring in advanced dementia.
The choice of physical investigations will be guided by
differential diagnosis, resource availability, patient and
carer preference and tolerability and local and national
guidelines. Blood tests, including full blood count, erythro-
cyte sedimentation rate (ESR) or C-reactive protein (CRP),
renal function, thyroid function, calcium, glucose, vitamin
B12, serum folate and liver function tests are often con-
ducted prior to secondary referral as a means of excluding
systemic illnesses that might cause, or exacerbate, cogni-
tive impairment. Other tests, such as fasting lipids, syphilis
serology, HIV testing, mid-stream urine, chest X-ray and
electrocardiography are used if indicated by clinical find-
ings, rather than forming part of an initial screen.
Structural imaging, using computed tomography (CT)
or magnetic resonance imaging (MRI), is recommended
by many authorities (National Institute for Clinical
Excellence, 2006), partly for exclusion of intracranial
pathology like tumours, normal pressure hydrocephalus
and subdural haematomas. MRI provides good views of
the hippocampi, allowing the identification of the atrophy
characteristic of AD. Modern CT scanners can provide
coronal reconstructions of the hippocampi to help in the
same way. MRI can also be helpful in detecting more sub-
tle changes, like frontal lobe atrophy, suggestive of FTD,
and especially of cerebrovascular disease in the white mat-
ter (lacunar infarcts and ischaemic white matter disease).
Functional perfusion imaging with single photon emis-
sion computed tomography (SPECT) and positron emis-
sion tomography (PET), where available, can highlight
characteristic patterns for the different pathological
causes of dementia and molecular imaging of amyloid and
tau is likely to become increasingly used (see Chapters 10
through 12).
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Screening and assessment instruments for
the detection and measurement of cognitive
impairment
LEON FLICKER
5.1 INTRODUCTION
A frequently used method in the ascertainment of demen-
tia in older people is the performance of a short cognitive
test to determine the need to perform further testing to
establish the diagnosis. The case for detection of milder
forms of cognitive impairment has not been established,
and therapeutic strategies targeted for patients with condi-
tions such as mild cognitive impairment (MCI) (Petersen
et al., 2001) have not been developed. Another use for
these tests is to detect changes in cognitive impairments
over time. Thus, the focus of this chapter remains on the
use of short cognitive tests to aid in the detection of older
people with dementia, and to monitor the progression
of cognitive impairment in people with dementia. These
short cognitive tests are commonly described as ‘screening
instruments’, but this is in fact a misnomer. Screening has
been defined as ‘An organized attempt to detect, among
apparently healthy people in the community, disorders
or risk factors of which they are unaware’ (Cadman et al.,
1984). The U.S. Preventive Services Task Force (Moyer
et al., 2014) has concluded yet again that the evidence is
insufficient to recommend for, or against, routine screen-
ing for cognitive impairment in older adults. However,
these short cognitive tests are used as a means of case
finding in certain clinical situations for which there is a
high prior probability of finding individuals with cogni-
tive impairment, usually associated with dementia or in
those individuals who are medically unwell, delirium. An
example of this situation is acute hospital admission for
people over the age of 65 years (Ames and Tuckwell, 1994).
44
5
5.2 DESCRIPTION OF TESTS
The short cognitive tests have been used in case finding for
over 50 years. A minor change that has occurred in the more
recently developed tests is the use of lengthier delayed recall
tasks, both cued and non-cued. One of the earliest instru-
ments was the Mental Status Questionnaire (MSQ) (Kahn
et al., 1960). In 1968, Blessed, Tomlinson and Roth described
the Information Memory Concentration (IMC) test, which
was validated against the criterion of neuropathology.
Hodkinson (1972) described a shortened version of the IMC
test and called this the Abbreviated Mental Test (AMT)
score. In North America, Pfeiffer (1975) described the Short
Portable Mental Status Questionnaire (SPMSQ) and Folstein
et al. (1975) devised the Mini-Mental Status Examination
(MMSE), which has undergone standardization (Molloy
et al., 1991). Subsequently, additional questions were added
to the MMSE and a modified scoring system was introduced
to produce a test called the 3MS (Teng and Chui, 1987).
Other short tests that have been developed include Kokmen’s
Short Test of Mental Status (STMS) (Kokmen et al., 1991), the
Mini-Cog (Borson et al., 2000) and the General Practitioner
Assessment of Cognition (GPCOG) (Brodaty et al., 2002)
all of which include the clock drawing tests. A short test has
been developed, which does not utilize orientation or other
questions prone to cultural bias, the Rowland Universal
Dementia Assessment Scale (RUDAS). All these instruments
have in common their brevity, taking 10 minutes or less to
administer with relatively little training.
One of the main problems with these cognitive tests
is the fact that they exhibit both floor and ceiling effects.
 Screening and assessment instruments for the detection and measurement of cognitive impairment 45
There have been attempts to develop tests that would be
more suitable for testing impaired patients (Plutchik et al.,
1971; Albert and Cohen, 1992). Longer tests and word lists
have the advantage that they are less prone to ceiling effects.
Word list instruments generally require some training.
These include the 7-minute screen (Solomon et al., 1998),
which is a test that comprises a cued recall task, verbal flu-
ency, an orientation test and a clock drawing task. Similarly,
the Syndrom Kurztest (SKT) (Lehfeld and Erzigkeit, 1997)
has nine subtests, which include naming, memory, atten-
tion, cued recall and visuospatial functioning. A very short
version of delayed free and cued recall tests has been devel-
oped called the Memory Impairment Screen (Buschke et al.,
1999), which consists of just four items. Another test, the
Montreal Cognitive Assessment (MoCA) (Nasreddine et al.,
2005), was recently developed for the purpose of detecting
MCI. It incorporates an adjustment for education level, with
those people scoring less than 26 classified as abnormal. It
also has included the clock drawing test. It has also been
used for the detection of people with dementia but at the
usual cut-off seems more sensitive but less specific (Larner,
2012). There have been relatively few validity studies at this
stage.
Several other survey instruments have been devel-
oped, which have incorporated both cognitive screen-
ing instruments and diagnostic schedules. These include
the Cambridge Diagnostic Examination for the Elderly
(Roth et al., 1986), Consortium to Establish a Registry
for Alzheimer’s Disease (Morris et al., 1989), Geriatric
Mental State schedule (Copeland et al., 1976) and a
Structured Interview for the Diagnoses of Dementia of
the Alzheimer’s type multi-infarct dementia (SIDAM)
and dementias of other aetiology according to the
International Classification of Diseases, 10th Edition
(ICD-10) and Diagnostic and Statistical Manual of
Mental Disorders, Third Edition, Revised (DSM-III-R)
(Zaudig et al., 1991). The cognitive components of the
Cambridge Diagnostic Examination for the Elderly (Roth
et al., 1986), the Alzheimer’s Disease Assessment Scale-
Cognition (ADAS-Cog) (Rosen et al., 1984) and the
Mental Deterioration Battery (Carlesimo et al., 1996) take
longer to administer and are not usually performed as ini-
tial brief tests, although the Organic Brain Scale (OBS)
from the Geriatric Mental State has been used as a stand-
alone test (Ames et al., 1992).
5.3 USE FOR THESE TESTS
The need for these ‘screening’ instruments has arisen
because there is good evidence that clinicians will com-
monly miss dementia in their routine practice without the
assistance of formal cognitive assessment (Williamson
et al., 1964; Mant et al., 1988; Valcour et al., 2000). It
remains a clearly defined guideline that for those individu-
als suspected of a cognitive disorder should have one of
these tests applied, and possibly all patients over the age
of 65 years who present acutely to hospital (Australian
Commission on Safety and Quality in Health Care, 2015).
Even before the arrival of specific symptomatic treat-
ments for the symptoms of Alzheimer’s disease, the pres-
ence or absence of significant cognitive impairment had
major implications for the management of patients. In par-
ticular, older individuals with multiple medical problems
requiring medications could not be managed appropriately
without an assessment for the presence of cognitive impair-
ment and some idea of its severity. Also, there is some evi-
dence that the earlier identification of people with dementia
and appropriate referral to support services and counselling
can alleviate some of the stresses associated with caring for
people with dementia and delay institutionalization (Green
and Brodaty, 2002).
These short cognitive tests have limited domains of
measurement. Table 5.1 refers to the domains of measure-
ment of the common assessment tools. Orientation figures
prominently in most of these tools and is a reflection of
recent memory acquisition. In a longitudinal study of cog-
nitive function in people with Alzheimer’s disease, it was
demonstrated that dementing processes particularly affect
remote memory, immediate memory and language function
(Flicker et al., 1993). Since memory impairment is a sine qua
non in the categorization of dementia in both the Diagnostic
and Statistical Manual of Mental Disorders, Fourth Edition
(DSM-IV) and ICD-10 criteria it is hardly surprising that the
short cognitive tests focus on this domain. More recently,
Diagnostic and Statistical Manual of Mental Disorders, Fifth
Edition (DSM-V) no longer specifies the requirement for
memory impairment for the classification of major neuro-
cognitive disorder but rather a decline in one or more cog-
nitive domains (American Psychiatric Association, 2013).
Exactly how this will be operationalized clinically is still
uncertain.
It is clear that these tests are highly correlated with each
other. For example, Stuss et al. (1996) observed that the pro-
portion of variance accounted for by a single common com-
ponent was in excess of 0.80 for the Mattis Dementia Rating
Scale, an abbreviated six-item version of the Orientation
Memory Concentration test adapted from Blessed et al.
(1968) a Mental State Questionnaire and an Ottawa mental
state examination. Also in this study there was no added
benefit from longer tests and the shorter cognitive tests
performed as well as longer tests with multiple domains. In
another study, the correlation between the AMT score and
MMSE was greater than 0.85 (Flicker et al., 1997). Similarly,
correlations between the MMSE and the ADAS-Cog have
been found to be strong, –0.9 (Burch and Andrews, 1987),
although the correlation between the MMSE and the STMS
was only 0.74 (Kokmen et al., 1991). In a comparison of the
MMSE and 3MS, both the modified scoring system and
the additional questions of the 3MS increased its discrimi-
natory ability, but at the expense of increased burden of
administration time and training requirements (McDowell
et al., 1997).
46 Dementia

Table 5.1 Cognitive domains in commonly used short cognitive tests

Visuospatial
Personal Short-Term Long-Term Visuo-
Test Information Orientation Memory Memory Attention Naming Construction Other
MSQ ♦ ♦ ♦
IMC ♦ ♦ ♦ ♦ ♦ ♦
AMT ♦ ♦ ♦ ♦ ♦ ♦
MMSE ♦ ♦ ♦ ♦ ♦ ♦
3MS ♦ ♦ ♦ ♦ ♦ ♦ ♦
SPMSQ ♦ ♦ ♦ ♦
OBS ♦ ♦ ♦ ♦ ♦
STMS ♦ ♦ ♦ ♦ ♦ ♦
GPCOG ♦ ♦ ♦
TICS ♦ ♦ ♦ ♦ ♦ ♦ ♦
MINI-COG ♦ ♦
RUDAS ♦ ♦ ♦
MoCA ♦ ♦ ♦ ♦ ♦ ♦
Abbreviations: MSQ, Mental Status Questionnaire; IMC, Information Memory Concentration; AMT, Abbreviated Mental Test; MMSE, Mini-
Mental Status Examination; 3MS, modified Mini-Mental Status Examination; SPMSQ, Short Portable Mental Status Questionnaire;
OBS, Organic Brain Scale; STMS, Short Test of Mental Status; GPCOG, General Practitioner Assessment of Cognition; TICS, Telephone
Interview for Cognitive Status; MINI-COG; RUDAS, Rowland Universal Dementia Assessment Scale; MoCA, Montreal Cognitive
Assessment.

One of the major advances in the last 5 years has been
the standardization of the methodology for reporting of
the validity of these tests (Noel-Storr et al., 2014). This will
allow the systematic review of the validity of these cogni-
tive tests over many settings. The Cochrane Group has
recently committed to reviews of Diagnostic Test Accuracy
for many of these cognitive tests (Davis et al., 2013), and
other tests including biomarkers, which will allow compari-
son of clinical utility across differing approaches. Using this
standardized methodology, the MMSE did not seem to per-
form well for detecting those patients who converted from
MCI to dementia with sensitivities ranging from 23% to
76% and specificities from 40% to 94% (Arevalo-Rodriguez
et al., 2015). On the other hand, the Mini-Cog when used for
the diagnosis of dementia within a community setting had
sensitivities in the individual studies reported as 0.99, 0.76 and
0.99 with specificities of 0.93, 0.89 and 0.83 (Fage et al., 2015).
These short cognitive scales appear robust in many set-
tings. The IMC test has been validated on telephone inter-
view (Kawas et al., 1995) as has the Telephone Cognitive
Assessment Battery (Debanne et al., 1997), and the telephone
version of the MMSE (Roccaforte et al., 1992). The Telephone
Interview for Cognitive Status (TICS) (Brandt et al., 1988) is
also a widely used instrument and because the word list is
capable of delineating subjects who may have a memory dis-
order, which does not fulfil criteria for dementia, is able to
identify conditions such as amnestic MCI. The instruments
have been used across national boundaries and have wide
applicability, e.g. the OBS has been found to have good validity
in three separate countries (Ames et al., 1992). Some attempt
has been made to develop self-administered tests, such as the
Early Assessment Self Inventory (EASI) (Horn et al., 1989).
The use of self-administered tests has been comprehensively
reviewed (Cherbuin et al., 2008) with some promising results
for the informant-based tests, but otherwise this method of
administration was not recommended. There is evidence that
the place of testing can cause significant changes in the test
score, with testing in a patient’s own residence being associ-
ated with a higher score (Ward et al., 1990).
These short cognitive screens obviously have their limi-
tations, the most obvious being that they test only limited
domains of cognition. Besides the use of full neuropsycho-
logical assessment, attempts have been made to develop
other short tests of specific functions. An example of this is
the executive interview (Royall et al., 1992), which attempts
to assess executive cognitive function. Also, the ability to
draw a clock has been extensively studied as a short test,
which examines other cognitive domains. It has been used
by itself or in conjunction with other cognitive tests such
as the SPMSQ or MMSE, or as part of the 7-minute screen,
GPCOG or STMS. Clock drawing may miss a quarter of
cognitively impaired individuals (Gruber et al., 1997).
Clock drawing may be able to detect cognitive alterations
not related to delirium or dementia, with abnormal clock
drawing being associated with other psychiatric disorders
(Gruber et al., 1997). Also it may provide additional infor-
mation to the MMSE as suggested by Ferrucci et al. (1996),
where the clock drawing test predicted cognitive decline in
older people independently of the MMSE.
Short cognitive tests are known to be sensitive to bias
associated with education, but adjustment for this effect
does not necessarily improve test performance (Belle et al.,
1996). For this reason, the RUDAS (Storey et al., 2004) was
developed, which has attempted to be less culturally biased
 Screening and assessment instruments for the detection and measurement of cognitive impairment 47
and uninfluenced by educational attainment. Special tests
may also be required in specific situations such as with
indigenous groups (LoGiudice et al., 2006).
Another consideration is that these tests may not be sen-
sitive to all stages of the disease. Stern et al. (1994) dem-
onstrated that there was a quadratic relationship with
dementia severity showing that the ADAS-Cog and IMC
test show greater deterioration for patients with moderate
dementia and that the deterioration is slower for mildly and
severely demented patients. This may represent the relative
insensitivity of the tests for patients with the least and great-
est impairment, or may reveal true patterns of progressive
cognitive decline at different parts of the disease process.
Attempts have also been made to shorten these tests even
further – for example, the 10-item AMT has been further
shortened to four items (Swain and Nightingale, 1997), but it
does seem to lose some predictive efficiency at this length. The
potential problem of inadequate specificity of short cognitive
tests for population screening has been revealed in a commu-
nity study: the Canadian Study of Health in Ageing (Graham
et al., 1996). In this study, the 3MS was used as a community
screen before a diagnostic battery. Cognitive impairment, not
dementia, was found to be more common than dementing
processes, with the prevalence of cognitive impairment not
dementia found to be 16.8%, whereas the prevalence of all
types of dementia combined was 8% (Graham et al., 1997).
The conditions identified within this category of cognitive
impairment included delirium, alcohol use, drug intoxica-
tion, depression, psychiatric disorders, memory impairment
associated with the ageing process and intellectual disability.
5.4 INFORMANT-BASED TESTS
Perhaps the most exciting development in the detection
of cognitive impairment in older people in recent times
has been the refinement and validation of structured tests
administered to informants. Examples of this type of test
include the DECO test – Deterioration Cognitive Observée
(Ritchie and Fuhrer, 1992) and the Informant Questionnaire
for Cognitive Decline in the Elderly (IQCODE) (Jorm and
Korten, 1988). Important advantages of these tests are that
they correlate relatively poorly with premorbid function
and are relatively insensitive to the effects of education.
The other consideration about informant questionnaires
is that they have shown lower correlations with the cogni-
tive tests: somewhere in the order of 0.6 (Flicker et al., 1997).
This is an important consideration in that their relatively low
correlation with cognitive testing per se implies they provide
additional independent information, which may assist in the
discrimination of people with functionally important cog-
nitive impairment. The work by Ritchie and Fuhrer (1992)
would suggest that they seem to be better able to discrimi-
nate mild dementia from normality as opposed to cognitive
screens such as the MMSE, although this was not replicated
by others (Flicker et al., 1997). This may represent a difference
in the choice of informants as much of the sample described
by Ritchie and Fuhrer (1992) were recruited through France
Alzheimer and may have represented carers that were well
attuned to the problems associated with dementia, while in
the other study (Flicker et al., 1997) informants were drawn
from attendees at a memory clinic.
There have been three Cochrane reviews of the IQCODE
over diverse settings. For community dwelling populations,
at a threshold of 3.3, the sensitivity was 0.80 (95% confidence
interval [CI] 0.75–0.85) and specificity was 0.84 (95% CI
0.78–0.90) (Quinn et al., 2014). For the primary care setting,
at a threshold of 3.2, sensitivity was 100% and specificity
was 76%, at a threshold of 3.7 sensitivity was 75%, and speci-
ficity was 98% (Harrison et al., 2014). For a secondary care
setting at a threshold of 3.3, the sensitivity was 0.91 (95%
CI 0.86–0.94) and specificity was 0.66 (95% CI 0.56–0.75)
(Harrison et al., 2015).
A meta-analysis (Jorm, 1997) suggests that informant
tests may perform better than short cognitive tests, but it is
important to emphasize that there was great heterogeneity
within this meta-analysis and clearly the test results were
dependent on the subject samples and the samples of infor-
mants. A subsequent meta-analysis confirmed relative inde-
pendence of education and premorbid ability but also that
these type of tests may be biased by depression and anxiety
in the informant and the quality of the relationship between
the informant and the subject (Jorm, 2004). Harwood et al.
(1997) also demonstrated comparable discriminatory abil-
ity of the AMT and the IQCODE in a sample of medical
inpatients over the age of 65 admitted to a general medical
unit. In that study, the 16 item version of the IQCODE was
utilized with good effect. The IQCODE has been validated
by longitudinal changes of cognitive tests (Jorm et al., 1996)
and also has been validated retrospectively against post-
mortem diagnosis (Thomas et al., 1994).
One of the important considerations for the use of com-
binations of tests or additional items is that the correla-
tion between individual tests should not be too great. The
importance of asymmetry of associations between tests to
increase the positive predictive value of combinations of
tests has been highlighted (Marshall, 1989). Hooijer et al.
(1993) found some improvement in diagnosis in using pairs
of short screening tests. This was not the case in work by
Little et al. (1987), where a short AMT score was found to
have better predictive value than longer combined tests.
To date, most work has focused on using either infor-
mant tests or short cognitive tests separately as a screen for
further investigations and management, but clearly the tests
can be combined. This was raised by Flicker et al. (1997),
where the lower correlations and asymmetry of the test
properties within different populations could be utilized so
that the combined tests’ sensitivity and specificity would be
improved. This is quite different to the use of the alteration
of cut-points, where a trade-off occurs between sensitiv-
ity and specificity. The judicious use of the combination of
informant and short cognitive tests potentially may result in
an increase in both sensitivity and specificity. The tests can
48 Dementia
be applied so that for the combination to be positive both
tests are required to be positive, which is called ‘in series’.
Alternatively, the combination of tests could be judged posi-
tive if either test is positive, which is called in ‘parallel’.
This has been demonstrated by Gallo and Breitner (1995)
where a telephone administered cognitive status was used as
a first screen followed by an informant test. The informant
test was falsely described as being more specific, but in fact
it was the combination of using the two tests in series that
resulted in the increased specificity needed for this two-
stage screen. Another example of this approach being used
in challenging population research is the work of Hall et al.
(1993, 1996). In these studies, a combination of short cogni-
tive tests and informant testing was used in cross-cultural
studies of African American, Cree Indian and Nigerian
populations, and the relative insensitivity of the informant
tests to the effects of culture and education improved the
performance of these combinations. The combination of the
MMSE and IQCODE has now been evaluated extensively.
In three separate studies (Mackinnon and Mulligan, 1998;
Knafelc et al., 2003; Mackinnon et al., 2003), the total evi-
dence suggested that the combination of tests performed
better than either test alone, and that the tests could be
combined usefully by either a requirement for both or either
test to be positive (in parallel) or calculating a new score
using a weighted sum rule.
Besides the characteristics of the population being
assessed, it is important to realize that the absolute preva-
lence of the condition will also cause a need for an adjust-
ment in the cut-points in both the cognitive and informant
tests. Very low prevalence will increase the need for speci-
ficity; otherwise, there will be a large number of patients to
further investigate. This is necessitated in both research and
clinical practice. It is important to emphasize that the cut-
points used in the combination of these tests in either series
or parallel, may be quite different to the ones normally
employed by the tests in isolation.
5.5 COSTS OF THE TESTS
Until relatively recently, these tests have generally been
administered freely without charge. The major expense has
been that of the clinicians’ time, both in training and admin-
istration. Two commonly used instruments, the MMSE and
TICS are now licensed for use by Psychological Assessment
Resources (Inc.). The MMSE may be administered free of
charge from memory or from an original paper (Folstein
et al., 1975) or from a source authorized by Psychological
Assessment Resources. Otherwise, there is a charge for using
the score sheets obtained from Psychological Assessment
Resources. Similar charges apply to the TICS. It would seem
a pity if these proprietary interests inhibit the use of these
short tests as often the major obstacle to the initial diagnosis
of dementia is applying one of these short tests when there
is clinical concern.
5.6 CONCLUSIONS
There is now available a plethora of short cognitive tests, which
appear useful in helping clinicians to determine whether
individuals require further assessment for the presence of a
cognitive disorder. The tests seem to perform in a similar fash-
ion. The characteristics of the population in which the tests
are used, seem to be at least as important to performance as
the test themselves. The addition of informant test informa-
tion appears more valuable rather than increasing the length
and complexity of the cognitive screen. It is difficult to predict
the performance of these tests, either singly, or in combina-
tion with informant tests, from one population to the next.
An improvement in the efficacy of cognitive assessments can
be most easily achieved by combining informant and short
cognitive tests to a single summative score, or using infor-
mant and cognitive tests with specific cut-points and rules of
combination. The most important limiting factor in clinical
practice is encouraging clinicians to use any one of these tests.
If clinical suspicion remains the combination of both, a short
cognitive test with an informant test is recommended.
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Neuropsychological assessment of dementia
GREG SAVAGE
6.1 INTRODUCTION
Dementia is a fundamentally neuropsychological concept,
describing the unravelling of the mind due to a brain dis-
order: neuro plus psychological. The disabling cognitive and
behavioural impacts of dementia are typically preceded by
gradually emerging signs of cognitive change, providing the
first inkling that something is not quite right. A brief cogni-
tive screening test by a geriatrician or neurologist may be
enlightening, but if the signs are subtle a referral for com-
prehensive neuropsychological testing should be made. The
emergence of clinical neuropsychology as a mainstream
specialty discipline in hospital outpatient clinics (e.g. so-
called ‘memory clinics’) has allowed for the quantitative
evaluation of cognitive decline with the kind of metric
resolution which healthcare professionals might reasonably
expect of an empirical investigation.
This chapter outlines the role of neuropsychological
assessment in helping to make a diagnosis of the underlying
cause of dementia. It characterizes the neuropsychological
domains affected in various kinds of dementia, the tests of
those domains used to inform neuropsychological opinion
and perspectives commonly taken by neuropsychologists in
forming an opinion. Other chapters in this volume provide
expert and comprehensive reviews of the clinical and cog-
nitive features of conditions associated with dementia ‒ so
this chapter will focus in a ‘hands-on’ manner on the process
followed by the neuropsychologist in responding to referral
questions. The chapter is intended to serve two audiences:
neuropsychologists fielding dementia-related referrals, and
other health professionals who make such referrals (in par-
ticular, those who do not use neuropsychological services
routinely, but might do so given a better understanding of
the assessment process).
The chapter adopts a broad definition of dementia, con-
sistent with the overall perspective of this volume. Coverage
focuses primarily on the most common form of dementia,
52
6
which is due to Alzheimer’s disease (AD), but extends to
other diseases and conditions associated with cognitive
decline. Many of these present late in the lifespan and are
contenders in differential diagnosis of the underlying dis-
ease. Accordingly, there is discussion of typical test find-
ings in cases of dementia with Lewy bodies (DLB), vascular
dementia (VaD), three kinds of frontotemporal dementia
(FTD) (the behavioural variant of FTD [bvFTD] and the
focal-onset variants known as semantic dementia [SD] and
progressive non-fluent aphasia [PNFA]) and also cognitive
impairment associated with cases of major depressive disor-
der (MDD), sometimes called depressive pseudodementia.
Other conditions where dementia is not a primary feature
will not feature here. Thus, while dementia develops in neu-
rodegenerative movement disorders such as Parkinson’s
disease and Huntington’s disease, the early diagnosis and
overriding clinical concerns relate to morbidity due to the
primary movement disturbance. Dementia due to infec-
tious diseases, toxic exposure, hydrocephalus or chronic
severe alcoholism is less common and prominent signs in
the clinical history may serve to argue against a more com-
mon dementia diagnosis, and to orient a neuropsychologi-
cal referral to specialist services.
Dementia is usually defined in terms of deteriora-
tion in two areas: cognition and instrumental activities
of daily living (IADL). Historically, classification systems
have required cognitive decline involving memory and at
least one other cognitive domain but recent clinical and
research consensus guidelines allow different combina-
tions of two domains (McKhann et al., 2011). When there
is measurable cognitive decline but the person is still cop-
ing adequately with daily activities, the term mild cogni-
tive impairment (MCI) is typically used. Many people are
referred to a neuropsychologist with this quasi-diagnosis
and turn out to have had prodromal AD when followed up,
reflecting an annual overall rate of transition from MCI
to ‘AD dementia’ estimated at around 10% (Bruscoli and
Lovestone, 2004).

6.2 PERSPECTIVES ON
NEUROPSYCHOLOGICAL
ASSESSMENT
Neuropsychological assessment of dementia cannot be
purely psychometric. It is placed squarely in the context
provided by a comprehensive interview with the patient and
an informant. This interview must leave the clinician with
a clear understanding of the time course of the emergence
of signs/symptoms, and the patterning of what seem to be
preserved versus declining abilities. A perspective on edu-
cational and vocational achievements will inform expecta-
tions about premorbid cognitive status, and the interview
can provide important information about lifetime exposure
to brain injuries or substances, which could account for
cognitive decline.
The assessment process outlined in this chapter is based
on a cognitive neuropsychological approach to clinical test-
ing (Mapou and Spector, 1995), which structures the test-
ing session and interprets test data according to processing
models developed in cognitive psychology. The process is
flexible and hypothesis driven in contrast to fixed-battery
approaches, and conclusions about higher cognitive func-
tions are parsimonious, taking into account the influences
of ‘foundation-level’ abilities such as attention and speed
of processing. Outcomes of the assessment are framed in
cognitive terms (e.g. memory problems being amenable to
cueing strategies or not) as opposed to performance-level
terms (e.g. verbal memory being placed in the low average
range), as these tend to be understandable by those mak-
ing referrals, as well as those who care for the patient. For
elaboration on this cognitive neuropsychological formulation
perspective see Savage (2016).
Neuropsychologists vary in terms of their utiliza-
tion of psychometric properties of tests. Those taking a
hypothesis-testing approach may administer subtests of
­
larger batteries, admixing with other ‘single-focus’ tests, and
might refer to a variety of normative databases without any
formal statistical comparison. Aggregation of subtest scores
into summary indexes can be seen as a confound, poten-
tially obscuring clinically meaningful differences across
subtests. In common with the fixed-battery approach, the
hypothesis-testing approach prescribes that tests should
possess robust psychometric properties in terms of reliabil-
ity and gracefully graded sensitivity to variation in perfor-
mance, even if the full potential for statistical analysis is not
used. Both approaches judge cognitive performance relative
to age-appropriate norms, and sometimes sex and educa-
tional level are taken into account.
Measured levels of performance, as well as differences
between performances for different domains, or over time,
are characterized using a range of parameters. The flag-
ship tests of the ubiquitous Wechsler suite are the Wechsler
Adult Intelligence Scale ‒ Fourth edition (WAIS-IV;
Wechsler, 2008) and Wechsler Memory Scale ‒ Fourth
Neuropsychological assessment of dementia 53
edition (WMS-IV; Wechsler, 2009a). Their intelligence quo-
tient (IQ) or Index scores have a normative mean of 100 and
a standard deviation of 15, and partitioning of the normal
distribution of IQs/Indexes into ranges provides descriptors
such as average (with IQs between 90 and 110), low aver-
age (80–90), high average (110–120) and so on. These scores
translate directly to Scaled Scores when subtests of the
Wechsler tests are discussed (mean = 10, standard devia-
tion = 3). Some tests provide percentile ranks, and others
use T-scores (mean = 50, standard deviation = 10). Z scores
(i.e. quantifying departure from average performance in
standard deviation units for a particular test) are frequently
used as a common currency in comparing performances
across a range of tests using different summary parameters.
6.2.1 COMPONENTS OF A BATTERY FOR
DEMENTIA ASSESSMENT
A typical test battery used when dementia is suspected takes
between one and two hours to administer and covers orien-
tation, ability to attend and manipulate information in mind,
speed of information processing (usually tested via psycho-
motor tasks), constructional praxis, executive functioning,
language and new learning and retention (usually for both
verbal and nonverbal material). A context for interpreting
performances in these domains is established by estimating
premorbid intellectual level. Neuropsychologists also try to
characterize recent mood state, usually by the administra-
tion of a formal self-report inventory (although such mea-
sures are invalid when memory impairment is prominent).
The following section describes commonly used tests
and their utility in differentiating between varieties of
potential diagnoses: AD, DLB, VaD, bvFTD, SD, PNFA and
depression. Table 6.1 outlines likely patterns of preserved
and impaired cognition in these disorders over the domains
covered in this section.
6.2.1.1 Tests of orientation and personal
and general information
Neuropsychologists usually begin testing with non-con-
fronting questions, which are administered by most health
professionals in some form; these are not psychometrically
sophisticated, but answers here can provide significant
insights into what to expect on later testing (e.g. mistak-
ing current age by years, or the year by a decade, or citing
past political leaders as current). Such strikingly aberrant
responses are common in early AD; occasional incorrect
responses may represent the ‘patchy dysmnesia’ often seen in
depressive illness. The Information and Orientation subtest
of the WMS-III has 14 items and tests orientation more thor-
oughly than its WMS-IV counterpart (the Brief Cognitive
Status Examination, with only six items); the first 10 items
of the Mini-Mental State Examination (MMSE; Folstein
et al., 1975) or the Addenbrooke’s Cognitive Examination-
III (ACE-III; Hsieh et al., 2013) may be used instead.
54 Dementia

Table 6.1 Typical patterns of cognition for conditions associated with dementia
Expected performance in various conditions
Cognitive Typical
domain tests AD DLB VaD bvFTD SD PNFA MDD
Orientation I/Oa Impaired Intact Impaired? Intact Intact Intact Variable
MMSEb
ACE-IIIc
Attention/ DSd Intact early on Impaired Impaired? Impaired Intact May be Impaired
working impaired
memory
Processing CDe Intact Intact? Impaired? Intact Intact Intact Impaired
speed
Reasoning Simf Intact early on Intact? Impaired? Impaired Impaired due Intact Intact
PCg to semantic
loss?
Language BNTh Impaired Intact Impaired? Intact Impaired Largely intact Intact
GNTi naming;
CFj effortful
speech
affects fluency
Executive LFk Mildly Impaired Impaired Impaired Intact early on Intact early on; Impaired
functioning CFj impaired? effortful
H&Bl speech may
CWITm affect speed
on language-
based tasks
Construction RCFTn Mildly Impaired Impaired? Mildly impaired Intact Intact Mildly
BDo impaired due to poor impaired
planning? due to poor
planning?
Memory LMp Impaired Impaired Impaired recall Impaired recall, May be Intact Impaired
VRq recall and recall, intact and intact impaired recall, intact
RAVLT  r recognition recognition? recognition? recognition? due to recognition?
CVLT-IIs semantic
HVLT-Rt loss?
BVMT-Ru
LLTv
RCFTn
Abbreviations: AD, Alzheimer’s disease; DLB, dementia with Lewy bodies; VaD, vascular dementia; bvFTD, behavioural variant frontotemporal
­dementia; SD, semantic dementia; PNFA, progressive non-fluent aphasia; MDD, major depressive disorder.
a Wechsler Memory Scale – Third edition (WMS-III) Information and orientation

b Mini-Mental State Examination

c Addenbrooke’s Cognitive Examination-III

d Wechsler Adult Intelligence Scale – Fourth edition (WAIS-IV) Digit Span

e WAIS-IV Coding

f WAIS-IV Similarities

g WAIS-IV Picture Completion

h Boston Naming Test

i Graded Naming Test (McKenna and Warrington, 1983)

j Category fluency

k Letter fluency

l Hayling and Brixton Tests

m Delis–Kaplan Executive Function System (D-KEFS) Color–Word Interference Test

n Rey Complex Figure Test

o WAIS-IV Block Design

p WMS-IV Logical Memory

q WMS-IV Visual Reproduction

r Rey Auditory Verbal Learning Test

s California Verbal Learning Test – Second edition

t Hopkins Verbal Learning Test – Revised

u Brief Visuospatial Memory Test – Revised

v Location Learning Test


6.2.1.2 Estimation of premorbid intellectual
level
Inferences about cognitive decline are necessarily made
with respect to expected levels of performance in the
absence of brain illness. Typically there are no ‘intact’ base-
line data available for comparison, and so broadly placed
estimates are made (e.g. average, high average, etc.). One
method takes account of educational background, voca-
tional achievements and/or demographic variables (either
informally or via input to normatively derived regression
equations). Another approach is to measure current abil-
ity in a domain which is usually resistant to even moderate
dementia, such as word knowledge: correct reading aloud of
so-called irregular words whose pronunciations do not fol-
low predictable spelling–sound rules suggests intact word
knowledge and tests incorporating graded difficulty afford a
psychometric estimate of likely premorbid intellectual level.
Typically used tests of word knowledge include the National
Adult Reading Test (NART; Nelson, 1982) and a recent vari-
ant, the Test of Premorbid Functioning (TOPF; Wechsler,
2009b), co-normed with the WAIS-IV and WMS-IV. Care
should be taken if SD is a differential under consideration:
while word knowledge is typically resilient against the
impact of neurodegeneration, this is by definition not the
case with SD.
A cognitively framed assessment then proceeds to assess
foundation-level domains such as concentration and speed
of thinking, as weaknesses here can undermine (and mis-
represent) higher-level functioning.
6.2.1.3 Tests of concentration and working
memory
Ability to engage in routine sequencing (concentration
or focused attention) and to hold information in mind
while working on a problem (so-called working memory)
is assessed for two purposes. A general purpose serves to
qualify interpretation of performances on more complex
or focal cognitive abilities, and an efficient strategy on the
part of the neuropsychologist is to establish how well the
patient can attend quite early in the course of the assess-
ment. Poor moment-to-moment concentration might ‘reca-
librate’ expectations in the examiner and suggest use of
simplified versions of tests, where floor-level performances
are less likely.
A specific purpose for assessing concentration and work-
ing memory is to provide differential diagnostic informa-
tion. Poor performance here can reflect dysfunction in
frontal systems and their connections to other brain regions:
Patients with depressive and/or anxiety disorders, bvFTD
or DLB often perform poorly on tests such as the Digit Span
and/or Letter–Number Sequencing subtests of the WAIS-IV
and Mental Control from the WMS-III (Wechsler, 1997).
Cases with mild AD, however, do not tend to have promi-
nent difficulty in this cognitive domain.
Neuropsychological assessment of dementia 55
6.2.1.4 Tests of processing speed
Speed of mentation is hard to measure without introduc-
ing confounds related to the task employed. Some think-
ing speed tasks use motoric responses to visual stimuli and
care must be taken to ensure a putative speed measure is
not overly reflecting the influence of other variables (e.g.
difficulty seeing or fixating visual stimuli, or motoric dif-
ficulty/slowness). A widely used test of processing speed is
the Coding subtest of the WAIS-IV, which measures speed
of transcription of symbols into a long series of numbered
boxes, guided by a number–symbol matching key. The
total number of symbols correctly transcribed within two
minutes indicates speed of the translation from number to
symbol. However, it can index other factors, such as visual
scanning of the arrays, motoric slowness, working memory,
associative learning of matches and sustained attention.
Reduced speed of processing (and the confounded influ-
ence of working memory and sustained attention) is not
usually compromised in mild or preclinical AD or in SD,
but can be seen in bvFTD, DLB, VaD and depression.
Against a background established in terms of both likely
premorbid capabilities and current foundation-level skills,
testing of higher mental functions can then proceed to be
interpreted.
6.2.1.5 Tests of language functioning
A typical neuropsychological battery used in dementia-
related referrals tends not to assess language comprehensively,
but ability to name objects is routinely assessed. Naming
reflects semantic access (and/or representation) as well as
phonological processing, and commonly used tests present
line drawings of objects graded by frequency of encounter.
The Boston Naming Test-2 (BNT-2; Kaplan et al., 2001) com-
prises 60 items, with a default entry point at item 30, and
allows for phonological cueing if the patient cannot name the
item spontaneously (assessing a so-called ‘tip-of-the-tongue’
state). It is often administered in either a 15- or 30-item short
form. Care should be taken to recognize that certain items
are culture-bound (e.g. beaver is intended to be an easy item,
but probably this is true only for North American residents).
Dysnomia is a prominent sign in mild AD and focal
dementias such as SD and PNFA; degraded semantic
knowledge is thought to be the problem in AD and SD, and
a phonological account is proposed in PNFA. Integrity of
semantic knowledge can also be assessed by testing vocabu-
lary and general knowledge (e.g. using the Vocabulary and
Information subtests of the WAIS-IV). Syntactic aspects
of language are usually preserved in all but severe cases of
dementia, and formal testing is rarely undertaken.
6.2.1.6 Tests of construction
Visuoconstructional ability is always tested in some form.
The Rey Complex Figure Test (RCFT; Meyers and Meyers,
1995) affords good insights into constructional praxis, and
56 Dementia
evaluating the organizational approach taken in copying
the figure informs an opinion about executive function-
ing. Dementia affecting posterior functions (e.g. in mild-
to-moderate AD and in DLB) can produce distortion in
reproduction of spatial relationships among elements of the
figure, often culminating in a bizarrely misshapen copy. In
contrast, distortion is seldom seen in dementias with ante-
rior degeneration (e.g. bvFTD, SD), although misalignment
may occur due to a poorly planned approach. Matching of
blocks to specified patterns is another frequently adminis-
tered test (e.g. the Block Design subtest of the WAIS-IV).
This test can be failed at easy levels in mild AD, and while
patients with bvFTD (and perhaps DLB) may have trouble,
they can benefit from provision of structure: once the test is
finished, using a Perspex overlay to segment the component
blocks may assist initiation of a response.
6.2.1.7 Tests of executive functioning
In an assessment tailored to be time efficient and mini-
mally frustrating, many neuropsychologists avoid lengthy
concept-formation tests such as the Wisconsin Card Sorting
Test (WCST), and prefer brief tests of the same construct
such as the Brixton test (Burgess and Shallice, 1997). Here,
the patient is required to anticipate the next location in a
spatial sequence; the patient is warned at the outset that
the sequential rule will change from time to time, and they
will need to pick up on the new sequence. Ability to inhibit
prepotent responses is often tested using a variant of the
Stroop test (e.g. the Color–Word Interference Test from the
Delis–Kaplan Executive Function System; D-KEFS; Delis
et al., 2001). Here, a series of colour names is printed using
incongruently coloured ink (e.g. the word red is printed in
blue ink); speeded naming of ink colour is normally difficult
due to a natural tendency to read the word itself, and failure
to inhibit this tendency (evident as slowness or error-prone
performance) indicates poor executive control. In a simi-
lar vein, the Hayling test (packaged with the Brixton) mea-
sures response latency and error rate in completing sentence
fragments with intentionally nonsensical final words (e.g.
London is a very busy: banana); executive failures lead to
either frankly predictable completions (e.g. city), or margin-
ally less predictable ones (e.g. location) or abnormally long
latencies to produce an acceptable response. Tests of strat-
egy formation and response inhibition are useful in charac-
terizing frontal systems dysfunction in cases with bvFTD,
and also in DLB and VaD. Cases with AD are less likely to
fail these tests because of flawed strategies or poor inhibi-
tion; rather, they may fail because they cannot understand
the nature of the task itself.
Ability to engage in abstract reasoning is an aspect of
executive functioning, which tends to decline gradually
in AD, and is impaired earlier and more prominently in
conditions which compromise frontal systems function-
ing. The Similarities and Picture Completion subtests from
the WAIS-IV test reasoning based on verbal and pictorial
materials, respectively, and can elicit concrete and literal
responses in dementias associated with hypofrontality, such
as bvFTD, DLB and often VaD.
Perhaps the most widely used test of executive func-
tioning, included in most batteries, involves word genera-
tion under time pressure and with compliance to a set of
stated rules. Letter fluency (sometimes incorrectly called
phonemic fluency) requires production of as many words as
possible which begin with a prescribed letter in a 1-minute
period. The D-KEFS version requires observance of three
rules: no proper nouns, no numbers and no variations on
the same word. Trials are undertaken for three letters (usu-
ally F, A and S), and the total score indexes flexible thinking
in a non-routine generation task requiring self-monitoring,
rule observance, mindful exploitation of lexical similari-
ties (e.g. flip suggesting flap and flop in quick succession)
and adaptability in the face of ‘thought blocking’. A vari-
ant, which is more structured (and hence normally easier),
simply requires generation of words on a given theme. This
category (or semantic) fluency test should also be given with
multiple trials for robust measurement: in the D-KEFS ver-
sion, two trials are given with different topics; an additional
trial requires switching between two topics (which adds
extra executive load).
Fluency tests are very informative in dementia assess-
ments, as the normal pattern of better performance on cat-
egory fluency than letter fluency tends to be reversed in even
mild or prodromal AD: letter fluency can be normal, but
category fluency fails badly due to deteriorating semantic
processing. This pattern may be seen in SD, but letter flu-
ency can also be impaired. In depression, bvFTD, DLB and
VaD letter fluency is typically impaired, with category flu-
ency following suit or remaining largely intact.
6.2.1.8 Tests of memory
Formal testing of learning and retention of new informa-
tion assesses integrity of episodic memory functioning and
is intended to characterize the forgetfulness in everyday life,
which is such a frequent complaint – either by the patient
or more often by significant others. Learning is sometimes
tested with only one exposure to material, but preferably
with repeated trials of exposure and testing, otherwise brief
attentional lapses can confound interpretation. Testing of
learning is performed immediately, but the most reveal-
ing data are usually provided after a delay of about 20–30
­minutes. Testing might require free recall of information,
cued recall or recognition of the information when pre-
sented among potentially confusable information. This gra-
dient between recall versus recognition failure maps onto
cognitive constructs of retrieval versus encoding/consolida-
tion problems, and this distinction is thought to have diag-
nostic value in discriminating among dementia types. In
brief, retrieval problems are characterized by poor recall but
better recognition performances, due to failure of frontally
mediated initiation of access to a stored memory trace; this
pattern is typically observed in depression, DLB, VaD and
bvFTD. In contrast, an encoding/consolidation problem

is thought to represent temporal lobe dysfunction, as seen
in AD and perhaps in SD to the extent that the informa-
tion source itself may be degraded. In these conditions, an
adequate memory trace is never formed and so patients per-
form poorly on both recall and recognition testing.
Assessment of unilateral memory disorders (e.g. in cases of
stroke, tumour or epilepsy) has resulted in a tradition of test-
ing memory using both verbal materials (usually word list,
word pairings and/or prose passages) and nonverbal materi-
als (usually drawn diagrams, faces and/or object locations).
Free recall of prose passages (e.g. WMS-IV Logical Memory)
is often tested, although performance here is not useful in
distinguishing between a temporal lobe encoding/consolida-
tion problem and a more frontally mediated retrieval-based
impairment. In addition, large amounts of information are
presented without multiple repeated trials, and attentional
problems can confound interpretation. Performance on free
recall word lists over repeated trials, combined with delayed
recall and subsequent recognition testing addresses both these
issues, and the Rey Auditory Verbal Learning Test (RAVLT)
(Rey, 1958; Strauss et al., 2006) is widely used in dementia-
related assessments. A similar test, the semantically clustered
California Verbal Learning Test ‒ Second edition (CVLT-II;
Delis et al., 2000) is popular in North America but inclusion
of a few culturally bound items may confound its use in other
English-speaking countries (e.g. where subway refers to a
road underpass and thereby does not fall into the semantic
cluster modes of transport). These tests are particularly use-
ful in the early detection of dementia, but the list length (15
and 16 items respectively) may prove overwhelming in mild-
to-moderate cases, resulting in floor effects, which preclude
measurement of deterioration over time. Easier semanti-
cally clustered versions such as the 12-item Hopkins Verbal
Learning Test ‒ Revised (HVLT-R; Benedict et al., 1998)
or 9-item CVLT-II Short Form are extremely useful when
screening of memory reveals strikingly impaired ability.
In the nonverbal domain, memory for designs is frequently
tested but relies on intact constructional ability. The Visual
Reproduction (VR) subtest of the WMS-IV measures recall for
a series of designs with increasing complexity after a 10-second
exposure; such immediate recall reflects working memory,
but subsequent recall after 30 minutes does reflect retention.
Incidental testing of recall for the Rey Complex Figure (i.e.
without informing the patient ahead of time) indexes reten-
tion, but can only be interpreted validly when the initial
copy was reasonably accurate and completed in an organized
manner. The same caveats applied above to prose passages
regarding attentional lapses and retrieval versus encoding/
consolidation interpretations apply to these visually based
free recall tests with only single exposure learning phases.
The Brief Visuospatial Memory Test – Revised (BVMT-R)
(Benedict, 1997) is a nonverbal analogue to the HVLT-R, and
uses repeated trials of free recall of six simple designs viewed
at once for 10 seconds; subsequent recognition testing after
delayed recall quantifies retrieval difficulty. The Faces sub-
test of the WMS-III tests immediate recognition memory for
photographs of faces, avoiding the working memory confound
Neuropsychological assessment of dementia 57
of Visual Reproduction by testing at the end of a series of 24
items; delayed recognition tests retention. Finally, the Location
Learning Test (LLT; Bucks et al., 2000) measures correct place-
ment of drawings of 10 common objects in a 5 × 5 grid over
multiple trials. It has good metric properties, which capture
the degree of error in misremembering location.
In all these tests, both verbal and nonverbal, patients
with AD tend to have difficulty with both recall and rec-
ognition modes of testing, and patients with bvFTD, DLB,
VaD and depression tend to have less difficulty on recogni-
tion testing.
6.3 COMMUNICATING A
NEUROPSYCHOLOGICAL OPINION
The outcome of the assessment is typically conveyed in a
formal report to the referrer. Neuropsychological reports
are usually comprehensive documents, which combine
appraisal of the clinical history, qualitative aspects of
behaviour on interview and throughout testing, and inter-
pretation of test scores, Here, the operative word is inter-
pretation: the score itself may be qualified by the manner in
which it was achieved (e.g. normatively average repetition
of digits might represent graceful arrival at a threshold of
difficulty, or a chaotic pattern of early failures on easy items,
which persists through to extremely difficult items; the total
score does not distinguish between these clinically quite
different performances). Overall, the assessment process
and the resulting opinion is fundamentally neuropsycho-
logical, not neuropsychometric. This should be reflected in
the conclusions reached: an opinion should be conveyed in
plain language with minimal recourse to statistics, and the
logic underlying the interpretation of the findings should
be transparent. If the referrer has primary responsibility
for clinical care of the patient, they will usually discuss the
findings and opinion in a review consultation, possibly in
a synthesis with conclusions from other investigations. It
is very useful to supplement this meeting with face-to-face
feedback from the neuropsychologist to the patient, in the
company of a carer; this provides the opportunity for clari-
fication and for discussing potential management strategies.
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Neuropsychiatric aspects of dementia
NILIKA PERERA, MEHRAN JAVEED, CONSTANTINE G. LYKETSOS AND IRACEMA LEROI
7.1 INTRODUCTION
‘Neuropsychiatric symptoms’ is an umbrella term that
describes the non-cognitive symptoms and behaviours that
often occur in people with dementia. These symptoms include
changes in mood and personality, perceptual abnormalities,
psychomotor disturbances (such as apathy, agitation, aggres-
sion, wandering and purposeless behaviour) and neurovegeta-
tive changes (such as sleep, appetite and energy disturbances).
Neuropsychiatric symptoms have been variously termed
‘behavioural and psychological symptoms of dementia’
(BPSDs), ‘non-cognitive changes’ and ‘challenging behav-
iours’. The importance and ubiquity of these symptoms are
highlighted by Alois Alzheimer’s first clinical description of
the condition which later became known as Alzheimer dis-
ease (AD). In this first case study, Alzheimer wrote:
The first noticeable symptoms of illness shown
by this 51-year old woman was suspiciousness of
her husband. Soon, a rapidly increasing memory
impairment became evident; she could no lon-
ger orient herself in her own dwelling, dragged
objects here and there and hid them, and at
times, believing that people were out to murder
her, started to scream loudly (Alzheimer, trans-
lated by Jarvik and Greenson, 1987).
Neuropsychiatric symptoms are a common first presen-
tation of most dementia syndromes and often prompt refer-
ral for assessment. In some cases, changes in personality or
behaviour in later life, namely a putative diagnosis of ‘mild
behavioural disturbance’ may be a harbinger of later demen-
tia. These changes are most likely secondary to frontotem-
poral degeneration, in an analogous way that a proportion of
people with ‘mild cognitive impairment (MCI)’ frequently
go on to develop later significant cognitive impairment war-
ranting a diagnosis of dementia (Taragano et al., 2009).
7
7.2 IMPACT OF NEUROPSYCHIATRIC
SYMPTOMS
The negative impact of neuropsychiatric complications on
people with dementia, caregivers and the community is
significant, and far greater than the impact of dementia-
related functional limitations or cognitive decline (Banerjee
et al., 2006). According to the Alzheimer Europe Dementia
Carers’ Survey, 50% of caregivers report such symptoms
as the most problematic aspect of caring for someone with
dementia.
Apathy, irritability and agitation are noted to be the most
prevalent neuropsychiatric symptoms in dementia in gen-
eral (Bergh and Selbæk, 2012), whilst agitation, aggression
and personality change are rated as the most troublesome
dementia-related symptoms for at least 16% of caregivers
(Georges et al., 2008).
Identifying neuropsychiatric symptoms in people with
dementia can aid in anticipating further cognitive deteriora-
tion and guiding clinical decision making (Javeed and Leroi,
2014). Neuropsychiatric complications are a significant risk
factor for institutionalization (O’Donnell et al., 1992), and
are associated with a worse prognosis and a more rapid rate
of illness progression (Paulsen et al., 2000). Furthermore,
the cost of caring for people with dementia with concurrent
neuropsychiatric complications is significantly greater than
the cost of caring for someone with dementia without such
complications (Murman et al., 2002).
Neuropsychiatric complications in dementia can mark-
edly increase the risk of injury to the person with demen-
tia and their caregiver(s). Caregivers also have an increased
risk of depression, anxiety and social isolation (Gonzalez-
Salvador et al., 1999; Brodaty and Donkin, 2009), although
this may depend on their own personal vulnerabilities, social
circumstances as well as the nature of the behavioural dis-
turbances. For example, in dementia related to Parkinson’s
disease (PD), those with emotional blunting related to apathy
59
60 Dementia
have significantly worse caregiver outcomes compared to
those with PD and apathy without emotional blunting (Leroi
et al., 2014). Moreover, in care homes or nursing facilities,
the risk of injury and insult to other residents and staff can
lead to a high turnover of staff leading to a less positive work
environment. This can precipitate further behavioural dis-
turbances and a reduction in the quality of life in residents.
Finally, if severe, the presence of neuropsychiatric symptoms
raises the risk of the person with dementia being managed
with restraints and antipsychotic medications which can
increase risk of mortality and morbidity and more rapidly
deteriorating cognition (Bianchetti et al., 1997).
7.3 EPIDEMIOLOGY AND SPECTRUM
OF NEUROPSYCHIATRIC
SYMPTOMS OF DEMENTIA
Neuropsychiatric symptoms are extremely common in
the dementias, despite variations in settings and cultures.
However, unlike the predictable decline seen in the cogni-
tive and functional abilities of dementia sufferers, neuro-
psychiatric symptoms may fluctuate in their presence and
intensity and could be eliminated through appropriate
management. This, in turn, could improve quality of life for
the person with dementia and their caregiver.
7.4 NEUROPSYCHIATRIC SYMPTOMS
AS PROGNOSTIC MARKERS
Neuropsychiatric symptoms can precede or follow the
emergence of cognitive and functional impairment and
may be predictive of more rapid decline in these domains.
For example, the risk of developing AD, the most common
type of dementia, increases with each episode of later-life
depression over the age of 65, if the depression is associated
with cognitive symptoms (Wilson et al., 2002). Moreover,
the Multi-institutional Research in Alzheimer’s Genetic
Epidemiology (MIRAGE) study found that depression
occurring many years before the onset of cognitive decline
may be a significant risk factor for the future development of
AD (Green et al., 2003). Social withdrawal may occur almost
3 years prior to the onset of the full dementia syndrome,
and anxiety and psychotic symptoms may also be portents
of later cognitive decline (Taragano et al, 2009). Finally,
apathy, characterized by loss of motivation and interest and
emotional blunting, is a frequent marker of conversion to
dementia in those with early or MCI. For example, in PD,
the only neuropsychiatric symptom that differs in fre-
quency and magnitude between those with intact compared
to those with impaired cognition is the syndrome of apathy,
which continues to worsen as cognition declines. This sug-
gests that the emergence of apathy is a proxy for the onset
of cognitive deterioration and should therefore be identified
and managed early (Leroi et al., 2012; Mauri et al., 2012).
7.5 NEUROPSYCHIATRIC SYMPTOMS
IN MILD COGNITIVE IMPAIRMENT
Neuropsychiatric symptoms affect between 40% and 75% of
people with MCI (Lyketsos et al., 2002; Hwang et al., 2004).
In the Cardiovascular Health Study (CHS), 43% of the 320
individuals who were identified as having MCI exhibited
neuropsychiatric symptoms, with depression, apathy and
irritability being the most common (Lyketsos et al., 2002).
7.6 NEUROPSYCHIATRIC SYMPTOMS IN
DEMENTIA IN COMMUNITY AND
CLINICAL SETTINGS
The Medical Research Council Cognitive Function and
Ageing Study (MRC CFAS) in United Kingdom (Brayne
et al., 2006) and the Cache County Study of Memory in
Aging (CCSMA) in Utah, United States (Breitner et al.,
1999) are landmark population-based studies of neuropsy-
chiatric symptoms. The MRC CFAS prospectively followed
13,004 individuals over the age of 64 for 10 years assessing
the participants’ cognition and neuropsychiatric symptoms
using the Mini-Mental State Exam (MMSE) and an adapted
Geriatric Mental State (GMS). Of the 587 individuals with
dementia, irritability was more common in those with less
severe cognitive dysfunction (MMSE score of ≥22), whereas
wandering, elation, apathy and psychosis were more com-
mon in those with more severe cognitive dysfunction
(MMSE <17) (Savva et al., 2009). Depression and anxiety
were more common in younger people with dementia, as
well as in those with vascular risk factors. In the CCSMA,
61% of all the participants with dementia had one or more
neuropsychiatric symptom in the month prior to interview.
Specifically, among those with a diagnosis of AD, 23% (n =
49) had delusions and 13% (n = 28) had hallucinations. In
contrast, in those with a diagnosis of vascular dementia
(VaD), point prevalences were 8% (n = 5) and 13% (n = 8)
for these symptoms respectively (Leroi et al., 2003).
Psychotic symptoms are relatively persistent and are
often seen in those with moderate or severe cognitive
impairment due to dementia (Savva et al., 2009). They most
commonly take the form of delusions of theft or jealously,
the phantom boarder syndrome or misidentification phe-
nomena (Harvey, 1996). In AD, the most common hallu-
cinations are visual (80%), which a notably more common
than auditory hallucinations (20%) (Leroi et al., 2003).
The prevalence of AD-related neuropsychiatric symp-
toms in clinic-based populations can be ascertained from the
European Alzheimer Disease Consortium’s dataset, which is
 Neuropsychiatric aspects of dementia 61

the largest pooled set of data relating to people with AD. These
cross-sectional data, which are derived from 12 treatment cen-
tres across Europe, include Neuropsychiatric Inventory (NPI)
scores (Cummings et al., 1997) from 2,354 clinic attendees
with a diagnosis of AD. They reveal that apathy is the most
common symptom, appearing in 55% of clinic patients fol-
lowed by anxiety and depression in about 37% (Aalten et al.,
2007). Delusions and hallucinations have a similar prevalence
to the population-based findings from the United States.
Residential and nursing home prevalence figures differ
slightly from the findings of population- or clinic-based
cohorts of people with dementia, with over 91% of those in
nursing home facilities having at least one behavioural prob-
lem (Tariot et al., 1993) with up to 60% having aggression
and non-aggressive agitation (Margallo-Lana et al., 2001).
This high proportion may be due, in part, to the higher rate
of detection, as well as the more advanced stage of dementia
of people in 24-hour care.
The Maryland Assisted Living Study (MALS) examined
a stratified random sample of residents in assisted living
(AL) facilities and established that 70% has clinically signif-
icant neuropsychiatric symptoms (Rosenblatt et al., 2004).
Residents in AL tend to be less cognitively and function-
ally impaired than those in nursing and care home facilities.
Interestingly, MALS revealed the magnitude and frequency
of symptoms to be twice as high in smaller AL facilities
(<15 beds) compared to larger AL facilities, likely reflecting
differences in care practices and even resident characteris-
tics (Leroi and Burns, 2007). This suggests that the specific
features of different residential types need to be consid-
ered when determining the prevalence of neuropsychiatric
symptoms in populations with dementia.
Within acute hospital settings, neuropsychiatric symp-
toms are also prevalent and need to be recognized and
managed. Sampson et al. (2014) reviewed 230 patients
admitted to an acute medical unit in the United Kingdom
and found moderately or severely troubling neuropsychia-
try symptoms in over 40% of patients. The most common
symptoms were aggression (57%) and ‘activity distur-
bances’ (44%). The same study also discovered that over
a third of patients reported sleep disturbances, depres-
sion, phobia or anxiety at some point during their hospital
stay, and that these and other neuropsychiatric symptoms
were associated with the risk of further adverse events and
higher mortality rates.
Aside from the specific setting, the prevalence of neu-
ropsychiatric symptoms may also vary with the specific
dementia subtype, although the rates and profiles of these
symptoms are most often not specific enough to reliably dis-
tinguish between the diagnostic sub-types. For example, in a
study population of people with AD and VaD, the rates with
which different NPI domains were endorsed did not signifi-
cantly differ (Leroi et al., 2003). In contrast, the neuropsychi-
atric manifestations of some of the ‘frontal lobe dementias’
are embedded within the diagnostic characteristics and can
be used to distinguish between the subtypes, as in Table 7.1.
In the Lewy body diseases, such as dementia with Lewy
bodies (DLB) and Parkinson’s disease dementia (PDD),
apathy, depression and visual hallucinations are particu-
larly prominent. Interestingly, in PD without dementia, the
same neuropsychiatric presentation is evident, but with a
lower frequency, suggesting that neuropsychiatric symp-
toms are a precursor to subsequent cognitive decline (Leroi
et al., 2012; Javeed and Leroi, 2014). Dopamine has a role in
reward, motivation, emotion regulation and motor function
and the above findings suggests that a spectrum of similar
but increasing pathology exists across the three disorders
depending on the distribution of Lewy bodies and subse-
quent damage to dopaminergic and cholinergic pathways
(Leroi et al., 2012).
7.7 RISK FACTORS FOR
THE DEVELOPMENT OF
NEUROPSYCHIATRIC SYMPTOMS
Genetic factors may play a role in the emergence of neuro-
psychiatric symptoms in dementia. The CCSMA established
an association between a positive apolipoprotein E gene
(ApoE 4) status and aberrant motor behaviour (Steinberg
et al., 2006). This study also showed women to have an
increased risk of developing anxiety and delusions in AD.
Genetic variations in dopamine- and serotonin-related

Table 7.1 Diagnostic characteristics of frontal lobe dementia

Type of frontal lobe
dementia
Frontotemporal
dementia (FTD)
(Mychack et al., 2001)
Semantic dementia (SD)
Progressive non-fluent
aphasia (PNA)
Diagnostic characteristics
• Insidious onset
• Gradual decline in social functioning and regulation of personal conduct, accompanied by
emotional blunting and behaviours that may be stereotypic, perseverative or stimulus bound
• Tends to have a predominance of right-sided temporal dysfunction
• Tends to present with aberrant social behaviour, hyperorality, hypersexuality and changes in
religious and ideological belief systems
• Predominance of left-sided temporal lobe pathology leads to compulsive behaviours
• Language dysfunction is a core presenting feature
• Behavioural symptoms are not prominent
62 Dementia
genes, such as the catechol-O-methyltransferase (COMT)
or 5-HTT gene-linked promoter region (5-HTTLPR), and
neurotrophins, such as brain-derived neurotrophic factor
(BDNF) are related to developing neuropsychiatric symp-
toms in AD (Borroni et al., 2010).
Ropacki and Jeste (2005) reviewed 55 studies published
on the epidemiology of psychosis in AD between 1990 and
2003. This review revealed that black ethnicity, low education
level, female gender and family history of dementia or psychi-
atric disorder to be weakly associated with increased risk for
psychosis in AD. However, the overall evidence for this risk
remains inconclusive except for psychosis, namely hallucina-
tions, being significantly associated with cognitive decline.
Finally, premorbid personality traits may predispose to
the later development of neuropsychiatric symptoms in AD.
Specifically, lower premorbid agreeableness is associated with
agitation and irritability symptoms in AD and also predicts
an ‘agitation/apathy’ syndrome. The relationship between pre-
morbid neuroticism and neuropsychiatric symptoms are less
straightforward, and premorbid neuroticism does not appear
to be associated with depression in AD (Archer et al., 2007).
7.8 CLASSIFICATION OF SYMPTOMS
Various classification schemes have been proposed to cap-
ture the range of behavioural and psychiatric presentations
in dementia. The symptoms could be ‘lumped’ or ‘split’ into
specific and definable syndromes or considered as mono-
symptomatic phenomena.
As per the ‘lumping’ approach, multiple statistical meth-
ods have been employed to examine neuropsychiatric symp-
toms according to ‘syndrome’. One of the largest analyses
was based on the European Alzheimer Disease Consortium’s
cross-sectional study of 2,808 patients with dementia from
12 different European clinical centres (Aalten et al., 2008).
Using principle component analyses, four neuropsychiatric
syndromes were identified across various dementia types and
included: ‘hyperactivity’ (agitation, aggression, euphoria, dis-
inhibition, irritability, aberrant motor behaviour), ‘psychosis’
(hallucinations and delusions), ‘affective symptoms’ (depres-
sion and anxiety) and ‘apathy’ (apathy and eating behaviours).
In contrast to the factor analytic approaches, latent class
analysis is a method that examines whether individuals tend
to cluster into groups (classes) based on their individual
clinical profile rather than examining the groupings of clin-
ical characteristics across individuals, as in the former case.
The latter method has revealed that three groups or classes
of AD patients typically manifest: Those with no neuropsy-
chiatric symptoms (40%) or with a monosymptomatic dis-
turbance (19%). A second class (28%) has a predominantly
affective syndrome, while a third class (13%) presents with
a psychotic syndrome (Lyketsos et al., 2000). A similar pat-
tern using latent class analysis emerged from the analysis by
Moran et al. (2004), however, aggression, rather than psy-
chosis, appeared more distinctly as a separate grouping.
The argument supporting a ‘split’ in symptoms is based
on findings of distinct underlying neuropathology of dif-
ferent individual symptoms. For example, delusions in
AD have been associated with the presence of neurofibril-
lary tangles (NFTs), and may be associated with an ‘affec-
tive syndrome’ and ‘psychotic’ syndrome. Hallucinations
appear to be more closely associated with degeneration of
cholinergic pathways (Perry et al., 1990; Lyketsos et al.,
2000). Hence, it may be misleading to ‘lump’ these different
symptoms under the rubric of ‘psychosis of AD’.
7.9 ASSESSMENT, RATING
AND DIAGNOSIS OF THE
NEUROPSYCHIATRIC SYMPTOMS
OF DEMENTIA
The assessment of neuropsychiatric symptoms should be
considered an essential part of a complete assessment of a
patient with dementia. Several assessment tools and rating
scales have been validated and can aid in the detection and
diagnosis of the symptoms, as well as their quantification.
Quantifying the frequency and severity of the symptoms
can be important, particularly as they may be the key focus
of a clinical management plan. It will also enable a clear
determination of the outcome of the therapeutic interven-
tion and aid in monitoring the patient’s progress. The most
commonly used and best-validated tools for assessing the
full range of symptoms include the informant-rated NPI
(Cummings et al., 1997), which is considered the gold stan-
dard assessment tool, and is often used as an efficacy out-
come measure in clinical trials. A clinician-rated version,
NPI-C is available in several languages (De Medeiros et al.,
2010). There is also NPI-NH, a nursing home version, which
could be used in such institutions (Wood et al., 2000).
Another commonly used full spectrum tool is the
behavioural pathology in Alzheimer disease rating scale
(BEHAVE-AD) (Reisberg et al., 1987). Other rating scales
focus on specific behavioural syndromes such as the Cornell
Scale for Depression in Dementia (CSDD) (Alexopoulos et al.,
1988), which is an informant-rated depression scale; the
Cohen-Mansfield agitation inventory (Cohen-Mansfield,
1986) for assessment of agitation and aggression; and the
apathy evaluation scale (AES) (Marin et al., 1991) for the
assessment of apathy and loss of motivation.
The clinical assessment of neuropsychiatric symptoms
can be enhanced through the use of diagnostic criteria
specific for particular syndromes. Such diagnostic criteria,
although not widely used in the clinical setting, have come
about due to attempts to operationalize the examination
of separate behavioural phenomena. The symptoms have
been classified into distinct sets of unique, validated crite-
ria, similar to the approach to categorization of symptoms
used by the American Psychiatric Association’s Diagnostic
and Statistical Manual of Mental Disorders. From a research
perspective, this approach fosters reliability and enables

the development of a sound evidence-base for management
strategies. Examples of such diagnostic criteria include:
‘Psychosis of AD’ (Jeste and Finkel, 2000); ‘depression of
AD’ (Olin et al., 2002); ‘sleep disorder and AD’ and ‘agita-
tion and AD’ (Sunderland et al., 2008). These criteria have
not, however, been adopted into standard clinical practice.
7.10 PATHOPHYSIOLOGY OF
NEUROPSYCHIATRIC SYMPTOMS
OF DEMENTIA
Some of the most significant recent advances in our under-
standing of neuropsychiatric symptoms of dementia have
arisen from new findings of the underlying pathophysiol-
ogy of these symptoms. A thorough understanding of such
pathophysiological processes will aid validation of the clus-
tering of the neuropsychiatric symptoms and syndromes
and further clarify whether mechanisms distinct from
those underlying cognitive symptoms exist. By understand-
ing the neurobiological basis of these symptoms, appropri-
ate interventions can be employed to improve quality of life
and reduce carer burden in AD sufferers.
Agitation and aggression occur frequently in AD and
cause a great deal of distress to both AD suffers and their
caregivers. In AD, agitation and aggression in isolation
may be significantly associated with impairment in activi-
ties of daily living (ADL) (D’Onofrio et al., 2012), although
a proportion of those with agitation will have underlying
delusions driving the behavioural problem. Considered
an ‘enigmatic syndrome’ in AD, the underlying neurobi-
ology of agitation and aggression is still not entirely clear
(Cummings, 2000a). The degree of agitation has been found
to be associated with the degree of grey matter loss in the
anterior cingulate bilaterally and the left insula (Bruen et al.,
2008). There is also some evidence for a link between these
symptoms and the glutamatergic system, which may be dis-
rupted due to the formation of NFT in frontal and cingulate
cortices (Tekin et al., 2001). This pathology may result in
an exaggerated response to triggers and other symptoms
such as depression, anxiety and psychosis, through the low-
ering of the threshold that triggers aggressive behaviour
(Senanarong et al., 2004). Although some have not been
able to show correlation, other studies have demonstrated
an association between agitation and delusions with the
presence of ApoE-ε4 (van der Flier et al., 2007).
Psychosis is one of the most common presenting neu-
ropsychiatric features in dementia, particularly in AD
and DLB, where visual hallucinations may be the present-
ing symptoms. Delusions occur frequently, particularly in
the earlier stages of dementia and in those who are older
(Leroi et al., 2003). Positron emission tomography (PET)
has shown reduced glucose metabolism in right frontal
regions of the brain in those suffering from delusions, with
severity linked to hypometabolism in prefrontal and ante-
rior cingulate regions (Lyketsos et al., 2011). Post-mortem
Neuropsychiatric aspects of dementia 63
neuropathological and neurochemical studies have gen-
erally considered hallucinations and delusions under the
common rubric of ‘psychosis’ and suggest that those with
psychosis and AD have more extensive degenerative changes
in frontal and temporal areas, compared with those AD
sufferers with no psychosis (Cummings, 2000a). However,
there is growing support for considering hallucinations and
delusions separately when considering the pathophysiology
of ‘psychosis’. In particular, the association between lower
levels of choline acetyltransferase levels in parietal and tem-
poral lobes of dementia sufferers with hallucinations (Perry
et al., 1990) and the relative efficacy of cholinesterase inhibi-
tors in treating hallucinations in dementia suggests a cho-
linergic basis for hallucinations (Cummings, 2000b).
Depression in dementia is common and over 30% of
people may experience depression in the month prior to
assessment for the presence of dementia (Lyketsos et al.,
2002), suggesting that depression may be part of the pro-
drome of dementia. Prevalence estimates of depression in
dementia vary due to multiple and complex factors, includ-
ing frequent comorbidity with apathy as well as the inabil-
ity of the depressed person with dementia to communicate
their distress and report their symptoms accurately (Lee
and Lyketsos, 2003). A family or past personal history of
depression may also be contributory. A recent UK study,
studying polymorphisms in dopamine gene pathways in
those with probable AD found an association between the
dopamine receptor 4 (DRD4) 2R allele and depression sug-
gesting a dopaminergic system in depression (Proitsi et al.,
2010). Those developing depression after the onset of AD
will often have had a positive family history of mood dis-
order or have suffered depression in early or midlife. The
subsequent presentation may therefore be a recurrence of
former symptoms. In contrast, for some, depression may
represent an emotional reaction to cognitive deficits, cere-
brovascular damage or a direct consequence of the neuro-
degenerative process (Lee and Lyketsos, 2003). The latter
process is most likely the same as that underlying ‘late-
life depression’, which is commonly prodromal to a later
dementia syndrome. Neuropathology studies have found
serotonergic deficits in the raphe nuclei (Chen et al., 2000)
and an excessive loss of noradrenergic neurones have also
both been implicated (Hermann et al., 2004), allowing these
mechanisms to be targets for pharmacological intervention.
Apathy, or loss of motivation or indifference, is consid-
ered the most common neuropsychiatric manifestation in
dementia and in the EADC study was found to occur in
almost 65% of AD patients (Aalten et al., 2007). Apathy
as syndrome appears to be stable across several forms
of dementia, including VaD, DLB and frontotemporal
dementia (FTD) (Aalten et al., 2008). As with depression,
apathy may be a prodrome of a dementia syndrome and in
MCI, comorbidity with the ‘lack of interest’ component of
the apathy syndrome predicted a higher rate of conversion
to AD (Onyike et al., 2007; Robert et al., 2008). Apathy is
very often under-recognized yet it has significant conse-
quences with greater levels of impairment in ADL, more
64 Dementia
associated with cognitive impairments and greater carer
burden. The most likely pathophysiology underlying apa-
thy syndromes is that which involves a lesion at any point
along the distributed frontal-subcortical network. The
location of the lesions may determine the particular mani-
festation of the apathy syndrome. For example, lesions
involving the mesiofrontal circuit, of which the anterior
cingulate gyrus forms a part of and which mediates goal-
directed and motivated behaviour, is likely to manifest in
lack of drive or action. Lesions involving the dorsolateral
frontal cortex are more likely to disrupt the cognitive and
executive functioning abilities required to generate goal-
directed behaviours (Landes et al., 2001). The importance
of these regions to the apathy syndrome is supported by
various studies, including the post-mortem findings of
greater NFT burden in the anterior cingulate (Marshall
et al, 2006), and the neuroimaging findings suggesting
that apathy is associated with decreased perfusion and
metabolism of fronto-subcortical brain areas and the ante-
rior cingulate (Benoit et al., 2002).
7.11 CONCLUSIONS
The neuropsychiatric symptoms of the various dementia
syndromes are common and nearly universal. It is now evi-
dent that certain neuropsychiatric phenotypes are linked
with particular underlying pathophysiological processes.
These symptoms, which may appear even before the cog-
nitive and functional decline has become apparent, have
significant consequences for both the patient and their
caregiver.
On an optimistic note, while therapeutic approaches to
the cognitive and functional decline remain limited, the
neuropsychiatric symptoms remain the most treatment
responsive aspects of dementia.
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Measurement of behaviour disturbance,
non-cognitive symptoms and quality of life
AJIT SHAH
8.1 BEHAVIOURAL AND
PSYCHOLOGICAL SYMPTOMS OF
DEMENTIA
8.1.1 DEFINITION
Behavioural and psychological symptoms of dementia
(BPSD) are defined as ‘a heterogeneous range of psychologi-
cal reactions, psychiatric symptoms and behaviours occur-
ring in people with dementia of any aetiology’ (Finkel and
Burns, 2000). They include disorders of behaviour, mood,
thought content and perception, and personality alteration
(Burns et al., 1990b, 1990c, 1990d, 1990e; Shah et al., 2005).
The definition of any individual BPSD should be hierarchi-
cal and allow discrimination among the cognitive and other
BPSD domains, different BPSD domains and individual
symptoms within an estimated BPSD domain (Shah, 2000).
8.1.2 DISORDERS OF BEHAVIOUR
8.1.2.1 Definition
A typical example of disturbed behaviour is aggression, but
similar arguments can be rehearsed for other behaviours.
Aggression has been variably defined (Shah, 1999a), but a
useful definition is: ‘Aggressive behaviour is an overt act,
involving the delivery of noxious stimuli to (but not nec-
essarily aimed) at another organism, object or self, which
clearly is not accidental’ (Patel and Hope, 1992a).
8.1.2.2 Samples, settings and data
collection methods
Table 8.1 illustrates the samples studied and methods of
data collection in several settings (Shah, 1999a). Essential
8
properties of instruments measuring BPSD are illustrated
in Table 8.2. An important characteristic of some instru-
ments measuring aggression is the spontaneous tendency of
aggression declining during serial measurements (Nilsson
et al., 1988; Shah, 1999b).
8.1.2.3 Comment
Although many instruments measure aggression, not all
the psychometric and other properties have been adequately
evaluated. Individual instruments have been developed for
use in specific settings, for specific diagnostic groups and
by specific groups of raters and their generalizability to
other settings, diagnostic groups and categories of raters are
unclear. For example, the rating scale for aggressive behav-
iour in the elderly (RAGE), although developed for use
by nursing staff to measure aggression in psychogeriatric
inpatients with dementia (Patel and Hope, 1992a), has been
used in nursing homes for all diagnostic groups (Shah et al.,
1997). Nevertheless, comparisons among individual scales
are emerging (Whall et al., 2013).
8.1.3 DISORDERS OF PERSONALITY
ALTERATION
8.1.3.1 Definition
Personality changes in dementia include emergence of new
traits (Dian et al., 1990; Siegler et al., 1991; Chatterjee et al.,
1992; Petry et al., 1988; Lautenschlager et al., 2007) or exag-
geration of existing traits (Lautenschlager et al., 2007).
8.1.3.2 Samples, settings and data
collection methods
Table 8.3 illustrates the data collection methods, ­samples
and the settings examining personality alterations.
67
68 Dementia

Table 8.1 Aggression: samples studied and methods of data collection

Samples
Undifferentiated dementia Haider and Shah (2004), Shah et al. (2004, 2005), Hinton et al. (2008),
Koopmans et al. (2009), Truzzi et al. (2013), Whall et al. (2013)
Alzheimer’s disease Burns et al. (1990b, 1990f, 1990a), Devanand et al. (1992a), Lyketos et al.
(2001), Shah et al. (2005), Senanarong et al. (2005)
Vascular dementia Sultzer et al. (1993), Shah et al. (2005), Pinto and Seethalakshmi (2006)
Huntington’s chorea Burns et al. (1990a)

Methods of Data Collection

Case-notes Haider and Shah (2004)
Semi-structured telephone interview Devanand et al. (1992a)
Postal questionnaire directed at staff Lukovits and McDaniel (1992)
Postal questionnaire directed at informal carers Lukovits and McDaniel (1992)
Staff completed incident forms Shah (1995)
Informal staff reports Hallberg et al. (1993)
Staff completed specially designed forms Winger et al. (1987), Palmsteirna and Wistedt (1987)
Staff completed formal rating scales Koopmans et al. (2009), Whall et al. (2013)
Informal carers completed formal rating scales Ryden (1988)
Informal carers completed informal forms Onishi et al. (2006)
Semi-structured interviews Devanand et al. (1992b), Senanarong et al. (2005), Shah et al. (2004, 2005),
Pinto and Seethalakshmi (2006), Hinton et al. (2008), Truzzi et al. (2013)
Direct observations Hallberg et al. (1993)
Voice recordings Hallberg et al. (1990)
Mechanical body movements Rindlisbacher and Hopkins (1992)

Table 8.2 Psychometric and other properties Studies included a comparison group of normal aged
of instruments measuring BPSD in dementia individuals (Rubins et al., 1987a, 1987b; Petry et al.,
1988; Cummings et al., 1990; Dian et al., 1990; Jacoub
Patient characteristics
User characteristics
and Jorm, 1996; Rankin et al., 2005; Talassi et al., 2007),
Type of instruments
vascular dementia (Sultzer et al., 1993) and frontotem-
Setting for administration
poral dementia (Miller et al., 1997; Rankin et al., 2005)
Data source
and compared Alzheimer’s disease (AD) with norms for
Output of the instrument inpatients (Meins and Dammast, 2000). Comparison
Psychometric properties with premorbid personality and normal aged individuals
Reliability: allows identification of personality changes (Siegler et al.,
Test-retest 1991; Chatterjee et al., 1992) and exclusion of personality
Inter-rater changes due to ageing (Rubins et al., 1987a, 1987b; Petry
Internal consistency et al., 1988; Cummings et al., 1990; Dian et al., 1990;
Validity: Rankin et al., 2005; Talassi et al., 2007), respectively.
Face Difficulties in measuring the type, nature and severity of
Content personality change include: reduced insight; judgement
Concurrent and memory may preclude use of self-reports (Petry et al.,
Construct 1988; Meins and Dammast, 2000; Rankin et al., 2005),
Predictive particularly, in frontotemporal dementia (Rankin et al.,
Incremental 2005); collateral account from relatives may be biased due
Sensitivity to change to emotions involved in it (Dian et al., 1990; Jacoub et al.,
Spontaneous tendency to decline over serial measurements 1994; Meins and Dammast, 2000), personality of the rela-
Time frame for symptoms tive acting as the carer and carer burden (Welleford et al.,
Training needs 1995; Meins, 2000).
Methods of administration
Qualification of users 8.1.3.3 Measurement instruments
Acceptability to rates
Costs The items irritability and disinhibition on the Neuro­
Source: Adapted from Zaudig, M, International Psychogeriatrics, psychiatric Inventory (NPI) (Cummings et al., 1994) cou-
8, 183–200, 1996. pled with case-note review examined socially disruptive
 Measurement of behaviour disturbance, non-cognitive symptoms and quality of life 69

Table 8.3 Samples, settings and methods of data collection for personality alteration
Samples
Undifferentiated dementias Siegler et al. (1991), Balsis et al. (2005)
Vascular dementia Dian et al. (1990), Sultzer et al. (1993), O’Connor (2000)
Alzheimer’s disease Rubins et al. (1987a, 1987b), Petry et al. (1988, 1989), Bozzola et al. (1992),
Chatterjee et al. (1992), Sultzer et al. (1993), Jacoub and Jorm (1996), Meins
and Dammast (2000), Rankin et al. (2005), Talassi et al. (2007)
Frontotemporal dementia Miller et al. (1997), Rankin et al. (2005), Mendez et al. (2006)
Huntington’s chorea Kirkwood et al. (2002)

Settings
Community sample Nilsson (1983), Jacoub et al. (1994), O’Connor (2000)
Dementia centre Miller et al. (1997)
Memory clinic sample Meins and Dammast (2000)
Mixed group of psychogeriatric inpatients Pearson (1990, 1992)

Methods of Data Collection

Specially designed personality
questionnaires administered to
relatives
As above and an open interview
Specially designed personality
questionnaire administered to patients
Petry et al. (1988, 1989), Chaterjee et al. (1992), Dian et al. (1990), Siegel et al.
(1991), Bozzola et al. (1992), Jacoub et al. (1994), Jacoub and Jorm (1996),
Talassi et al. (2007), Balsis et al. (2005), Rankin et al. (2005)
Rubins et al. (1988a,b)
Nilsson (1983), Pearson (1990, 1992), Rankin et al. (2005)

and antisocial behaviour in AD and frontotemporal demen-
tia (Miller et al., 1997). The Brooks and McKinlay (1983)
personality inventory, used originally on patients who have
undergone a brain injury, was administered to relatives
of dementia sufferers (Petry et al., 1988, 1989; Cummings
et al., 1990; Talassi et al., 2007). The 11 personality items on
the Blessed Dementia Rating Scale (Blessed et al., 1968) were
alone used (Bozzola et al., 1992; Balsis et al., 2005) combined
with six open-ended questions (Rubins et al., 1987a, 1987b).
In psychiatric inpatients and day patients with organic
disorders, impulsiveness correlated with extraversion but
psychoticism was not noticed on the Eysenck Personality
Inventory (EPI) (Pearson, 1990, 1992). Subjects with mild–
moderate dementia and neurotic disorders scored high for
neuroticism on the EPI in a community sample (Nilsson,
1983). The premorbid trait of neuroticism in AD was associ-
ated with ‘troublesome behaviour’ (Meins et al., 1998).
8.1.3.4 Clinical features
Changes in personality features include: coarsening of
affect, disinhibition, increase in passivity, apathy, spon-
taneity, irritability, belligerence, demanding attention,
indifference, egocentricity, less conscientiousness, lower
extraversion, higher neuroticism and higher openness
(Seltzer and Sherwin, 1983; Ishii et al., 1986; Petry et al.,
1988, 1989; Cummings et al., 1990; Siegler et al., 1991;
Bozzola et al., 1992; Chatterjee et al., 1992; Welleford
et al., 1995; Jacoub and Jorm, 1996; Meins and Dammast,
2000). Patients with AD, compared with normal elderly
people, had greater changes on 12 personality traits by
being more out of touch, less self-reliant, less mature, less
enthusiastic, less stable, more unreasonable, more lifeless,
more unhappy, less affectionate, less kind, more irritable
and less generous after the onset of dementia (Petry et al.,
1988); similar results were observed in vascular demen-
tia (Dian et al., 1990). A significant shift from positive
to negative characteristics was observed after the onset
of AD in 12 out of the 18 adjectives forming the Brooks
and McKinlay Personality Inventory (Talassi et al., 2007).
Acquired extroversion has been reported to be associ-
ated with frontotemporal dementia (Mendez et al., 2006).
Forensic behaviours, like indecent exposure and shoplift-
ing were more common in frontotemporal dementia than
AD (Miller et al., 1997). A 3-year follow-up projects emerg-
ing of four patterns of personality alteration in AD: (1)
change at onset with little change as the disease progresses,
(2) ongoing change as the disease progresses, (3) no change
at all and (4) regression of previously altered personality
characteristics (Petry et al., 1989). Personality changes can
precede a clinical diagnosis of AD (Balsis et al., 2005) and
Huntington’s disease (Kirkwood et al., 2002).
8.1.3.5 Comment
The relationship between personality changes and BPSD
may be part of the same phenomena, aetiologically linked
or discrete entities. Several personality change features
listed above overlap with features of frontal lobe dysfunc-
tion (Dian et al., 1990) and depression (Sultzer et al., 1993).
Paucity of data on psychometric and other properties of
instruments measuring personality suggests the need for
rigorous evaluation of existing instruments (Strauss and
Pasupathi, 1994) and development of new instruments
70 Dementia
measuring personality features that are sensitive from the
premorbid to illness state and allow separation of personal-
ity changes due to ageing (Strauss et al., 1997); sadly, this has
not occurred so far.
8.1.4 DISORDERS OF MOOD
8.1.4.1 Definition
Depressed patients may have cognitive deficits and depres-
sion may precede the onset of dementia either as an early
presentation of incipient dementia or as a risk factor (Verhey
and Visser, 2000; Jorm, 2001; Korcyzn and Halperin, 2009).
Also, depressive symptoms and illness in dementia require
careful definition due to overlap of features such as per-
sonality changes and cognitive impairment, especially
frontal lobe dysfunction (Weiner et al., 1997) and apathy
(Starkstein et al., 2005).
8.1.4.2 Samples, settings and data
collection methods
Table 8.4 illustrates the diagnostic categories, settings and
methods of data collection. Despite an absence of ‘gold
standard’ diagnosis of depression in dementia (Verhey and
Table 8.4 Sample, settings and methods of data collection for disorders of mood
Samples
Undifferentiated dementia
Vascular dementia
Alzheimer’s disease
Settings
Community
Outpatient clinic
Nursing homes
Mixed settings
Acute and continuing care psychogeriatric wards
Methods of Data Collection
Self-rating scales
Interviewer-rated scales directed at patients
Interviewer-rated scales directed at carers
Combination of interviewer and observer rating
Combination of interview and collateral sources
Pure observer scales
Visser, 2000), instruments have been validated against def-
initions of depression according to Diagnostic and Statis­
tical Manual of Mental Disorders, Third Edition (DSM-III)
(Reifler et al., 1986; Cummings et al., 1987; MacKenzie
et al., 1989), Diagnostic and Statistical Manual of Mental
Disorders, Third Edition, Revised (DSM-IIIR) (Burns et al.,
1990e; Skoog, 1993; Weiner et al., 1997), Diagnostic and
Statistical Manual of Mental Disorders, Fourth Edition
(DSM-IV) (Brodaty and Luscombe, 1996), Research Dia­
gnostic Criteria (Alexopoulos et al., 1988) and Tenth
Revision of the International Classification of Diseases and
Related Health Problems (ICD-10) (Burns et al., 1990c).
8.1.4.3 Measurement instruments
Table 8.4 illustrates the self-rated and interviewer-rated
scales. Data on psychometric and other properties for
these instruments are gradually emerging (Korner et al.,
2006). They are generally less accurate as cognitive impair-
ment increases and insight decreases (Ott and Fogel,
1992) because good attention, concentration, memory and
judgement are required for their completion (Burke et al.,
1989) and the discrepancy between depression reported by
patients and carers increases in this context (Ott and Fogel,
1992; Cohen-Mansfield et al., 2013). Thus, instruments
using collateral sources of information (e.g. relatives or
Shah et al. (2004), Aalten et al. (2006)
Cummings et al. (1987), Brodaty and Luscombe (1996),
Shah et al. (2005)
Burns et al. (1990c), Lyketsos et al. (2001), Shah et al.
(2005), Lam et al. (2006), Debruyne et al. (2009)
Lyketsos et al. (2001), Shah et al. (2004, 2005)
Cummings et al. (1987), Brodaty and Luscombe (1996)
Brodaty et al. (2001)
Alexopoulos et al. (1988), Burns et al. (1990c)
Akoo and Shah (1998), Ellanchenny and Shah (2001)
Ott and Fogel (1992), Korner et al. (2006), Debruyne et al.
(2009)
Cummings et al. (1987), Ott and Fogel (1992), Brodaty and
Luscombe (1996)
Brodaty and Luscombe (1996), Shah et al. (2004, 2005),
Aalten et al. (2006), Lam et al. (2006), Debruyne et al.
(2009)
Sunderland et al. (1988), Ott and Fogel (1992)
Katona and Aldridge (1985), Alexopoulos et al. (1988),
Korner et al. (2006)
Shah and Gray (1997), Akoo and Shah (1998), Ellanchenny
and Shah (2001)
 Measurement of behaviour disturbance, non-cognitive symptoms and quality of life 71
nurses) to supplement clinical examination were developed:
Depressive Signs Scale (Katona and Aldridge, 1985), the
Cornell Scale (Alexopoulous et al., 1988) and the Depression
in Dementia Mood Scale (Sunderland et al., 1988). The
Cornell Scale has been used most widely (Shah et al., 2004,
2005; Aalten et al., 2006; Korner et al., 2006; Debruyne
et al., 2009). The Geriatric Depression Scale (GDS) has also
been proved to have good psychometric properties (Korner
et al., 2006).
8.1.4.4 Comment
The prevalence of depressive symptoms and illness in AD
was 0%–87% (median 41%) and 0%–86% (median 19%),
respectively (Wragg and Jeste, 1989; Verhey and Visser,
2000; Starkstein et al., 2005). This variability may be due
to: measurement instruments being insensitive in severe
dementia or those with severe dementia may not experi-
ence complex emotions like depression (Burns et al., 1990c);
depression in dementia may lack traditional clinical fea-
tures (Verhey and Visser, 2000) and depressive symptoms
may be transient (Ballard et al., 2001).
8.1.5 DISORDERS OF THOUGHT
CONTENT AND PERCEPTION
8.1.5.1 Definition and classification
The definitions of hallucinations and delusions in dementia
are the same as for other psychiatric disorders (Cummings
et al., 1987). Presence of at least 7 days is an added require-
ment to exclude delirium. Auditory (Cummings et al., 1987;
Burns et al., 1990e), visual (Cummings et al., 1987; Burns
et al., 1990e) and olfactory (Rubins and Kinscherf, 1989)
hallucinations have been studied. Delusions were then
divided in four groups: (1) simple persecutory, (2) complex
persecutory, (3) grandiose and (4) those associated with spe-
cific neurological deficits (Cummings, 1985). Another clas-
sification for delusions was delusions of theft, delusions of
suspicion and systematized delusions (Burns et al., 1990d).
There are four types of misidentifications: (1) people in the
house, (2) misidentification of mirror images, (3) misiden-
tification of television and (4) misidentification of people
outside the house (Burns et al., 1990e).
8.1.5.2 Samples, settings, data collection
methods and measurement
instruments
Table 8.5 illustrates the samples, settings, methods of data
collection and instruments used to measure psychotic
symptoms. Several semi-structured interviews and spe-
cially designed forms measure psychotic symptoms along
with several other BPSD, thus producing diluted data on
pure psychotic features (Ballard et al., 1995).
8.1.5.3 Comment
The prevalence of delusions (Cummings et al., 1987; Burns
et al., 1990d; Selbeck et al., 2014), hallucinations (Burns
et al., 1990e; Ballard et al., 1995) in AD and vascular
dementia range from 20% to 50%, 17% to 36%; 11% to 34%,
respectively. The boundaries between hallucinations, delu-
sions and misidentification syndromes are often blurred
(Whitehouse et al., 1996) and delusions are difficult to dif-
ferentiate from confabulations (Cummings et al., 1987). The
definitions and descriptions of the psychopathology require
refinement and clarity (Trabucchi and Bianchetti, 1996).
For example, professional caregivers and family caregiv-
ers may give different information to complete the whole
picture of delusions and hallucinations (Cohen-Mansfeild
et al., 2013) and symptoms keep changing with the pas-
sage of time (Selbaek et al., 2014). A systematized checklist
containing 17 categories of psychotic symptoms is the only
pure instrument designed to measure psychotic features,
but poorly evaluated (Ballard et al., 1995). Psychometric
and other properties of instruments measuring psychotic
symptoms have been poorly studied and require rigorous
evaluation. Clinicians will generally treat psychotic symp-
toms in dementia only if the patient is distressed or if there
is risk of harm to others or self, but none of the extant
instruments measure these facets and such instruments
need to be developed.
8.1.6 A WAY FORWARD
Research should be directed at comparing different instru-
ments measuring the same BPSD domain with each other,
generating data on all of their properties, refining these
instruments to improve their properties, adapting them
for use in different settings, different dementia diagnos-
tics groups, different severities of cognitive impairment
and by introducing different types of raters to enable data
collection in a comparable common currency, as well as
develop guidelines and protocols for their use in research
and clinical practice (Shah and Allen, 1999); this would be
the beginning of a revolution which is yet to happen (Whall
et al., 2013). This, in turn, would facilitate examination of
the interrelationship between individual BPSD symptoms
within and across different BPSD domains (Van Der Linde
et al., 2014). This is also beginning to happen with uni-
variate analysis (Brodaty et al., 2001), latent class analysis
(Lyketsos et al., 2001; Lam et al., 2006) and factor analysis
(Hope et al., 1997; Dechamps et al., 2008; Youn et al., 2008;
Savva et al., 2009; Truzzi et al., 2013). Ultimately, such anal-
ysis will allow identification of the nosological validity of
the empirically derived five BPSD domains by establishing
symptom and syndrome clusters (Lyketsos et al., 2001; Lam
et al., 2006) and, in turn, facilitate a greater understanding
of the demographic, clinical, genetic, biochemical, neuro-
physiological and neuroanatomical correlates of BPSD and
their longitudinal course and prognosis; this too is in the
beginning stages (Trzepacz et al., 2013).
72 Dementia

Table 8.5 Samples, settings, methods of data collection and instruments used to measure psychotic symptoms
Setting
All nursing home residents Brodaty et al. (2001)
Undifferentiated dementia Haider and Shah (2004), Shah et al. (2004), Aalten et al. (2006), Onishi et al.
(2006), Hinton et al. (2008), Dechamps et al. (2008), Koopmans et al. (2009)
Vascular dementia Cummings et al. (1987), Shah et al. (2005), Hsieh et al. (2009)
Lewy body dementia Ballard et al. (1995)
Alzheimer’s disease Cummings et al. (1987), Burns et al. (1990d, 1990e), Lyketsos et al. (2001), Shah
et al. (2005), Lam et al. (2006), Pinto and Seethalaskmi (2006), Hancock and
Lavner (2008), Hsieh et al. (2009)
Fronto-temporal dementia Hancock and Lavner (2008)

Setting
Community Skoog (1993), Lyketsos et al. (2001), Aalten et al. (2006), Hinton et al. (2008)
Memory clinic Ballard et al. (1995), Hancock and Lavner (2008)
Outpatient clinic Cummings et al. (1987), Lam et al. (2006)
Referrals to psychogeriatric service Ballard et al. (1995), Shah et al. (2004, 2005)
Day hospital Haider and Shah (2004)
Inpatients Trabucchi and Bianchette (1996)
Nursing homes Brodaty et al. (2001), Onishi et al. (2006), Hinton et al. (2008), Dechamps et al.
(2008), Koopmans et al. (2009)
Continuing care Onishi et al. (2006)
Group homes Onishi et al. (2006)
Mixed Burns et al. (1990d, 1990e), Whitehouse et al. (1996), Pinto and Seethalaskmi (2006)

Methods of Data Collection

Patient interview Cummings et al. (1987)
Interview with caregiver Shah et al. (2004, 2005), Aalten et al. (2006), Lam et al. (2006), Pinto and
Seethalaskmi (2006), Hinton et al. (2008), Dechamps et al. (2008), Koopmans
et al. (2009)
Formal scales completed by caregivers Hancock and Lavner (2008)
Unvalidated scales completed by Onisihi et al. (2006)
caregivers
Case-notes Cummings et al. (1987), Haider and Shah (2004)

More recently, a narrower concept, health-related quality of

8.2 QUALITY OF LIFE life (HRQoL) has emerged. HRQoL has been defined as ‘the
individual’s subjective perception of the impact of a health
8.2.1 DEFINITION OF QUALITY OF LIFE condition on life’ (Smith et al., 2003; Banerjee et al., 2002).

There are several definitions of quality of life (QoL) and
sometimes it is not defined (Lawton, 1997). The best defini-
tion is that from the World Health Organization (WHO):
‘individuals perception of their position in life in the con-
text of the culture and value system in which they live, and
in relation to their goals, expectations, standards and con-
cerns’ (WHOQOL Group, 1995).
QoL is a multidimensional construct that includes the
subjective experience of the patient in addition to objective
criteria (Lawton, 1994; Ettema et al., 2005). Lawton (1991)
described QoL as a multidimensional construct that should
include objective (observable) indices of well-being, judged
against socio-normative criteria, in addition to the individ-
ual’s own subjective perception of his or her position in life.
8.2.2 MEASUREMENT OF QOL AND
MEASUREMENT INSTRUMENTS
The measurement of QoL in dementia poses unique chal-
lenges. Impairments in memory, language and judgement
can interfere with the self-evaluation of dementia, partic-
ularly in the later advanced stages of the disease. The lack
of a universally accepted definition of QoL or a ‘gold stan-
dard’ measure of QoL raises important questions about the
validity of available measures (Shah et al., 2005). Concerns,
such as these, have led to questions such as, whether instru-
ments to measure QoL in dementia should be self-rating,
proxy-rating or a combination of both (Banerjee et al., 2002;
Smith et al., 2003; Davies et al., 2014; Moyle et al., 2014).
 Measurement of behaviour disturbance, non-cognitive symptoms and quality of life 73

Proxy measures by informal or professional carers may be
necessary in severe dementia when patients have poor com-
prehension and communication skills (Smith et al., 2007;
Davies et al., 2014; Moyle et al., 2014).
Generic and dementia-specific instruments have been
used to measure QoL in dementia. Generic measures allow
for comparisons with other diseases, but the use of demen-
tia-specific measures of QoL have been favoured because
the symptoms of dementia are very different from those of
other disorders (Rabins and Kasper, 1997; Selai et al., 2001).
Selected instruments for measuring QoL in dementia are
illustrated in Table 8.6.
8.2.3 COMMENT
The measurement of QoL in dementia poses unique chal-
lenges. Impaired judgement, reduced insight, cognitive
impairment, personality changes, affective and psychotic
symptoms, physical morbidity and temporary fluctuations
make the subjective assessment of QoL difficult. However,
the measurement of QoL is beneficial in the screening and
monitoring of psychosocial problems in individual patients,
population surveys of perceived health problems, clinical
audit, measuring outcome in health service and evaluation
research, clinical trials and in cost-utility analysis (CUA).
Future research efforts should focus on: developing an
agreed definition of QoL in dementia with operational crite-
ria; developing (existing) instruments that have robust psy-
chometric data that are valid, reliable, sensitive to change
and can be used across various care settings and with differ-
ent levels of severity in dementia. This is beginning to hap-
pen including: impact of grief (Shuter et al., 2013) and other
features of dementia (Bosboom and Almeida, 2014), refine-
ment of psychometric properties (Cooke and Chaudhury,
2013; Mjorud et al., 2014; Papastavrou et al., 2014), exami-
nation of the QoL towards the end-of-life in the palliative

Table 8.6 Quality of life scales in dementia

Scale Severity Respondent
Alzheimer’s Disease-Related Quality of Life (ADQRL) Mild to severe Caregivers
Rabins et al. (1999)
Bath Assessment of Subjective Quality of Life in Dementia Mild to moderate Patients
(BASQID)
Trigg et al. (2007)
Cornell-Brown Scale for Quality of Life in dementia (CBS-QoLD) Mild to moderate Clinician with carer and
Ready et al. (2002) patient input

Cognitively Impaired Life Quality Scale (CILQ) DeLetter et al. Severe Nursing caregivers
(1995)
Dementia Care Mapping (DCM) Kitwood and Bredin (1994) Moderate to severe Trained rater

Dementia Quality of Life (DQoL) instrument Mild to moderate Patients

Brod et al. (1999)
Developing a method to measurethe quality of life in family Mild to moderate Proxy and patient
carers of people with dementia (DEMQOL) (Smith et al., 2007)
The Pleasant Events Schedule ‒ AD (PES-AD) (Logsdon and Teri, Mild Proxy and patient
1997)
Progressive Deterioration Scale (PDS) (De Jong et al., 1989) Mild to severe Proxy

Psychological Well-being in Cognitively Impaired Persons Severe Proxy

(PWB-CIP) (Burgener and Twigg, 2002)
Quality of Life Assessment Schedule (QoLAS) (Selai et al., 2001) Mild to moderate Patient and proxy

Quality of Life in Late-Stage Dementia (QUALID) (Weiner et al., Severe Proxy

2000)
A dementia specific QoL questionnaire rated by professionals Mild to moderate Professional caregiver
that can be applied in residential care: QUALIDEM (Ettema
et al., 2007)
Source: Adapted from Black, B.S. and Rabins, P.V., Dementia, Arnold Hodder, London, 2005.
74 Dementia
care context (Crowthers et al., 2013; Kumar and Kuriakose,
2013; Davies et al., 2014) and development of models for
quality of life adjusted to years based on functional impair-
ment (Kasai and Megura, 2013), which could be used in
cost-utility analysis.
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Cross-cultural issues in the assessment of
cognitive impairment
AJIT SHAH
9.1 INTRODUCTION
Cross-cultural studies comparing two or more ethnic
groups in one country and those comparing populations
across two or more countries will be discussed with partic-
ular reference to methodology, measurement instruments,
aetiology, protective and risk factors.
9.2 INTERNATIONAL DEMOGRAPHIC
CHANGES AND THEIR
IMPLICATIONS
The size of the elderly population is increasing worldwide
because of increase in life expectancy and fall in the birth
rates (Oeppen and Vaupel, 2002; Shah and MacKenzie, 2007)
and there is an increase in 80-year-olds (Jeune and Skythe,
2001; Shah, 2007a). The prevalence of dementia doubles every
5.1 years after the age of 60 (Hofman et al., 1991). Thus, with
the increase in the elderly population, the absolute number
of dementia cases will also increase worldwide.
9.3 DIAGNOSTIC ISSUES
Cognitive tests standardized in one cultural group may not
be appropriate for another because they are influenced by cul-
ture, education, language, literacy, numeracy, sensory impair-
ment, unfamiliarity with test situations and anxiety (Chandra
et al., 1994; Lindesay et al., 1997; Lindesay, 1998; Stewart et al.,
2003; Prince et al., 2003, 2004; Crane et al., 2006; Inzelberg
et al., 2007; Jacob et al., 2007; Kalaria et al., 2008; Gagnon
et al., 2013; Khan and Tadros, 2013; Choi et al., 2014).
9
Education can influence performance on cognitive tests
(Choi et al., 2014), including the mini-mental state examina-
tion (MMSE) (Folstein et al., 1975). The Chinese MMSE has
developed different cut-off scores predicting dementia for
different educational levels of respondents with good speci-
ficity and sensitivity (Katzman et al., 1988; Zhang et al.,
1990; Sahadevan et al., 2000); this has also been suggested
for other cultural groups (Murden et al., 1991; Gurland et al.,
1992) and for different cognitive measurement instruments
(Gagnon et al., 2013), but may reduce sensitivity (Gagnon
et al., 2013). Illiterate subjects may be unable to complete
tests which require reading, writing and drawing (Katzman
et al., 1988; Chandra et al., 1994; Rajkumar and Kumar, 1996)
and illiteracy may reduce access to information related to
orientation in time and general knowledge (Lindesay, 1998;
Khan and Tadros, 2013). Innumerate subjects may be unable
to perform tests involving calculations (Chandra et al., 1994;
Livingston and Sembhi, 2003). Subjects with lower levels of
education may have difficulties in understanding the nature
of the test and may feel that the questions are irrelevant and
of little practical value (Chandra et al., 1994; Bhatnagar and
Frank, 1997; Khan and Tadros, 2013).
Tests identifying the discrepancy between age and date
of birth (Bhatnagar and Frank, 1997; McCrakken et al.,
1997) may disadvantage those born in remote villages
with poor birth registration facilities and those who have
altered age and date of birth to facilitate migration and
entry into various institutions (Rait et al., 1997). Culture-
specific questions (e.g. about monarchy or politicians) also
disadvantage ethnic minority elders (Bhatnagar and Frank,
1997; McCrakken et al., 1997), although these can be modi-
fied (e.g. date of independence of the country of origin)
(Chandra et al., 1994; Rait et al., 1997). Cultural concepts of
orientation in time and place (Ganguli et al., 1995; Lindesay
et al., 1997) and preferential use of western or traditional
calendars (Kua, 1992; Lindesay et al., 1997; Rait et al., 1997)
79
80 Dementia
can also influence performance. Orientation items work
well within the dominant culture but less so in some ethnic
minority groups (Rait et al., 1997; Livingston and Sembhi,
2003); this was the case noted among Singapore Chinese
population (Kua, 1992), but not among Liverpool Chinese
(McCrakken et al., 1997).
9.4 MEASUREMENT INSTRUMENTS
Several instruments measuring cognitive impairment have
been developed by adapting existing instruments (mostly
those developed in England) by either using a Delphi panel
of experts from the culture of interest or more widespread
consultation within the culture of interest, translation and
back-translation by separate groups of bilingual translators
and iterative field pretesting to ensure content, semantic,
technical, criterion and conceptual equivalence with the
parent version of the instrument for each item (Chandra
et al., 1994; Shah et al., 2005b). The aim is to produce a
culture-fair, education-free and analogous instrument. This
should be followed by pilot testing to determine the distri-
bution of the scores and the ability to discriminate between
dementias with various levels of severity (Chandra et al.,
1994; Gagnon et al., 2013). Clear validation against a gold
standard diagnosis of dementia is also required, together
with determination of various psychometric properties
(Livingston and Sembhi, 2003; Shah et al., 2005b). Ideally,
the psychometric profile of the newly developed instrument
should be similar to or better than the parent version.
The MMSE has been developed in several languages
including Arabic (Inzelberg et al., 2007), Chinese (Serby
et al., 1987; Katzman et al., 1988; Salmon et al., 1989; Yu
et al., 1989; Xu et al., 2003), Korean (Park and Kwon, 1990;
Park et al., 1991), Finnish (Salmon et al., 1989), Italian (Rocca
et al., 1990), Yoruba (Hendrie, 1992), Spanish (Escobar et al.,
1986; Anzola-Perez et al., 1996), Thai (Phanthumchinda
et al., 1991), Hindi (Ganguli et al., 1995; Rait et al., 2000a),
Punjabi (Rait et al., 2000a), Urdu (Rait et al., 2000a), Bengali
(Kabir and Herlitz, 2000; Rait et al., 2000a), Malyalam
(Shaji et al., 1996), Gujarati (Lindesay et al., 1997; Rait et al.,
2000a) and Sinhalese (De Silva and Gunatilake, 2002).
Comparisons between these different versions are problem-
atic because not all have been developed using rigorous pro-
cedures and/or a satisfactory psychometric evaluation.
The abbreviated Mental Test Score (Quereshi and
Hodkinson, 1974) has been developed in several south
Asian languages and have been put to use among African
Caribbean population in the United Kingdom (Rait et al.,
1997, 2000a, 2000b). A Korean version of the Alzheimer’s
Disease Assessment Scale (ADAS) (Rosen et al., 1984) has
been developed (Youn et al., 2002). The MMSE, selected items
of the Consortium to Establish a Registry for Alzheimer’s
Disease (CERAD), a neurospychological test battery (Morris
et al., 1989) and The Cambridge Cognitive Examination
(CAMCOG) component of the Cambridge Examination
for Mental Disorders of the Elderly (CAMDEX) interview
schedule (Roth et al., 1986) have all been evaluated among
elderly members of the African Caribbean group in the
United Kingdom (Richards and Brayne, 1996; Richards
et al., 2000). In this population, normative data is available
for the orientation items of the MMSE, selected items of
the CERAD neurospychological test battery and the clock
drawing test (Stewart et al., 2001a). The 10-word learning
test from the CERAD battery has been proved successful in
establishing a diagnosis of dementia study among popula-
tions in India, China, Southeast Asia, Latin America and
the Caribbean (Prince et al., 2003). The Alzheimer’s Disease
Questionnaire (Breitner and Folstein, 1984) which gathers
information on history of cognitive impairment among
first degree relatives, has been translated into Chinese and
Spanish and has been administered by bilingual workers
(Silverman et al., 1992). The Informant Questionnaire on
Cognitive Decline in the Elderly (IQCODE) (Jorm et al.,
1991) has been developed for use among illiterate Chinese
population (Fuh et al., 1995). A dementia screening instru-
ment, the Community Screening Interview for Dementia
(CSI-D), a cognitive test for subjects and an informant
interview has been developed for use among Cree Indians
in Canada (Hendrie et al., 1993; Hall et al., 2000), English-
speaking Canadians (Hendrie et al., 1993; Hall et al., 2000)
and Yoruba Nigerians in Ibadan (Hendrie et al., 1995b;
Hall et al., 2000), Jamaicans (Hall et al., 2000), African
Americans in Indianapolis (Hall et al., 2000), Koreans
(Liu et al., 2005) and in study populations in India, China,
Southeast Asia, Latin America and the Caribbean (Prince
et al., 2003), with good psychometric properties. The Chula
Mental Test, developed for use in Thailand by selecting and
adapting items from several existing screening tests, has
been found to reduce the influence of literacy on scores
(Jitapunkul et al., 1996). A Spanish (for use among Mexican
Americans) (Royall et al., 2003) and Brazilian Portuguese
version (Fuzikawa et al., 2003, 2007) of the clock drawing
test have been evaluated; both these versions were reported
to aim at being education-free instruments. A clock reading
test, developed in Germany, has been reported to be reli-
able and sensitive in detecting Alzheimer’s disease (AD)
and Lewy body dementia (Schmidtke and Olbrich, 2007). A
cognitive assessment instrument, the Kimberely Cognitive
Assessment Tool, has been developed for indigenous
Australians and has good psychometric properties, includ-
ing good sensitivity and specificity in detecting dementia
(LoGuidice et al., 2006).
A unique approach involving use of three instruments,
the Geriatric Mental State examination (GMS) (Copeland
et al., 1976), the Community Screening Interview for
Dementia (CIS-D) and the 10-word list-learning task from
the CERAD battery appropriately translated into native lan-
guages and an algorithm derived from these instruments
have been shown to have high sensitivity and specificity in
the diagnosis of dementia in culturally diverse populations
 Cross-cultural issues in the assessment of cognitive impairment 81
like India, Iran, China, Southeast Asia, Africa, Latin
America and the Caribbean (Prince et al., 2003, 2008).
9.5 THE DIFFERENTIAL PREVALENCE
AND INCIDENCE OF DEMENTIA
SUBTYPES
Published studies of the prevalence of dementia in UK eth-
nic minority groups generally do not report on the relative
prevalence of individual subtypes of dementia (Bhatnagar
and Frank, 1997; Lindesay et al., 1997; McCrakken et al.,
1997; Livingston et al., 2001). Anecdotally, it is believed that
vascular dementia (VaD) may be more common than AD
among elders in the Indian subcontinent (Bhatnagar and
Frank, 1997) and African Caribbean population (Richards
et al., 2000; Livingston et al., 2001; Stewart et al., 2001a;
Livingston and Sembhi, 2003); one study demonstrated this
in the UK African Caribbean population (Stevens et al.,
2004). In the United Kingdom some risk factors for VaD are
more prevalent among the ethnic groups than in the indig-
enous population, such as diabetes in Asians (Mather and
Keen, 1985; Samantha et al., 1987) and hypertension as well
as cardiovascular diseases in Asians and African Caribbean
population (Balarajan, 1996; Ritch et al., 1996; Taylor et al.,
2013). Native Americans with AD in the United States are
reported to have a higher prevalence of cardiovascular risk
factors including diabetes, hypertension and heart disease
than white Americans (Weiner et al., 2003).
The prevalence of dementia in ethnic minority groups
in other countries is also variable. A study of Chinese resi-
dents in U.S. nursing homes reported a prevalence of 95%
dementia patients with the ratio of VaD to AD estimated
as 4.4 to 1 (Serby et al., 1987), but there was no indigenous
group with which this study could be compared. Studies
in the United States have reported a higher prevalence of
dementia in African Americans (Still et al., 1990; Heyman
et al., 1991; Perkins et al., 1997) and Hispanics (Perkins
et al., 1997) than in white Americans, although this was not
found in a study conducted on severe dementia in African
Americans (Schoenberg et al., 1985). African Americans and
Latinos had significantly higher prevalence and incidence
of dementia than non-Latino white Americans (Gurland
et al., 1995, 1999), but these ethnic differences disappeared
after applying background controls for age and educational
attainment. Also, there was no difference between the three
groups selected for studying individual subtypes of demen-
tia. Another study reported a higher prevalence of VaD
coupled with higher prevalence of strokes and hypertension
among African Americans (Heyman et al., 1991; Perkins
et al., 1997).
A U.S. study, using an informant risk questionnaire
(Alzheimer’s Disease Risk Questionnaire) administered to
non-demented elderly day-care centre attenders, reported
a significantly increased risk of dementia in first degree
relatives of Jews and Italians compared to Chinese and
Puerto Ricans (Silverman et al., 1992). This raises the issue of
discrepant environmental exposure, as the first two groups
had migrated to the United States significantly earlier.
In a Canadian study, the prevalence of all dementias and
AD was 4.2% and 0.5%, respectively, in Cree Indians and
4.2% and 3.5%, respectively, in English-speaking Canadians
(Hall et al., 1993). An Israeli study of presenile AD, using
hospital discharge diagnosis as a proxy for incidence rates,
reported age- and sex-adjusted incidence rates to be higher
in European and American Jews than those from Asia or
Africa (Treves et al., 1986), raising the possibility of both
environmental and genetic risk factors. Pollitt (1997), quot-
ing Zann (1994), reported that the prevalence of dementia in
Aborigines in Northern Queensland was 20%, with alcohol-
related dementia accounting for majority of the cases.
A recent review of developing countries reported that
the age-adjusted prevalence of dementia in 65-year-olds
and above was consistently low in India and sub-­Saharan
Africa, although it was high in some Asian and Latin
American countries (Kalaria et al., 2008). Although, the
rates are variable, the overall report shows low prevalence
of dementia in Asian and African countries. Similar find-
ings were observed in the 10/66 Dementia Research Group
study when the DSM-IV diagnosis was used, but the preva-
lence rates were more consistent across countries when the
10/66 dementia algorithm and diagnosis was used (Llibre
Rodriguez et al., 2008). Almost universally, the prevalence
of dementia increases with age and generally it is more
common in women. A meta-analysis of the world literature
reported that the incidence of VaD and AD exponentially
increases with age (Jorm and Jolley, 1998). Eastern coun-
tries had a lower incidence of AD, but there was no differ-
ence in the incidence of VaD between European and eastern
countries (Jorm and Jolley, 1998). The prevalence of AD is
generally lower in Japan and China (Hasegawa et al., 1986;
Shibayama et al., 1986; Li et al., 1989, 1991) and that of VaD
generally higher (Hasegawa et al., 1986; Shibayama et al.,
1986; Li et al., 1989), although the ratio of the prevalence of
AD to VaD is increasing in these countries (Fujishima and
Kiyohara, 2002; Li et al., 2007) with the passage of time. The
10/66 incidence studies, using similar methodology across
all studied countries and when using the less controversial
DSM IV diagnosis of dementia, reported low incidence for
dementia in several Latin American countries and China
(Prince et al., 2012).
The variable prevalence rates for dementia and its sub-
types across different ethnic groups in a single country
and across different countries may be due to methodologi-
cal issues including: the sensitivity of screening instru-
ments and case-finding methods (Osuntokun et al., 1992;
Hall et al., 1993; Prince et al., 2003); diagnostic criteria
(Osuntokun et al., 1992; Hall et al., 1993; Prince et al., 2003;
Llibre Rodriguez et al., 2008; Prince et al. 2012); sampling
frames and procedures (Osuntokun et al., 1992); screen-
ing personnel (Hall et al., 1993) and interrater reliability
82 Dementia
(Osuntokun et al., 1992); age and demographic character-
istics of study populations (Osuntokun et al., 1992); educa-
tional attainment and literacy (Hall et al., 1993; Prince et al.,
2003) and cultural factors (Shah et al., 2005b).
9.6 GENETIC AND ENVIRONMENTAL
INFLUENCES
If the differences in the prevalence and incidence persist
after overcoming the methodological issues, then cross-
cultural studies have the potential to allow investigation
concerning the underlying genetic and environmental
risks, protective factors and the interaction between them
(Amaducci et al., 1991; Osuntokun et al., 1992; Hall et al.,
1993). If the risk of dementia was solely due to genetic factors
then migrants would share the same incidence as in their
country of origin (Graves et al., 1994). Thus, comparison
of the incidences faced by same ethnic groups in different
communities, at different stages of socio-economic devel-
opment and differing environments, while maintaining
genetic homogeneity, may allow identification of environ-
mental risk factors (Graves et al., 1994). To meet this end,
cross-cultural incidence and prevalence studies designed to
overcome the methodological difficulties, using screening
and diagnostic instruments that are culture-fair, education-
free and analogous instruments with similar case-finding
methods in age- and sex-stratified samples have emerged
(Prince et al., 2003; Llibre Rodriguez et al., 2008; Prince
et al., 2012).
9.6.1 ENVIRONMENT
Despite comparable overall rates of dementia in Japan
and the United States, the prevalence of VaD is highest in
Japan, intermediate in Hawaii and the lowest in mainland
United States, with an opposite trend observed in the rates
of AD (Graves et al., 1994). The prevalence of AD among
Japanese Americans in Washington (Graves et al., 1996)
and Honolulu (White et al., 1996) is closer to the num-
bers found in white American population than Japanese
population in Japan, suggesting an environmental aetiol-
ogy. A prospective cohort study of Japanese Americans
reported that those who led a traditional Japanese lifestyle
had a slower decline in cognition over 2 years (Graves et al.,
1999), also suggesting the importance of environmental fac-
tors. Additionally, the lower prevalence of cardiovascular
disease among Japanese Americans may also explain slower
rates of cognitive decline (Graves et al., 1999). Furthermore,
increasing physical activity was associated with lower rates
of dementia in the same Japanese American cohort (Taafe
et al., 2008). However, a study of first-generation Japanese
migrants from Miyagi prefecture to Brazil (Meguro et al.,
2001a) reported a similar prevalence of dementia, VaD and
AD to that in Miyagi prefecture in Japan (Ishii et al., 1999),
despite the migrants having a higher prevalence of diabetes
mellitus and cerebrovascular disease (Meguro et al., 2001b).
The authors have posited that the prevalence of dementia
was not affected by environmental factors because environ-
mental effects may take considerable time to emerge, per-
haps showing symptoms in subsequent generations.
The Indo-U.S. cross-national study reported a prevalence
of 0.84% of all dementias among rural Indians near Delhi,
a significantly lower figure than a community sample in
Pennsylvania (Chandra et al., 1998). An incidence study in
the same geographical area reported one of the lowest inci-
dences for AD in the world (Chandra et al., 2001). A study of
Singapore Malays and Chinese reported a higher prevalence
of dementia among Malays than Chinese (Kua and Ko,
1995); the difference was mainly accounted for by a higher
prevalence of multi-infarct dementia in Malay women
compared with Malay men and Chinese women. A preva-
lence and incidence study comparing rates among Yoruba
Nigerians in Ibadan and African Americans in Indianapolis
reported lower prevalence and incidence rates for dementia
and AD among the Nigerians (Hendrie et al., 1995a, 2001),
again suggesting the importance of environmental aetio-
logical factors. The 10/66 cross-national study using similar
methodologies across different countries reported relatively
low incidence of dementia in Latin American countries and
China when using DSM-IV criteria (Prince et al., 2012).
9.6.2 GENETICS
An early pilot population-based prevalence study reported
a strong association between Apo lipoprotein E (ApoE)
∈4 allele and AD in African Americans (Hendrie et al.,
1995b) suggesting that ApoE ∈4 is a risk factor independent
of ethnicity. However, this was not observed in Nigerians
(Osuntokun et al., 1995; Gureje et al., 2006), Kenyans (Chen
et al., 2009) and Cubans of African ancestry (Teruel et al.,
2011), despite a high prevalence of ∈4 allele in the commu-
nity in these groups; in the Cuban population sample the
effect of the ApoE ∈4 allele was attenuated (Teruel et al.,
2011). Similarly, the prevalence of ApoE ∈4 allele is higher
in AD in those people form North America and Northern
Europe and lower in those from Asian, Southern European
and Mediterranean countries (Crean et al., 2011). This dis-
crepancy may be explained by differences in the expres-
sion of ApoE alleles or of ApoE receptors, interaction with
unidentified modifier genes or environmental factors inter-
acting with genes. Furthermore, there was lower deposition
of A4 β-amyloid found in post-mortem brains of Nigerian
subjects without dementia compared with a similar series
from Australia (Osuntokun et al., 1994). Additionally, ApoE
∈4 alleles may have a differential effect on different types of
memory in different ethnic groups (Barnes et al., 2013); the
presence of this allele predicted greater decline in seman-
tic and working memories in whites compared with blacks.
These observations may help to explain a lower prevalence
and incidence of AD in Nigeria.
A strong association between ApoE ∈4 homozygous
status and AD has been observed among Caucasians
 Cross-cultural issues in the assessment of cognitive impairment 83
(non-Hispanic white Americans), African Americans and
Hispanics in population-based prevalence studies in the
United States (Maestre et al., 1995; Tang et al., 1996; Sahota
et al., 1997); despite these associations, the relative risk of
developing AD was found to be the highest in Caucasians
compared to the other two groups suggesting a gene–­
environment interaction. However, when considering het-
erozygous ApoE ∈4 status, this relation was either weaker
(Maestre et al., 1995) or absent in African Americans
(Tang et al., 1996; Sahota et al., 1997) in comparison with
Caucasians and Hispanics. A similar weak association was
found between ApoE ∈4 status and cognitive impairment
in African Caribbean population in the United Kingdom
(Stewart et al., 2001c) and Cubans of African ancestry.
The presence of depressive symptoms and ApoE ∈4 allele
markedly increased the risk of dementia, including AD, in
Japanese American men (Irie et al., 2008).
A population-based incidence study, with controlling
apparatus for education, family history of AD and other risk
factors like hypertension, demonstrated a strong association
between combined homozygous and heterozygous ApoE ∈4
status and AD in white Americans, African Americans and
Hispanics in the United States (Tang et al., 1998); Japanese
(Ohara et al., 2011), Tunisian (Rassas et al., 2012) and Indian
(Bharath et al., 2010) studies with regard to controls applied
to similar variables, demonstrated a strong link between
ApoE ∈4 allele and AD. Furthermore, in the presence of
at least one ApoE ∈4 allele, the cumulative risk of develop-
ing AD up to the age of 90 years was higher in the African
American and Hispanic groups compared with the white
American group, although a Norwegian study reported
that the effect of ApoE ∈4 on AD becomes weaker with
increase in age (Sando et al., 2008a). These observations col-
lectively suggest that the effect of ApoE ∈4 on AD is weaker
and ‘dose dependent’ in African Americans compared with
white Americans and to a lesser extent Hispanics. Moreover,
a Cuban study demonstrated high prevalence of ApoE ∈4
alleles in those with a strong influence of African ancestry,
but the effect of this allele were attenuated (Teruel et al., 2011).
It is possible that the presence of other environmental factors
or modifier genes may reduce the ApoE ∈4–­associated risk
of developing AD in African Americans (Sahota et al., 1997;
Tang et al., 1998). These environmental factors or modifier
genes may be able to alter the risk of one dose of ApoE ∈4
more easily than two doses (Maestre et al., 1995).
Another explanation for these findings is that there may
be differential linkage disequilibrium between unidentified
AD susceptibility gene and ApoE ∈4 alleles in different eth-
nic groups (Maestre et al., 1995). A further explanation is the
differential survival of those with ApoE ∈4 alleles, although
this observation is not supported by reports that ApoE ∈4 in
white subjects is unchanged with age (Maestre et al., 1995;
Tang et al., 1996) and either unchanged (Tang et al., 1996) or
increased (Maestre et al., 1995) with age in African Americans.
Also, the frequency of ApoE ∈4 in AD in whites and African
Americans is reported to decline (Maestre et al., 1995) or
remain unchanged (Tang et al., 1996) with age. However,
despite a decline in ApoE ∈4 frequency in AD with increase in
age, other genetic and environmental factors may increase the
risk of developing AD in African Americans and Hispanics
in the absence of this allele (Tang et al., 1998). A population-
based incidence study of Japanese American men reported
a significant association between ApoE ∈4 and AD (Havlik
et al., 2000). Also, ApoE ∈4 was found to be a risk factor for
AD in women but not men in Venezuela suggesting that gen-
der may also be an important factor (Molero et al., 2001).
Chandra and Pandav (1998) have speculated that high
serum cholesterol levels may interact with ApoE ∈4 alleles
to produce AD based on evidence of low serum cholesterol
levels in rural Indians and a low prevalence of AD (Chandra
et al., 1998). Moreover, low serum levels of cholesterol was
observed at least 15 years before the onset of dementia, par-
ticularly in AD and subsequently remained low in Japanese
American men and was suggested to be associated with
early stages in the development of dementia (Stewart et al.,
2007). However, the Indian observations were not supported
by the ApoE type in the same population-based Indo-U.S.
prevalence study, where the frequency of ApoE ∈4 was sig-
nificantly lower in the Indian sample than in the U.S. sample
and the strength of association between ApoE ∈4 and AD
was same in both samples (Ganguli et al., 2000). These find-
ings collectively may derive one explanation because one of
the lowest prevalence and incidence rates for AD in the world
is the Indian sample (Chandra et al., 1998, 2001). The authors
concluded that the different prevalence in the two samples
cannot be explained by differential risk or modifier risk fac-
tors pertaining to ApoE polymorphism and they speculated
that there may be additional risk or protective factors, sur-
vival effects or contributory environmental factors.
In a convenience sample of Cherokee Indians in Texas
(United States), the risk of developing AD declined with an
increase in the genetic degree of Cherokee ancestry and this
relationship was independent of ApoE ∈4 allele (Rosenberg
et al., 1996). However, the protective effect of Cherokee
ancestry declined with age. These findings suggest a com-
plex interaction between genetic and environmental factors
determining AD.
An increased risk for VaD in the presence of APOE E4
allele has been reported in India and a meta-analysis of 29
studies conducted (Bharath et al., 2010; Yin et al., 2012), but
it still requires careful research.
9.7 EDUCATION
The role of educational attainment as a risk factor for
dementia is controversial, but its examination across dif-
ferent cultural groups may shed further light on the role of
environmental factors or gene–environment interaction.
Low levels of education were associated with very mild and
mild dementia in Hong Kong (Lam et al., 2008). Illiteracy
was identified as a risk factor for incident cases of AD in a
South Korean sample and this link was more pronounced
84 Dementia
with increase in age (Lee et al., 2008). Lower levels of educa-
tion were associated with AD even when ApoE ∈4 status was
controlled for in a Norwegian sample (Sando et al., 2008b).
Levels of education were strongly correlated with the preva-
lence of dementia in Latinos, African Americans and non-
Latino white Americans in the United States (Gurland et al.,
1995, 1999), but the differences in prevalence disappeared if
age and education controlling apparatus was used, suggest-
ing that education may be an important environmental risk
factor independent of ethnicity. In a community study of
African Caribbean population in London, hypertension and
diabetes were specifically associated with cognitive impair-
ment in those with low levels of education (Stewart et al.,
2001c). In a South Korean study, a similar association was
found between cognitive impairment and systolic blood
pressure, with patients diagnosed earlier suffering from dia-
betes and random glucose levels in subjects with no formal
education (Stewart et al., 2003).
These findings may be explained by several hypotheses
which require rigorous testing:
●● Subjects with lower levels of education may have less
well-controlled hypertension or diabetes (Gurland et al.,
1995, 1999; Stewart et al., 2001c, 2003).
●● Cognitive batteries may not be sufficiently sensitive to
measure cognitive impairment in those with high levels
of education (Stewart et al., 2001c).
●● Those with high levels of education may have developed
sufficient cognitive reserve to be less vulnerable to the
effects of hypertension and diabetes (Gurland et al.,
1995, 1999; Stewart et al., 2001c, 2003).
●● Cerebral damage due to hypertension or diabetes
may be severe in those with lower levels of education
(Stewart et al., 2003).
Paradoxically, in a study of subjects with familial AD,
high levels of education were associated with earlier onset of
dementia (Mejia et al., 2003). This was explained by earlier
detection of symptoms in those with higher levels of educa-
tion due to greater intellectual and environmental demands
(Mejia et al., 2003).
9.8 LIFE EXPECTANCY AND THE
EPIDIMIOLOGICAL TRANSITION
HYPOTHESIS
A theoretical model of the epidemiological transition in
dementia has been developed using incidence and preva-
lence data from different countries (Suh and Shah, 2001;
Shah and Zarate-Escudero, 2014). According to this model
all societies sequentially move through four hierarchical
stages:
●● Low incidence–high mortality society
●● High incidence–high mortality society
●● High incidence–low mortality society
●● Low incidence–low mortality society
Within this model several factors contribute to the
­prevalence of dementia:
●● The overall incidence (and thus, the prevalence) will be
low in societies where life expectancy is short because
fewer subjects will reach the age where there is a risk of
dementia. The selective survival of those not at risk of
dementia may further influence such a trend. It is pos-
sible that early mortality rate, selects for genetic and/or
constitutional factors that protect against neurodegen-
erative disorders is responsible.
●● Mortality and survival after the onset of dementia also
influences prevalence rates. In societies where survival
after the onset of dementia is short, the prevalence may
be low even if the incidence is not.
●● The incidence itself is important because uneven dis-
tribution of protective or risk factors for dementia will
vary the incidence.
●● In socio-economically less developed societies, infec-
tious diseases associated with poor socio-economic
factors will reduce life expectancy with fewer indi-
viduals reaching the age of risk for dementia. Such
a society has been described as low incidence–high
mortality society. With improvement in basic ­medical
care, the average life expectancy will increase and
reach the threshold age where there is risk for demen-
tia (Li et al., 2007; Lam et al., 2008). This will lead
to a gradual transition from a low incidence–high
mortality society to high incidence–high mortality
society. The observed high prevalence of demen-
tia in a socio-economically deprived area of Brazil
may represent this stage of epidemiological transi-
tion (Scazufca et al., 2008). Furthermore, in socio-­
economically developed societies, the mortality
associated with dementia may decrease because of
greater availability of medical care and ­technology.
This will lead to a gradual transition from high
­i ncidence–high ­mortality society to a high incidence–
low mortality society. In socio-economically well-off
societies, efforts to improve the control of risk factors
for dementia (such as those for VD) may reduce the
incidence of dementia leading to a gradual transition
to low incidence–low mortality society. There is evi-
dence that the ratio of AD to that of vascular disease
is increasing in some Asian countries due to reduction
in the incidence of strokes (Fujishima and Kiyohara,
2002; Li et al., 2007).
●● The transition from a low incidence–high mortality
society to low incidence–low mortality society may
unfold in several ways depending upon availability of
medical services, advances in medical care and technol-
ogy, public health policies and efforts undertaken to
control risk factors for dementia and promote protective
factors for dementia in a given society.
 Cross-cultural issues in the assessment of cognitive impairment 85
A similar epidemiological transition model has been
developed for other mental disorders in old age (Shah,
2007b) and for the elderly suicide rates (Shah, 2010; Shah
and Zarate Escudero, 2014).
9.9 FUTURE DIRECTIONS
Cross-cultural studies of dementia have focussed primar-
ily on cognitive impairment. Behavioural and psychological
symptoms of dementia (BPSD) have not been well-studied
in cross-cultural studies (Shah and Mukherjee, 2000; Shah
et al., 2005b). Cross-cultural measures of BPSD that are
culture-fair and analogous to those used in western coun-
tries are emerging (Shah et al., 2004, 2005a, 2005c). BPSD
require close examination in cross-sectional and longitudi-
nal studies conducted to study the prevalence and incidence
of dementia in cross-cultural settings; these studies should
be designed to examine genetic and environmental risk fac-
tors and the interaction between them for both cognitive
impairment and BPSD.
Very few cross-cultural studies have examined neuro-
chemical, neuroanatomical and neurohistological changes
in dementia (Amaducci et al., 1991) and structural and
functional imaging have hardly been used in cross-cultural
studies. These techniques should be applied in rigorous
population-based cross-cultural studies of both cognitive
impairment and BPSD, using cross-culturally validated
measures of cognitive impairment and BPSD. This approach
would provide powerful means of exploring environmental
and genetic factors and the interaction between them. The
clustering of less common dementias, such as Huntington’s
disease, prion dementias and Parkinsonism–dementia
complex of Guam in some cultural groups may also shed
light on genetic and environmental interactions (Graham
et al., 1998).
The epidemiological transition hypothesis for dementia
also requires further study. This can initially be achieved
using data from incidence and prevalence studies from
individual countries and data on socio-economic sta-
tus (e.g. gross national domestic product), life expectancy
and proxy measures of the quality of medical services (e.g.
infant mortality rates) ‒ all available from the World Health
Organization. One statistical model of the proposed epi-
demiological transition hypothesis is that of an inverted
U-shaped curve following a quadratic equation Y = A +
BX - CX 2 (where Y is the incidence of dementia, X is the
socio-economic status and A, B and C are constants). This
approach could be combined with measurement of genetic
and environmental factors, which, in turn, would enable
careful examination of these factors and their interaction as
societies develop socio-economically.
The development of these sophisticated international
research programmes will require considerable develop-
ment of specialist services for these groups worldwide if
they are to be feasible (Shah, 2008, Shah et al., 2008).
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Structural brain imaging
ROBERT BARBER and JOHN T. O’BRIEN
10.1 INTRODUCTION
This chapter focuses on the use of structural imaging,
­magnetic resonance imaging (MRI) and computed tomog-
raphy (CT) in dementia.
From a clinical-orientated perspective, the ability to
visualize the structure of the live brain directly means
MRI and CT scans play a central role in diagnosis, pro-
viding both positive and negative predictive information.
Traditionally, imaging in dementia was applied to ‘rule
out’ pathologies that may be responsible for cognitive
impairment, including the so-called treatable or reversible
causes. Increasingly, the application of imaging recognizes
dementia subtypes have characteristic changes that can be
identified at various stages of the illness. This shift to use
imaging to ‘rule in’ these changes can increase diagnostic
accuracy and confidence, and is increasingly becoming a
part of the new clinical diagnostic criteria for dementia
subtypes. Reflecting this change, structural imaging is now
regarded as a core investigation in the clinical assessment
of patients with possible dementia: a practice endorsed
by international consensus guidelines for the assessment
of those suspected of suffering from dementia (see Table
10.1). Indeed, expectations are growing and imaging can
be central to helping individuals and their families under-
stand and adjust to the diagnosis of dementia. To optimize
the benefits of imaging, clinicians should know how best
to incorporate these techniques into their practice, includ-
ing how to interpret their findings in the wider context of
global clinical presentation and communicate their rel-
evance to patients and carers.
From a research-oriented perspective, imaging provides
a window to help understand the neurobiology of demen-
tia in life. To date, studies have focused on identifying bio-
markers that aid the differential diagnosis of dementia and
the early identification of patients who are on a trajectory to
92
10
develop dementia. It has also been used in clinical trials of
putative disease modifying agents to aid sample selection
(stratification/enrichment) and as a surrogate measure to
­monitor patient safety and adverse events.
There are a number of important longitudinal studies
in progress trying to improve the clinical utility of neuro-
imaging and evaluate how best to combine different imag-
ing modalities as well as their relationship with bio-fluid
markers and clinical phenotypes. At present, however,
there is a lack of standardization in how imaging biomark-
ers are acquired and measured to draw definitive conclu-
sions regarding combination of biomarkers which offer the
best diagnostic and prognostic accuracy (Jack et al., 2011a;
Frisoni et al., 2013). An added obstacle, especially in demen-
tia, stems from the relative lack of pathological validation of
in vivo imaging findings – either because of the difficulty
in obtaining a donor for brain and/or the gap in time (often
years) between scan acquisition and brain tissue autopsy
analysis, if the scan is available.
10.2 BACKGROUND TO CT AND
MRI AND THEIR CLINICAL
APPLICATION
10.2.1 COMPUTED TOMOGRAPHY
This chapter focuses on X-ray-based CT; other CT modali-
ties, notably, single-photon emission computer tomography
(SPECT) and positron emission tomography (PET), are cov-
ered in Chapter 11.
The first human X-rays from the 1890s were crude ‘sha­
dow’ images from a hand placed on a photographic plate.
Fast-forward to the 1970s and advances in computer tech-
nology allowed the first patient brain scan to be acquired by
combining single images or ‘slices’ (‘tomography’ is derived

Table 10.1 Examples of guidelines for use of imaging in dementia
U.S./Canadian guidelines
Canadian Consensus Conference on Dementia (Patterson
et al., 2001)
Cranial computed tomography (CT) scan is recommended if
one or more of the following criteria is present.
A. Age less than 60 years
B. Rapid, (e.g. over 1–2 months) unexplained decline in
cognition or function
C. Short duration of dementia (less than 2 years
D. Recent and significant head trauma
E. Unexplained neurological symptoms, e.g. new onset of
severe headache or seizures
F. History of cancer (especially in sites and types that
metastasize to the brain)
G. Use of anticoagulants or history of a bleeding disorder
H. History of urinary incontinence and gait disorder in the
early stages of dementia (as may be found in
normopressure hydrocephalus)
I. Any new localizing sign (e.g. hemiparesis or Babinski
reflex)
J. Unusual or atypical cognitive symptoms or presentation
(e.g. progressive aphasia, gait disturbance)
Practice Parameters: Diagnosis of dementia (evidence-
based guidelines) from the American Academy of
Neurology (Knopman et al., 2001)
Recommends structural neuroimaging with either a non-
contrast CT or MRI scan in the routine initial evaluation of
patients with dementia, usually is appropriate.
from the Greek word tomos meaning ‘slice’). On-going
advances have continued to improve patient experience
and safety, as well as technical features such as spatial and
temporal resolution and processing times allow the brain to
be imaged in seconds. The development of multi-slice CT
has made three-dimensional (3D) reconstruction possible,
so images are no longer limited to the axial plane. As with
the first X-ray, the CT image ultimately depends on electron
density and the differential absorption of X-rays by body
tissue, in such a way that high-density structures like bone
appears white and low-density tissue, whereas, water and fat
appear black.
CT and MRI have various advantages and disadvan-
tages as summarized in Table 10.2. As a general rule, CT
is adequate for ‘ruling out’ most intra-cerebral lesions such
as tumours, metastases, strokes, subdural haemtomas,
hydrocephalus and bone trauma, but has a limited role to
play in comparison to MRI for ‘ruling in’ degenerative dis-
orders such as Alzheimer’s disease (AD), though CT coro-
nal reconstruction now allows reasonable assessment of the
degree of temporal atrophy. CT is a lesser sensitive marker
of vascular disease, especially when mild and/or associated
Structural brain imaging 93
UK/European guidelines
EFNS: Guidelines for the diagnosis and Management of
Alzheimer’s disease (AD) (Hort et al., 2010)
Recommends CT or magnetic resonance imaging (MRI)
performed once for every patient. For AD, hippocampal
atrophy is best seen with the help of MRI scan but may
also be visualized on the more modern type CT scanner
and yields sensitivity and specificity values between 80%
and 90% in most studies. For practice purposes, a
standard magnetic resonance protocol involves at least
coronal T1 and axial T2 or fluid-attenuated inversion
recovery (FLAIR) sequences.
The UK National Institute of Health and Care Excellence
(NICE) Guidance on Dementia (guidance.nice.org.uk/
cg42, 2006)
Structural imaging should be used in the assessment of
people with suspected dementia to exclude other
cerebral pathologies and to help establish the subtype
diagnosis. MRI is the preferred modality to assist early
diagnosis and detect subcortical vascular changes,
although CT scanning could be used. Imaging may not
always be needed in those presenting moderate to
severe dementia, if the diagnosis is already clear.
Specialist advice should be taken when interpreting scans
in people with learning disabilities.
with small vessel disease in comparison to newer magnetic
resonance (MR) sequences. Clinically, CT is used more
widely than MRI, probably reflecting its greater availability,
ease of use and lower cost, though the evidence base relating
to the utility of structural imaging in dementia is predomi-
nantly from MRI studies.
10.2.2 MAGNETIC RESONANCE IMAGING
This chapter focuses on structural MRI; other MRI modali-
ties, notably, functional MRI, are covered in Chapter 20.
MRI is a non-invasive chemical probe that utilizes the
electromagnetic properties of protons to generate high-
resolution 3D images of the body’s internal structures. MRI
scanners use powerful magnetic fields, up to 60,000 times
greater than the earth’s magnetic field and under the con-
trolled environment of the MR scanner, protons inside body
tissues are induced to act like microscopic radio transmit-
ters. 3D images are then constructed by detecting and pro-
cessing these signals. About two-thirds of the human body is
water, composed of hydrogen nuclei or protons. The ability
94 Dementia

of MRI to distinguish different structures and pathologi-
cal changes is based upon the variation in the water con-
tent (protons) and alterations in the cellular environment
that affects the behaviour of protons: a difference in water
content of less than one per cent is enough to distinguish
Table 10.2 Comparison between computed tomography
(CT) and magnetic resonance imaging (MRI)
CT MRI
Shorter scan times (<10 Higher spatial and
seconds, good for restless anatomical resolution
patients)
Widely available Superior soft tissue
definition and contrast
Lower cost Uses non-ionizing
radiation (in that way
safer)
Better tolerated by patients Wider application for
quantitative analysis
Better for lesions with little Image in multiple planes;
or no water content (e.g. therefore superior
meningiomas) and views of middle and
detection of acute posterior fossa,
intracerebral haemorrhage pituitary, brain stem,
and spinal cord
Good for bone abnormalities Greater sensitivity to
and detecting calcification detect white matter
pathology and lesions
causing epilepsy (such
as inflammatory disease
and hippocampal
sclerosis)
normal and abnormal tissue. A major strength of MRI is its
versatility to visualize changes in both grey and white mat-
ter by changing the type of imaging sequences. The princi-
pal sequences and their application to study brain diseases
are summarized in Table 10.3.
Clinically, MRI provides a method to study atrophy and
cerebrovascular disease (CVD), as well as various causes of
grey and white matter abnormalities. These include demy-
elinating, infective, inflammatory, toxic or metabolic condi-
tions. There are a number of important contraindications to
MRI, as summarized in Table 10.4.
10.3 ASSESSMENT OF BRAIN ATROPHY
AND VASCULAR DISEASE
In the patients suspected of suffering from dementia, a primary
use of structural imaging is to investigate the contribution of
atrophy and vascular disease in the clinical presentation.
10.3.1 ASSESSING AND MEASURING
ATROPHY
Imaging provides information about the structural integ-
rity and size of the brain. Any reduction in the size of the
brain is a visual end point of cell death and MRI is an excel-
lent tool to assess and track atrophy. In this way, MRI can be
viewed as a biomarker for neuronal degeneration or injury,
such as neuron loss, shrinkage and synapse loss (Jack, 2011).
When interpreting scans, it is important to be systematic.
A useful algorithm to follow has been proposed by Harper
et al. (2014). Before assessing atrophy, this algorithm guides
the observer to start checking for any ‘surgical pathologies’,

Table 10.3 Main types of MRI sequences

Main sequences:

Conventional sequences:
• T1-weighted: Commonly used clinical scan provides good definition of anatomy and grey/white matter contrast
• T2-weighted: Provides high contrast and definition of soft tissue pathology (increased water content) – useful to detect
ischaemic changes
• Proton density: Provides good brain/cerebrospinal fluid (CSF) contrast
• Fluid-attenuated inversion recovery (FLAIR): Sensitive to changes in white matter (while suppressing the signal from the
CSF) and useful to detect ischaemic changes

Additional sequences:
• T2* gradient echo (or susceptibility weighted imaging): Can identify micro-haemorrhages or micro-bleeds suggestive
of cerebral amyloid angiopathy or small vessel disease (SVD)
• Magnetization transfer imaging (MTI): Sensitive to changes in structural integrity of tissue
• Diffusion-weighted imaging (DWI): Provides information about the microscopic diffusion of water molecules and
integrity of axons. Diffusion tensor imaging (DTI) is a type of diffusion scan taken in multiple planes that can identify
white matter tracts – so called tractography. It gives an impression of microstructure, coherence and connectivity of
white matter tracks – see Chapter 11 for further details
• Perfusion-weighted Imaging (PWI) including arterial spin labelling (ASL): Provides information about the status of brain
tissue perfusion – see Chapter 11 for further details

Table 10.4 Contraindications of MRI
• MRI scanners can be noisy, patients feel confined and
they are required to remain still for varying amounts
of time to avoid motion artefacts: approximately
5% –10% of people feel that they are unable to
tolerate the scan and may experience claustrophobia.
• Ferromagnetic implants, e.g. pacemakers,
intracranial aneurysm clips, cochlear implants,
neurostimulators: cardiac pacemakers can
deprogram and misfire so structural imaging with
CT scan is the only option.
• Ferromagnetic objects may irritate eyes.
• Orthopaedic implants are not contraindicated
though may introduce local artefacts.
such as tumours, hematomas and arteriovenous malforma-
tions. This can be followed by an assessment of any signal
changes (mainly relevant in MRI) based on the premise
that the appearance within a single tissue type should be
relatively uniform and the presence of hyperintensity or
hypointensity within the tissue can often reflect pathology.
When evaluating atrophy, its pattern and extent should be
determined, including areas where brain tissue appears per-
severed. This would involve checking for general and lobar
patterns of cortical atrophy, noting any asymmetry and
anterior-posterior gradient, as well as any evidence of basal
ganglia, brainstem or cerebellum atrophy. T1-weighed MRI
or CT is commonly used for detecting atrophic changes.
There are a number of ways to assess atrophy, each with
advantages and disadvantages. Visual rating scales offer the
advantage of speed, simplicity and ease of application in
clinical settings, though they are inherently subjective and
limited in terms of quantification. Nevertheless, in the case
of Alzheimer’s disease (AD), visual rating scales of medial
temporal lobe atrophy (MTA) can distinguish AD from
controls with a sensitivity and specificity of around 85%
(Scheltens et al., 2002), findings that also correlate with neu-
ropathological changes in autopsy (which in turn indicate
atrophy in AD is more closely linked to abnormalities in tau
pathology than amyloid burden).
Moving away from visual rating scales, MRI can be used to
measure atrophy with a high degree of spatial resolution (<1
mm), with the development of high resolution imaging allow-
ing the sub-field architecture of the structures such as hippo-
campus to be measured. Research centres have developed a
myriad of techniques to try and reliably measure specific struc-
tures using manual, semi-automated or automated approaches.
As expected, these methodologies are more adept at quantify-
ing structural changes, but require higher levels of technical
expertise and are less transferable to the clinical setting.
In research settings, measurements are increasingly based
on automated imaging software packages. These approaches
are aimed at achieving quicker, in-depth and less operator-
dependent way of measuring brain structures, though there
has been a lack of standardization between research centres
in their design and application. However, when applied in
Structural brain imaging 95
a standardized way, automated approaches offer reproduc-
ibility and efficiency, especially advantageous in large-scale
multicentre studies. Techniques such as voxel-based mor-
phometry (VBM) can examine changes in all parts of the
brain, detect grey matter loss and make detailed comparisons
between diagnostic groups. Newer techniques allow the cor-
tical grey matter to be segmented from the rest of the brain to
derive a measure of cortical thickness in regions of interest,
demonstrating subtle differences as small as 0.2 mm in thick-
ness can be significant (Dickerson et al., 2011).
Atrophy can be measured one point at a time or sequen-
tially over a long period of time. Cross-sectional studies allow
comparisons to be made between diagnostic groups usually
with healthy age-matched controls, whereas, longitudinal
studies can measure the same structure in the same individ-
ual at two different time points, thereby reducing the vari-
ance due to inter-subject differences. This technique, usually
focused on serial measurements of hippocampal and whole-
brain volume, is sufficiently sensitive to detect very small vol-
ume changes in the order of a few millilitres, which can be
important during the pre-symptomatic or early stages of the
disease when changes can be subtle (Scahill and Fox, 2007).
Regulatory authorities are keen for biomarkers to be used in
clinical trials so the biological impact and safety of new treat-
ments can be appraised. Used as surrogate endpoint, serial
MRI imaging can reduce the number of subjects required
compared to clinical outcome measures (Hampel et al., 2011).
Notwithstanding the advantages of serial scanning, there are
a number of methodological challenges: atrophy rates can
vary considerably between subjects, serial scanning of patients
with advancing dementia can be problematic; currently, a gap
of at least 6 months between scans is required before volume
change can be consistently detected. There are technical and
cost implications, especially for studies that require many
years to determine the predictive relevance of MRI biomark-
ers; and ultimately there is a need for post-mortem validation.
With advancing age, approximately 0.5% of brain vol-
ume is lost every year, and as our brains become smaller our
ventricles become larger, often at a faster rate. The pace of
this change accelerates with age, particularly after 70 years
of age and appears to be associated with greater cognitive
decline. The hippocampus appears to be particularly sensi-
tive to the effects of ageing (as well as AD pathology) and
atrophies at a faster rate than other structures.
These age-related changes are common but not inevitable
and there is considerable variation between changes in indi-
viduals. Atrophy is likely to be influenced by a number of
factors, including genetic status (such as presence of apoli-
poprotein E [ApoE] ε4 alleles), health status (such as hyper-
tension and diabetes), socio-economic status and possibly,
dietary and hormonal factors too.
Compared to age-matched controls, increased rates
of brain atrophy and ventricular enlargement have been
documented in most major forms of dementia, including
AD, dementia with Lewy bodies (DLB), vascular dementia
(VaD), frontotemporal dementia (FTD), corticobasal degen-
eration (CBD), progressive supranuclear palsy (PSP) and
96 Dementia

Huntington’s disease (HD) (O’Brien et al., 2001; Whitwell
et al., 2007a). However, serial measures of global atrophy
are unlikely to distinguish individual patients with different
types of dementia, although, measures of regional atrophy
may be more discriminating. For example, in AD, the rate of
hippocampal atrophy is greater than the global atrophy rate –
approximately 3%–8% compared to 1%–3% depending on
the study. Conversely, patients with FTD have a greater rate
of frontal lobe atrophy compared to those with AD (Krueger
et al., 2010). Individuals who develop mild cognitive impair-
ment (MCI) also have accelerated patterns of regional atro-
phy compared to cognitively normal individuals.
10.3.2 ASSESSING AND MEASURING
VASCULAR DISEASE
Neuroimaging plays a central role in characterizing the bur-
den of CVD. Indeed, findings from population-based MRI
studies have helped to shape and redefine our understand-
ing of the spectrum of pathologies that are associated with
vascular cognitive impairment. However, interpreting the
relationship between CVD detected on imaging and the
clinical presentation of an individual patient can be prob-
lematic and these reasons are discussed later in the chapter.
CVD is inherently heterogeneous with diverse underly-
ing pathophysiological mechanisms. These changes can be
detected on imaging as cortical ischaemic or haemorrhagic
strokes due to large vessel disease, subcortical infarcts, lacunes,
white matter hyperintensities (WMH) (on MRI), prominent
perivascular spaces and cerebral micro-bleeds. In addition, vas-
cular disease may occur due to a ­subarachnoid haemorrhage,
subdural haematoma or vascular ­ malformations. Hypoxic
damage can result from a significant cerebral hypoperfusion,
for example, following a cardiac arrest, which may cause wide-
spread ischaemic damage, particularly, in ‘watershed’ areas.
MRI studies have recognized that small vessel disease
(SVD) is both prevalent with advancing age and the most com-
mon vascular cause of dementia which has emphasized the
need to define the imaging characteristics of SVD in a more
consistent way. As summarized in Figure 10.1 and discussed

Recent small subcortical White matter Lacune Perivasular space Cerebral microbleed
infarct hyperintensity

Example image

T2
Schematic

DWI FLAIR FLAIR T1/FLAIR T2*/SWI

Usual diamater ≤20 mm Variable 3–15 mm ≤2 mm ≤10 mm

Comment Best identified on DWI Located in white matter Usually have Most linear without Detected on GRE seq.,
hyperintense rim hyperintense rim round or ovoid, blooming
DWI ↑ ↔ ↔/(↓) ↔ ↔
FLAIR ↑ ↑ ↓ ↓ ↔

T2 ↑ ↑ ↑ ↑ ↔

T1 ↓ ↔/(↓) ↓ ↓ ↔
T2*-weighted GRE ↔ ↑ ↔ (↓if haemorrhage) ↔ ↓↓

Figure 10.1 Magnetic resonance imaging (MRI) findings for lesions related to small vessel disease show examples (upper)
and schematic representation (middle) of MRI features for changes related to small vessel disease, with a summary of imag-
ing characteristics (lower) for individual lesions. DWI, diffusion-weighted imaging; FLAIR, fluid-attenuated inversion recovery;
SWI, susceptibility-weighted imaging; GRE, gradient-recalled echo. ↑ Increased signal, ↓ Decreased signal, ↔ Iso–intense
signal. (Reprinted from The Lancet, 12(8), Wardlaw, J.M. et al., Neuroimaging standards for research into small vessel disease
and its contribution to ageing and neurodegeneration, 822–838, Copyright 2013, with permission from Elsevier.)

in detail below, Wardlaw et al. (2013) have proposed a stan-
dard set of definitions for the MRI characteristics of SVD.
10.3.2.1 White matter disease
In a CT scan, white matter lesions (WMLs) appear as areas
of reduced attenuation, commonly reported as white matter
hypoattenuation, hypodensities or leukoaraiosis.
In MRI scan, WML appear as hyperintense (WMH) on
proton density, T2-weighted and fluid-attenuated inversion
recovery (FLAIR) MR images, as illustrated in Figure 10.2.
There have been a number of approaches undertaken to
characterize and rate WMH. Broadly, WHM can be divided
into those immediately adjacent to the ventricles (periven-
tricular hyperintensities [PVH]) and those located in the deep
white matter (deep white matter hyperintensities [DWMH]).
As shown in Figure 10.3, PVH can be further subdivided
into caps (frontal and occipital) and bands and DWMH into
punctate foci, early confluent foci and large confluent areas
(Fazekas et al., 1987). In a similar way that is used to measure
atrophy, WMH can be assessed using simple rating scales,
semi-quantitative scales or automated software programmes.
When interpreting the significance of any change to the
appearance of white matter, it is important to assess the pat-
tern, location and severity of these changes along with any
other abnormalities affecting the cortical areas, basal gan-
glia and brain stem. Technical factors, such as, the imag-
ing parameters used, as well as clinical variables like the
patient’s age and known medical co-morbidities also need
to be considered. This is necessary because different scan
sequences and parameters vary in their sensitivity to detect
small vessel disease; WML are extremely common with
advancing age (8%–95% depending on the study) and ulti-
mately they are unlikely to result from a single cause; also
WML commonly coexist with other changes. Indeed, WML
can be found in all major forms of dementia, as well as a host
of other conditions, including multiple sclerosis (MS), amy-
loid angiopathy, hydrocephalus, various leukodystrophies,
cerebral oedema, neurosarcoid and conditions resembling
late life depression. Potential pathological mechanisms for
WMH are shown in Table 10.5. It is important to distin-
guish infarcts from WMH as summarized in Table 10.6 and
illustrated in Figure 10.4.
FLAIR PD T2
Figure 10.2 Comparison of FLAIR, proton density
(PD) and T2-weighted images from the same indi-
vidual: note differences in appearance of white matter
hyperintensities.
Structural brain imaging 97
That being said, as white matter changes it becomes more
extensive, extending bilaterally into the deeper white matter
tracts as confluent hyperintense areas on T2-weighted and
FLAIR, then current convention is to infer these changes
likely to result from underlying vascular disease (so-called
‘WMH of presumed vascular origin’ by Wardlaw et al.,
2013). The location of DWMH could have an important
bearing on the clinical phenotype with the “disconnection”
of key cortical–subcortical circuits mediating their effect on
brain function. PVH, on the other hand, may have less bear-
ing on the clinical outcome and is less closely coupled with
vascular mechanisms.
The progression of white matter changes are likely to be
influenced by various cardiovascular factors. The emerging
picture suggests WML and atrophy share similar risk fac-
tors, and there may well be an inter-relationship between
these MRI variables; for example, higher rates of cerebral
atrophy and ventricular dilatation have been associated
with severe WML. Importantly, WML could also be a target
for treatment, including treatment of hypertension associ-
ated with reduced risk of WML progression in cognitively
normal subjects (Firbank et al., 2007).
10.3.2.2 Other changes associated with
small vessel disease
10.3.2.2.1 LACUNAE OR LACUNAR INFARCTS
These are small discrete changes deep within the brain
that are thought to be the legacy of an old infarct. As sum-
marized in Figure 10.1, Wardlaw et al. (2013) proposed
the definition of a ‘lacune of presumed vascular origin’ as
a round or ovoid, subcortical, fluid-filled (similar signal
as cerebrospinal fluid [CSF]) cavity, between 3 mm and
(a) (b) (c)
(d) (e)
Figure 10.3 Examples of white matter lesions on FLAIR.
(a) No periventricular hyperintensities (PVH). (b) Mild PVH
(frontal and occipital caps). (c) Moderate to severe PVH
(frontal and occipital caps). (d) Punctate deep white mat-
ter hyperintensities (DWMH) in frontal and parietal lobes.
(e) Large, early confluent DWMH.
98 Dementia

Table 10.5 Histopathology associated with white matter lesions in dementias

Lesion type Pathology
Periventricular hyperintensities Less extensive PVH: loss of
(PVH) ependymal lining, increased
interstitial fluid, gliosis, myelin
pallor and dilatation of perivascular
spaces.
More extensive irregular PVH, which
extend into the deep white matter:
likely to correspond to areas of
reactive gliosis, lacunar infarction,
loss of myelin, perivascular spaces
and arteriolar thickening.
Deep white matter hyperintensities Punctuate WMH: reduced myelination
(DWMH) and perivenous damage.
Early confluent areas: show evidence
of perivascular rarefaction of
myelin, fibre loss and gliosis.
Confluent WMH: have a similar
histopathology as irregular PVH,
including microcystic infarcts.
Possible mechanisms
In part, secondary to atrophy processes
Frontal caps extremely common in late life
could be considered ‘normal’ and
secondary to age-related changes
More extensive PVH probably linked to
vascular risk factors.
Punctate lesions are probably not
associated with ischaemia/infarction.
Ischaemic damage implicated as lesions
become larger and more confluent.
Other possible causes of white matter
change include focal cerebral oedema,
hypoxia, acidosis, chronic perfusion
changes, Wallerian degeneration of
axons secondary to neuronal loss in
neocortex.

Table 10.6 Differences between cerebral infarcts and DWMH on MRI

Infarcts DWMH (of presumed vascular origin)

• Hypointense on T1 and proton density weighted images
• Hyperintense on T2-weighted images
• Well defined, wedge shape if peripheral
• Often single or low numbers
• Often evidence of cortical extension
• May be associated with focal enlargement of ventricles
and sulci
• Hyperintense on T2/FLAIR and proton density
weighted images
• Isodense on T1-weighted images (can be hypointense)
• Range from punctuate to diffuse confluent lesions
• Often multiple
• Restricted to white matter with no cortical extension
• Ventricles and sulci remain unchanged

about 15 mm in diameter, consistent with a previous acute
small deep brain infarct or haemorrhage in the territory
of one perforating arteriole. Lacunar infracts occur in
about 20% of older people considered healthy without any
significant symptom, though they are associated with an
increased risk of stroke (Vermeer et al., 2007) and their
impact may be greater if there are pre-existing patholo-
gies, such as AD.
10.3.2.2.2 MICRO-BLEEDS
Interest in the significance, and therefore, detection of
cerebral microhaemorrhages or micro-bleeds (CMBs) has
increased over the recent years based on a convergence of
findings that indicate their prevalence and clinical relevance
is potentially greater than previously appreciated. Partly,
this is due to the application of newer MR sequences which
are much more sensitive at detecting these small (2–5 mm)
round foci of low but homogeneous signal, notably T2*
gradient-echo (or susceptibility weighted imaging). These
changes are thought to be due to a small leakage of blood
which has left a residue of iron (haemosiderin). Population-
based MRI studies indicate CMB increases significantly
with advancing age and presence of ApoE 4 allele reaches as
high as nearly 40% of those over 80 years (Sveinbjornsdottir
et al., 2008; Vernooij et al., 2008; Romero et al., 2014).
However, whether CMB has a direct impact on cognitive
function is still to be determined, especially because they
often coexist with other vascular pathologies.
It has been hypothesized that CMB result from at
least two pathological mechanisms. CMB occurring in
deeper structures, such as, the thalamus, basal ganglia,
brainstem and cerebellum, result from vascular micro-
angiopathy caused by hypertension and atherosclerosis.
In addition to this, deep CMB often coexists with other
types of SVD, such as WMH and lacunar infarcts. CMB
are also associated with vascular risk factors and an

increased risk of stroke recurrence (Cordonnier et al.,
2007; Vernooij et al., 2008).
Conversely, lobar CMBs are thought to be more closely
related to cerebral amyloid angiopathy (CAA). The presence
of CAA could be a possible factor in explaining why some
patients with AD treated with β-amyloid immunothera-
pies experienced an increase in CMBs: the hypothesis of an
antibody-mediated inflammation which further compro-
mised the integrity of blood vessels already affected by CAA
is plausible but yet to be corroborated. In response to con-
cerns that patients in AD immunotherapy trials were expe-
riencing ‘vasogenic oedema’ and microhaemorrhages, the
amyloid-related imaging abnormalities (ARIA) MR criteria
was introduced to standardized safety monitoring (Sperling
et al., 2011).
10.4 ALZHEIMER’S DISEASE
MRI has been used to study established clinical AD (as a
diagnostic marker) and increasingly, the preclinical stages
of AD (as a prognostic marker), variably referred to as the
asymptomatic, presymptomatic, preclinical and prodromal
phases of AD progression (Dubois et al., 2010).
10.4.1 EARLY AND ESTABLISHED AD
Generalized brain atrophy and ventricular enlargement are
common in AD. Typically, these changes are symmetrical,
(a) (b)
(c) (d)
Figure 10.4 Example of frontal stroke on (a) axial FLAIR,
(b) proton density, (c) coronal T1-weighted and
(d) T2-weighted.
Structural brain imaging 99
though, often prominent in the medial and posterior brain
regions, asymmetry may, however, be present. It is also pro-
gressive: individuals with AD lose brain volume at approxi-
mately two-to-four times more than the rate of healthy
controls (range 1%–4% vs. 0.3%–0.7% depending on study).
Broadly, atrophy is envisaged to progress in a way that mirrors
the established version of Braak staging. Indeed, atrophy on
MRI in AD can be seen as a marker for neurofibrillary tangles
and tau related neurodegeneration (Jack et al., 2010, 2011b).
That being said, generalized atrophy per se can be rela-
tively non-specific, and characteristically, AD is associated
with early and accelerated atrophy of medial temporal lobe
structures. By the time an individual is diagnosed with AD,
he/she can have hippocampi, parahippocampi, entorhinal
cortex and amygdalae that are 40%–50% smaller than nor-
mal. This level of atrophy can easily be visualized on MRI,
as illustrated in Figures 10.5 and 10.6.
MTA is also common, occurring in 80%–90% of patients
with AD, compared to 5%–10% occurrence in healthy sub-
jects. MTA has been defined in numerous ways, but on an
average it has a specificity of 80% to distinguish AD from
controls (Frisoni et al., 2013), with some studies reaching
accuracy levels of 85%–100% (Jack, 2011).
MTA is a relatively sensitive marker of AD pathology,
especially tau pathology, which is more closely linked to the
rate of brain loss than β-amyloid burden (Whitwell et al.,
2008). Importantly, MTA is not unique to AD and can occur
in a number of other conditions, including other types of
dementia, such as DLB, VaD and FTD, as described below.
The overlap in tau pathologies between different types of
dementia is one factor why MTA is less specific and links
(a)
(b)
(c)
(d)
Figure 10.5 (a–d) Examples of graded medial temporal
atrophy (MTA): arrows point to hippocampi.
100 Dementia
(a)
AD
(b)
Control
(c)
DLB
Figure 10.6 Comparison of medial temporal atrophy in
(a) Alzheimer’s disease (AD) (b) dementia with Lewy
­bodies (DLB) and (c) normal controls.
between atrophy and neuropathology are probably, less
closely associated with advancing age (Burton et al., 2009,
2012). Lesser degrees of MTA are also seen in Parkinson’s
disease, temporal lobe epilepsy, schizophrenia and depres-
sion. Ultimately, MRI can provide secondary, not primary
evidence of AD (de Leon et al., 2007).
Furthermore, as MTA occurs with advancing age the
specificity of MTA as a biomarker for AD declines with
increase in age, especially above 80 years. There is evidence
that the link between atrophy and neuropathology disso-
ciates advancing age and becomes less predictable (Savva
et al., 2009; Burton et al., 2012). Conversely, individuals
who develop early onset AD may have less noticeable MTA
(especially the non-­amnestic form of AD) but prominent
posterior cortical atrophy, affecting the posterior cingulated
and precuneus (Frisoni et al., 2007). The pattern of atrophy
in individuals affected by autosomal dominant AD (ADAD)
can also differ from individuals with sporadic AD, with evi-
dence of smaller basal ganglia, notably putamen and thala-
mus which may be evident in asymptomatic subjects (Cash
et al., 2013; Lee et al., 2013).
Although MTA appears to be necessary for the develop-
ment of AD, it is not sufficient to explain all symptomatic
changes and as Jack et al. (2002) speculate, MTA is a good
marker for early AD but as the disease progresses beyond
the limbic areas, measures of neocortical atrophy may be a
better marker of advanced disease.
To summarize, MTA occurs early in the course of AD
and increases with increasing severity of dementia. As MTA
is associated with the clinical diagnosis of AD and transition
from MCI to AD, there have been recommendations to include
estimates of MTA in revised criterion for the diagnosis of AD
(Dubois et al., 2007) and MCI due to AD (Albert et al., 2011).
In terms of WML, most studies show that patients with
AD have more extensive PVH and DWMH than controls.
Loss of white matter integrity probably occurs for a number
of reasons, including a secondary downstream event to the
primary cortical pathology, amyloid angiopathy and con-
current ischaemic damage.
10.4.2 PROGNOSTIC SIGNIFICANCE
OF MRI IN AD
Accelerated atrophy rates, notably affecting the hippo-
campus, can be evident in about 3–10 years prior to transi-
tion to dementia, depending on the area of study. By the
time mild symptoms are apparent, hippocampal volume
reductions may exceed 25%. Jack and collaborators from
the Alzheimer’s Disease Neuroimaging Initiative (ADNI)
have proposed an AD biomarker model to map the stag-
ing of the illness. This model, evolving as new evidence
emerges, broadly hypothesizes that changes to topo-
graphical structures as measured by MRI are secondary
to neuronal injury and in particular, tau related neurode-
generation. These structural changes are a downstream
consequence of other pathologies, putatively abnormali-
ties in β-amyloid metabolism detectable via CSF and PET
amyloid biomarkers years before the MRI changes are evi-
dent (Jack et al., 2010). This model may account for the
reason why MRI appears to perform less, as both a diag-
nostic and prognostic marker for AD when compared to
amyloid imaging, with the caveat that head to head com-
parisons are few in number and that the accuracy of each
AD biomarker as much dependent on how the biomarker
measured on the biomarker itself (Frisoni et al., 2013). In
the latest revision of this model, 18F-fluroodeoxyglucose
PET and MRI changes are modelled to occur coinciden-
tally as the last biomarkers become abnormal, but they are
most closely coupled to the emergence and progression of
cognitive impairment (Jack et al., 2013). This model helps
to conceptualize the potential interrelationship between
the different imaging biomarkers but the clinical utility of
predicting outcome for individual patients is still inaccu-
rate. This temporal ordering of MRI findings in relation
to other biomarkers and clinical symptoms is supported
by findings from two separate cohorts involving subjects
with sporadic AD and subjects with ADAD Presenilin 1
E280A mutation carriers (Villemagne et al., 2013; Fleisher
et al., 2015).
Individuals with MCI are at an increased risk of devel-
oping dementia (see Chapter 20), with such individuals
increasingly thought to represent a group with ‘prodromal
AD’. Detection of MCI due to prodromal AD is, therefore,
important and the role of neuroimaging in MCI has been
extensively studied. Overall, baseline temporal lobe atro-
phy correlates with future cognitive decline and conversion
from MCI to AD with the changes in MCI usually being
intermediate between normal subjects and AD subjects.
The intermediate nature of these results is reflected in the
relatively lower sensitivity (62%) and specificity (73%) of
measures of MTA on MRI for the discrimination of patients
with MCI, who subsequently progress to AD from patients
with MCI who do not progress to AD (Frisoni et al., 2013).
It is possible that composite MRI measures involving MTA
plus other grey matter regions and white matter changes
can improve the prediction of individual subjects with MCI
at risk of developing AD (Misra et al., 2009).

More recent studies have focused on evaluating whether
biomarkers can help identify subjects who are cognitively
normal but destined to develop impairments. Emerging
findings suggest that this may be possible with mea-
sures of cortical thickness predictive of cognitive decline
over 3 years in clinically normal individuals at baseline
(Dickerson et al., 2012).
10.5 DEMENTIA WITH LEWY BODIES
The most consistent MRI finding in patients with DLB is
greater preservation of medial temporal lobe (MTL) struc-
tures compared to those with AD (Barber et al., 2000, 2001;
Burton et al., 2009). These autopsy verified differences have
been observed visually, as shown in Figure 10.6, and on a
range of more detailed morphometric measures, includ-
ing cortical thickness (Watson et al., 2015). Preservation
of MTL has been incorporated into the revised criteria
for clinical diagnosis of DLB (McKeith et al., 2005), and is
consistent with the finding that patients with DLB tend to
maintain memory function for a longer time compared to
patients with AD.
Therefore, observing preservation of MTL can be use-
ful in distinguishing DLB and AD, as it would be unusual
to find hippocampal volumes significantly preserved in
AD: the inference being that a patient without MTL (or
indeed global atrophy) is unlikely to have significant bur-
den of underlying AD-type pathology. Over a long period
of time, patients with DLB also show less progression in
MTA (and probably global atrophy) than those with AD:
again the inference here is accelerated atrophy rates reflect
AD-pathology more than DLB-pathology (Mak et al.,
2015a,b; Nedelska et al., 2015).
However, the clinical utility of MTA to distinguish DLB
and AD is likely to weaken with advancing age and dis-
ease progression and this finding in isolation is not reliable
enough to make a specific diagnosis of DLB for an individ-
ual patient. In this regard, a dopamine transporter scan is
likely to provide greater discrimination at distinguishing
DLB from AD than MRI scan.
From a research perspective, findings suggest combin-
ing measures of cortical thickness from different brain
areas that can enhance the discrimination of DLB from AD,
achieving a sensitivity and specificity of over 80% (Lebedev
et al., 2013). In the future, multimodal imaging protocols
that combine structural and functional modalities may also
improve discrimination further. For example, a combined
measure of hippocampal atrophy, cortical amyloid and
occipital lobe metabolism achieved an accuracy of 98% for
distinguished DLB from AD, better than any of the mea-
surements (Kantarci et al., 2012).
There is also a general trend among patients with DLB
who have less global atrophy compared to patients with
AD, but greater atrophy of subcortical structures, including
the substantia innominata and dorsal midbrain. Indeed, a
Structural brain imaging 101
pattern of relatively focused atrophy of the midbrain, hypo-
thalamus and substantia innominata, with a relative spar-
ing of the hippocampus and temporoparietal cortex, is more
likely to occur in DLB compared to AD (Whitwell et al.,
2007b).
Structural imaging changes in DLB are broadly similar
to those seen in patients with Parkinson’s disease dementia
(Watson et al., 2009). Subjects with DLB probably share a
similar distribution, prevalence and severity of WML to AD
on MRI, intermediate in severity between normal controls
and those with VaD (Barber et al., 1999), though studies
conducted till now are not conclusive (Burton et al., 2006).
10.6 FRONTOTEMPORAL DEMENTIA
FTD is characterized by atrophy of the frontal and anterior
temporal lobes. A normal MRI scan does not necessarily
exclude the illness, especially early stages of the illness, and
in such instances functional imaging may assist the diagno-
sis. If both structural and functional imagings are normal,
however, the risk of making a false positive diagnosis of FTD
may be increased (Kipps et al., 2009). As subjects with FTD
can have varying degrees of MTA, the pattern of prominent
frontotemporal anterior atrophy can assist in its differentia-
tion from other types of dementia, such as AD. Annual rates
of whole-brain atrophy are increased compared to controls
in all types of dementia. Asymmetrical pattern of atrophy
is also suggestive of FTD pathology than AD pathology
(Harper et al., 2014). FTD consists of a number of clinical
phenotypes with differing, though, overlapping MRI find-
ings, as summarized in Table 10.7 (see also Figure 10.7).
Approximately 20% of patients with FTD have an auto-
somal dominant pattern of inheritance, primarily linked
to one of three mutations (progranulin, microtubule-­
associated protein tau and chromosome nine open reading
frame 72). Different patterns of atrophy have been described
for these three groups compared to sporadic FTD (Rohrer
and Warren, 2011; Whitwell and Josephs, 2012), as summa-
rized in Table 10.8. As seen in subject with ADAD, individ-
uals who carry one of these genetic mutations can develop
subtle structural changes; in this instance in the insula and
temporal lobes onset of symptoms was predicted 10 years
before (Rohrer et al., 2015).
Provisional findings indicate WML is common with AD
and DLB, less severe than VaD though. Their pathological
basis, however, is likely to be different and reflect gliosis
rather than ischaemic damage or amyloid angiopathy.
10.7 VASCULAR DEMENTIA
The term vascular dementia implies that there is a defin-
able threshold above which the presence of dementia can
be attributed to the burden of CVD. The inherent difficulty
102 Dementia
in demarcating this threshold, coupled with a broadening
in our understanding of the spectrum and continuum of
CVD, has led many to prefer the concept of ‘vascular cog-
nitive impairment’ for defining this relationship (Gorelick
et al., 2011).
Table 10.7 MRI findings in frontotemporal dementia
(FTD) by clinical phenotype
Characteristic Structural
Clinical Phenotype Change
Behavioural variant of Varying degrees of atrophy
FTD occurring along the frontal-
to-temporal lobe axis,
occasionally including the
parietal lobes
Progressive nonfluent Usually symmetrical, left-sided
aphasia (PA) perisylvian atrophy (inferior
frontal and antero-superior
temporal regions)
Semantic dementia Usually asymmetrical (especially
(SD) as shown in anterior left temporal pole)
Figure 10.7 and significant (‘knife edge’
appearance of gyri)
Atrophy may become bilateral
as the illness progresses, but
usually atrophy still left
> right hemisphere
Table 10.8 MRI findings in FTD by genotype
Characteristic structural
Genotype – mutations changea
Progranulin gene Asymmetrical pattern of
atrophy
Early involvement of the
temporal, inferior frontal
and inferior parietal lobes
Microtubule-associated Symmetrical pattern
protein tau gene Involvement of anteromedial
temporal and orbitofrontal
lobes
Chromosome 9 open Symmetrical pattern
reading frame 72 Variable pattern of cortical
atrophy – usually involving
dorsolateral, medial and
orbitofrontal lobes, with
additional loss in anterior
temporal lobes, parietal
lobes, occipital lobes and
cerebellum in some
subjects
Sporadic FTD Frontal and anterior temporal
atrophy
a
Rohrer and Warren, 2011; Whitwell and Josephs, 2012
Broadly, the research criteria for VaD (Chui et al., 1992;
Roman et al., 1993) is based on linking the presence of
dementia (which may be non-amnestic in profile) to CVD
manifest in imaging as cortical infarcts, infarcts in strategic
brain areas (such as the thalamus), multiple lacunar infarcts,
extensive white matter change (usually defined as area >25%),
or combinations thereof (so-called mixed cortical and sub-
cortical dementia). CVD may also be associated with atro-
phy and ventricular enlargement corresponding to an area of
infarction with subsequent local cell loss. SVD is now consid-
ered to be the commonest form of VaD and associated ‘sub-
cortical’ vascular pathologies, as described in Figure 10.1.
Implicit in the criteria for VaD is that the clinical sig-
nificance of CVD can be inferred by considering their size,
number and location. But the precise relationship between
cognitive impairment and vascular change needs fur-
ther exploration and can be confounded by the presence
of other pathologies, such as AD. Probably, the strongest
evidence linking the severity of CVD with greater cogni-
tive impairment relates to the burden of WML and SVD.
Bearing in mind the effect different imaging modalities and
sequences have on the detection of CVD, the more exten-
sive these changes, the more we can infer the presence of
vascular pathology and the fact that this change is likely to
be clinically relevant. In the case of WML, this would be
the presence of large confluent DWMH. However, as dis-
cussed beforehand, mild degrees of WML are almost uni-
versal in cognitively normal people with advancing age and
commonly seen in patients with degenerative dementia, so,
given the varied pathologies that can cause WML, assigning
the clinical relevance to this level of change is less straight-
forward. Determining the clinical relevance of other types
of SVD in individual patients can also be a challenge. For
example, incidental ‘silent’ lacunar infarcts occur in 20%–40%
of elderly people and CMB is equally common later in life.
Discerning the impact of large vessel strokes can raise
similar challenges. Approximately 30% of people who have
suffered a stroke progress to develop a dementia, but the
Figure 10.7 Patient with clinical diagnosis of seman-
tic dementia showing bilateral anterior temporal lobe
atrophy, left > right side: coronal and axial T1-weighted
images. (Courtesy of Prof. T. Griffiths.)

findings from studies examining the relationship between
topography and severity (number and volume) have been
inconsistent. It is also likely, that, ‘non-vascular’ variables
influence whether cognitive deficits develop in the presence
of vascular disease. For example, generalized changes such
as cortical atrophy and MTA as well as variables, such as,
age and level of education may play an important role in the
development of post-stroke dementia.
Finally, the prevalence of pathologically confirmed mixed
dementias (AD and VaD) is now widely recognized and it is
possible that the two pathologies have a synergistic effect
such that the presence of AD-type pathology can increase
the clinical sequelae of CVD, and vice-versa. Furthermore,
there is evidence, that, when both cortical atrophy (such as
MTA) and CVD coexist, measures of atrophy more closely
explain the variance in cognitive function, suggesting con-
comitant AD pathology has a significant impact on the
emerging clinical presentation. The recognition that vas-
cular and degenerative diseases share similar risk factors
introduces another level of complexity to their relationship.
As Scheltens (2009) states, the absence of operational crite-
ria for mixed dementia means that the clinician is often left
to judge which diagnostic category best fits!
Table 10.9 MRI findings in other diseases associated with cognitive impairment
Disorder
Variant Creutzfeldt–Jakob disease (vCJD)
Sporadic CJD (sCJD)
Huntington Chorea (HC)
Progressive supranuclear palsy (PSP)
Corticobasal degeneration
Multisystem atrophy (MSA)
Normal pressure hydrocephalus (NPH)
CADASIL (cerebral autosomal dominant arteriopathy
with subcortical infarcts and leukoencephalopathy)
Multiple sclerosis (demyelinating disease)
Infections/inflammation
Structural brain imaging 103
10.8 OTHER DEMENTIAS
Less common types of dementia with relatively distinct
neuroradiological features on MRI are summarized in
Table 10.9. Uncommon types of dementia are further dis-
cussed in Chapter 20.
10.9 FINAL COMMENTS
There is a convergence of opinion that structural neuro-
imaging should be considered in the investigation of all
patients with suspected dementia and where possible per-
formed at least once during their illness. Functional imag-
ing can also have an important, complimentary role in
enhancing diagnostic accuracy (see Chapter 11). An impor-
tant question is perhaps, ‘If I need to make a diagnosis and
plan treatment, what sort of imaging do I need to perform?’
A CT scan will, for cost and practical reasons, usually be
the imaging modality most often used, although an MRI, if
accessible and feasible, would almost always be the superior
MRI findings
Symmetrical hyperintensity in the pulvinar (posterior) nuclei of
the thalamus relative to the anterior thalamus (pulvinar sign).
Other features are hyperintensity of the dorsomedial
thalamic nuclei, caudate head and periaqueductal gray
matter (PG)
High signal changes in the putamen, caudate and/or thalamus
and cortical gyri (cortical ribboning). DWI has a high
sensitivity and specificity for sCJD, (especially in detecting
cortical changes compared with other MRI sequences)
Bilateral caudate atrophy may also have reduced volume of
other basal ganglia structures and frontal lobes
Brain stem atrophy and non-specific mild atrophy
May have bilateral (symmetrical) frontal lobe atrophy possibly
extending posteriorly (paracentral region)
Olivopontocerebellar or basal ganglia atrophy depending on
variant
Marked ventricular enlargement, with rounding of anterior
horns of lateral ventricles. Ventricular enlargement is
proportionate to sulcal widening – sulci normal, no
significant white matter pathology
Evidence subcortical infarcts and confluent hyperintensities
potentially extending into the temporal poles (which may be
non-enhancing)
Usually, one T2 lesion at least in two of four locations
(juxtacortical, periventricular, infratentorial, and spinal cord)
and a new T2 lesion on a follow-up scan. Consider using
contrast agent (e.g. gadolinium) T1 to identify new lesions
May appear as multifocal/confluent areas of hyperintensities
104 Dementia
imaging modality. Having selected a modality, it is impor-
tant to interpret what we ‘see’ in the context of clinical his-
tory in order to arrive at a clinical diagnosis that fits best.
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Functional brain imaging and connectivity in
dementia
KLAUS P. EBMEIER, NICOLA FILIPPINI, CLARE E. MACKAY, SANA SURI AND
VYARA VALKANOVA
11.1 INTRODUCTION
Neuroimaging offers a window into the living brain and thus
provides unique access to the understanding of normal and
pathological processes associated with ageing. Structural
imaging has diagnostic and, to some extent, prognostic value
in dementia (see Chapter 10). This chapter reviews the litera-
ture on functional imaging in dementia and also considers
new methods for looking at both structural and functional
connectivity in the brain. It explores whether these tech-
niques – some of which are novel, others have been used for
several decades – have added to our understanding of patho-
logical ageing. In particular we will focus on whether any of
the many imaging acquisition and analysis techniques can be
used as biomarkers to help the clinician with diagnosis, prog-
nosis or evaluating treatments (Valkanova and Ebmeier, 2014).
Although several different image modalities will be
described, neuroimaging studies of brain function in
dementia largely fall into two categories: (1) the study of rest-
ing blood flow and (2) measurement of brain changes due to
a specific task. This chapter starts with a brief description
of methods of emission tomography, functional magnetic
resonance imaging (fMRI) and diffusion tensor imaging
(DTI) before describing applications in patients.
11.2 IMAGING METHODS
11.2.1 SINGLE PHOTON EMISSION
COMPUTED TOMOGRAPHY (SPECT)
SPECT uses γ-emitting biologically relevant molecules
injected intravenously to be distributed to the brain. The
11
three-dimensional reconstruction of tracer distribution in
the brain gives a biologically meaningful map of blood flow,
receptor binding capacity or similar measures. Collimators
are used to admit photons coming from a defined direc-
tion to the photosensitive crystal. By design, this method
of directional filtering only allows for a small proportion of
emitted photons to be detected, which limits the sensitiv-
ity of SPECT. The attenuation of γ rays during their path
through brain is modelled making simple assumptions of
homogenous attenuation across the brain and head. Some
common applications of SPECT are listed in Table 11.1.
Gamma emitters with half-lives of 6–12 hours can be pro-
duced some distance from the scanner. Because of the long
half-life, only limited numbers of exposures are possible.
The isotopes employed (123I and 99mTc) are relatively large
and tend to change the pharmacology of the substituted
molecule. The extensive pharmacological development
work may, therefore, be one of the explanations for the rela-
tively limited number of SPECT-ligands available.
11.2.2 POSITRON EMISSION
TOMOGRAPHY (PET)
PET uses positron emitters to label physiological brain pro-
cesses. Positrons are non-stable elementary particles; within
millimetres’ travel they react with an electron to generate
two photons with a defined energy moving at approximately
180° away from each other. The detection of such coinci-
dence signals with a detector ring makes it possible to iden-
tify spatial as well as intensity information. Collimators are
not required and signal detection is more sensitive. Positron
emitting nuclei, particularly 11C, are easily incorporated
into biological molecules, without changing their chemical
characteristics. Positron emission is relatively energetic –
only short exposure to radiation is possible, the short decay
107
108 Dementia
Table 11.1 Some common applications of SPECT and PET
Tracer Isotope Mode
HMPAO a 99m Tc-SPECT
IMPb 123I-SPECT
ECDc 99mTc-SPECT
Water 15O-PET
Oxygen 15O-PET
FDGd 18F-PET
Glucose 11 C-PET
Abbreviations: SPECT, single photon emission computed tomography; PET, positron emission tomography.
a Hexamethylpropyleneamine oxime.
b N-isopropyl-(iodine-123)p-iodoamphetamine.
c Ethylene cysteinate dimer.
d Fluoro-deoxyglucose.
half-lives require on-site radiochemistry to incorporate the
nuclei into physiologically active compounds. In turn, short
half-lives allow for repeated application of tracers. Usually
transmission scans with a γ source in the detector rings are
used to quantify the attenuation across the brain.
11.2.3 FUNCTIONAL MAGNETIC
RESONANCE IMAGING
fMRI investigates brain function in a non-invasive fash-
ion. It relies on the blood-oxygen-level dependent (BOLD)
contrast to measure haemodynamic signal changes related
to neural activity. Oxy- and deoxy-haemoglobin have dif-
ferent ferromagnetic properties and affect a magnetic field
differently. The relative concentration of oxyhaemoglobin
increases in active brain areas, as blood flow increases more
than oxygen extraction.
Repeated examinations are usual, as within each sub-
ject high signal-to-noise ratios can be achieved by repeat-
ing scans many times. Brain activations with well-defined
BOLD signal have been obtained for functions such as lan-
guage, movement, hearing and memory. Signal changes
may be generated by synaptic activity that can be excitatory
or inhibitory (Arthurs and Boniface, 2002) and located at
a distance from the site of neuronal body activity. As the
BOLD signal is an indirect measure of neuronal activ-
ity greatly dependent on vascular components (i.e. cere-
bral blood flow [CBF], cerebral blood volume and vascular
compliance), brain oxygen metabolism and the coupling
between these measures, any change in one of these factors
may affect the magnitude of the signal. While this is not
a major problem when BOLD fMRI is used for anatomical
localization and mapping of neuronal activity, quantitative
interpretation of the signal in clinical populations is less
straightforward. Baseline perfusion measures and a more
accurate fMRI analysis model may be essential for correctly
interpreting group differences (Uludag et al., 2004). FMRI
analyses continue to be developed in a research context and
are by no means standardized. The clinical use of fMRI in
dementia is therefore an emerging field.
Physiology Clinical Use
Perfusion Yes
Perfusion Yes
Perfusion Yes
Blood flow Rare
Oxygen uptake No
Glucose uptake (aerobic + Yes
anaerobic)
Glucose uptake (aerobic) No
11.2.4 BLOOD FLOW MAGNETIC
RESONANCE IMAGING (ARTERIAL
SPIN LABELLING)
Arterial spin labelling (ASL) makes it possible to obtain
quantitative information about local tissue blood flow
(Wong et al., 1997). It is based on the modification of blood
magnetization in an artery (e.g. carotid) by magnetically
labelling blood flowing into the brain. Thus, ASL uses, as
a ‘tracer’, magnetically labelled water in flowing blood.
Blood flowing into the imaging slice exchanges with tissue
water, also altering tissue magnetization (Detre et al., 1992).
A ­perfusion-weighted image can be generated by subtract-
ing an image in which inflowing water molecules have been
spin labelled from an image without spin labelling. ASL
can be used to obtain either a static measurement of rest-
ing blood flow, or can be measured dynamically to obtain a
more quantitative fMRI signal. Compared with the BOLD
signal, ASL offers certain advantages, such as improved
sensitivity to slow changes in neural activity, reduced inter-
subject variability (Wang et al., 2003) and generally reduced
sensitivity to susceptibility artefacts (Detre and Wang,
2002). Furthermore, ASL provides a quantitative measure
of the CBF, which may be more closely related to neuronal
activation than the BOLD signal (Miller et al., 2001). It also
allows for a more specific functional localization because
the blood flow signal can be better spatially localized to
the site of neuronal activity, the ASL signal reaches the
activity peak earlier and has less variance in peak latency
compared with the BOLD signal. Perfusion-related altera-
tions have been observed across a variety of neurodegen-
erative disorders (Hu et al., 2010), and these changes may
reflect disease-related pathophysiological processes. ASL has
been less frequently used in research compared with fMRI
because of its low signal-to-noise ratio, poorer temporal
resolution, mainly due to the pairwise acquisition of label
and control images, as well as the required delay time for the
tagged blood to flow into imaging slices. It has smaller sig-
nal changes (typically less than 1%) compared with BOLD,
and only few established imaging sequences.

11.2.5 DIFFUSION TENSOR IMAGING
As described in Chapter 10, most of the research into struc-
tural deficits associated with dementia concerns grey mat-
ter. However, white matter pathology has also been reported
in Alzheimer’s disease (AD) and is noted in many other neu-
rodegenerative diseases. DTI is a structural imaging tech-
nique that is used to investigate the integrity of white matter
pathways in the brain. Diffusion-weighted images measure
the movement of water molecules within tissue, and when
acquired in multiple directions, are sensitized to diffusion in
all directions in the brain. Two quantitative measurements
are typically obtained from DTI data: (1) the total amount of
diffusion in a voxel variously referred to as the apparent dif-
fusion coefficient (ADC) or mean diffusivity (MD; to avoid
confusion with major depression we will use the acronym
ADC for this quantity) and (2) a measurement of the extent
to which diffusion is constrained to a particular direction
and is usually called fractional anisotropy (FA). In white
matter, the orientation of axons and myelin sheaths deter-
mine that diffusion will be easier along the tract (parallel)
(a) (b)
(c) (d)
Figure 11.1 (See colour insert.) Diffusion tensor imaging
provides quantitative measures of (a) apparent diffusion
coefficient (ADC) and (b) fractional anisotropy (FA). Brighter
signal means more average diffusion and more constrained
diffusion for ADC and FA, respectively. Note that grey and
white matter do not differ in ADC but have very different
FA values, such that FA provides a map of the myelinated
axons of white matter. By calculating the tensor informa-
tion, the direction of diffusion can be determined in each
voxel (c), from which tracts can be reconstructed (d). Panel
(c) shows the principal diffusion direction in the region
including the genu of the corpus callosum depicted by
the red box in panel (b). In panel (d), a tract of the forceps
minor (yellow) has been reconstructed by placing a single
‘seed’ voxel (blue) in the genu of the corpus callosum.
Functional brain imaging and connectivity in dementia 109
than across it (perpendicular); thus, it has a higher FA than
grey matter (Figure 11.1b). In contrast, grey and white mat-
ter has very similar values of ADC, because the amount of
water movement is approximately equal (Figure 11.1a).
Alterations of ADC and FA have been reported in many
diseases using a variety of methods: a region of interest (ROI)
across which mean ADC or FA is averaged can be compared
between individuals. This technique is simple, but deter-
mining the ROI is subjective, can be difficult to replicate
and information available in other areas of the brain may be
missed. Voxelwise techniques allow comparisons to be made
over the whole brain, but multi-subject registration is par-
ticularly problematic for FA data because of the variability
of white matter tracts. Tract-based spatial statistics (TBSS)
is a conservative voxelwise technique that reduces registra-
tion problems by comparing FA or ADC projected to the
centre of each major tract (Smith et al., 2006). Finally, by cal-
culating the tensor of the diffusion direction (Figure 11.1c),
reconstructions of white matter tracts can be made (Figure
11.1d). This tractography is used to define individual tracts
of interest for calculating mean FA or ADC.
11.3 BRAIN ACTIVITY PATTERNS USED
IN CLINICAL PRACTICE
There are no strictly applicable ‘rules’ for diagnostic imag-
ing, as Alzheimer-like pathology can be found in a sub-
stantial proportion of the brains of non-demented patients
(Neuropathology Group, 2001). In addition, the diagnoses
of AD and vascular dementia (VaD) are not mutually exclu-
sive so that mixed patterns are likely to occur in a signifi-
cant proportion of patients. Finally, at an advanced stage,
all dementias tend to involve large portions of the brain,
preferentially (and in all likelihood) association cortex, so
any differential features will disappear.
AD is said to initially be present with posterior cingulate
(Minoshima et al., 1997) or medial temporal (Callen et al.,
2002) reductions in brain activity, but soon after bilateral
posterior temporo-parietal reductions in brain activity also
appear (Holman et al., 1992). In blood flow and glucose
metabolism studies of patients with mild cognitive impair-
ment (MCI), temporo-parietal association areas, posterior
cingulate and hippocampus are associated with a higher
risk of progressive cognitive decline (Wolf et al., 2003).
During later stages, reductions in prefrontal activity occur,
so that some authors have suggested computing a ratio of
association cortex activity over primary sensory-motor
cortex activity as a diagnostic index for AD (Herholz et al.,
1999; Herholz, 2014). Frontotemporal dementias (FTDs),
i.e. those that initially present with functional impairment
of anterior parts of the brain, have a variety of underlying
pathologies, from Pick’s disease to AD and other tauopa-
thies to ­ubiquitin-positive, tau-negative cases. Vascular dis-
ease is likely to result in patchy lesions of brain perfusion,
often asymmetrical in distribution, or localized in ‘water-
shed’ regions of the brain.
110 Dementia
Experience of imaging clinical dementia with Lewy bod-
ies (DLB) patients suggests little difference in perfusion pat-
terns from AD, although occipitotemporal changes have
been described (Ishii et al., 1999; Minoshima et al., 2001).
11.4 DIAGNOSTIC SENSITIVITY AND
SPECIFICITY
As described in more detail in Chapter 57, the clinical and
pathological diagnoses of dementia are not always congruent.
The question about the true ‘gold standard’ for the evalua-
tion of imaging studies, therefore, arises: Should functional
imaging reflect the distribution and severity of brain cell
loss or pathological deposits, or should it be representative
of patients’ functional impairment or their symptoms and
signs? Either association would be of interest, but the most
important purpose of imaging is of course the facilitation of
effective treatment. Often the predictive validity of imaging
methods is not known, but it should be ascertainable using
standard empirical methods. By the time the brain comes to
post-mortem, a large number of confounding mechanisms
will have intervened, associated with the natural history of
dementia, additional illness and treatment, and the selection
bias resulting from low uptake of post-mortem examinations.
11.5 DIAGNOSTIC ACCURACY
OF FUNCTIONAL IMAGING
CURRENTLY USED IN CLINICAL
PRACTICE
11.5.1 ALZHEIMER’S DISEASE
Bilateral temporo-parietal hypo-metabolism has been fre-
quently reported for AD compared with normal volun-
teers. A systematic review and meta-analysis of literature
in SPECT and dementia (Dougall et al., 2003) found that
using data pooled from 27 studies, SPECT successfully
discriminated between healthy elderly controls and AD
with a pooled sensitivity of 77% against a pooled specific-
ity of 89%. Additional significant abnormalities have been
reported for AD in posterior cingulate (Minoshima et al.,
1997) and hippocampus (Elgh et al., 2002). For very early
AD, reductions in posterior cingulate tend to be greater
than in ­parieto-temporal and frontal association cortices
(Minoshima et al., 1997). Entorhinal cortex and hippo-
campal metabolic reductions have been successfully used
as a classifier in the discrimination of cognitively normal
controls from MCI (De Santi et al., 2001) with a diagnostic
accuracy of 81% and from AD using the temporal neocortex
with a diagnostic accuracy of 100% (De Santi et al., 2001).
In a prospective longitudinal analysis using the ratio of
deoxyglucose uptake in association cortex over primary
sensory-motor cortex for classification, initial metabolic
impairment was significantly associated with subsequent
clinical deterioration, thus predicting for patients with mild
cognitive deficits the progression to AD (Herholz et al., 1999).
In advanced AD, bilateral parieto-temporal perfusion
deficits are reported to be more frequent and severe (Nitrini
et al., 2000) with a reported odds ratio (OR) of 17.0 (95%
confidence interval [CI]: 3.1–94.2) for severe AD (Mini-
Mental State Examination [MMSE]: <10) and an OR of 5.2
(95% CI: 1.1–24.4) for moderate AD (MMSE: 10–17).
Initial studies using ASL and magnetic resonance imag-
ing (MRI) to measure blood flow in AD and FTD confirm
the established emission computed tomography results (Du
et al., 2006; Takahashi et al., 2014).
Reduced CBF in AD patients relative to healthy controls
has been demonstrated with ASL in brain regions typically
affected by Alzheimer type pathology, such as precuneus, pos-
terior cingulate, parietal association cortex and inferior tem-
poral lobe (Johnson et al., 2005; Alsop et al., 2008). Alsop et al.
also reported significantly greater CBF values in AD patients
relative to controls in the hippocampus, and more broadly
the medial temporal complex, after correcting for grey mat-
ter differences (Alsop et al., 2008). This finding emphasizes
the necessity to account for morphological differences when
investigating functional or physiological differences in stud-
ies involving AD patients. Moreover, it suggests that poten-
tial compensatory or pathological mechanisms may modulate
neural activity in brain regions where atrophy occurs. In
another study comparing AD, MCI and healthy controls, the
AD patients showed the lowest CBF values within the poste-
rior cingulate, precuneus and parietal lobes relative to healthy
controls and MCI, whereas the MCI patients had reduced CBF
values in the right inferior parietal lobe compared with the
healthy participants (Xu et al., 2007). There is also some evi-
dence to suggest that metabolic PET is able to distinguish pos-
terior cortical atrophy from AD and DLB (Spehl et al., 2014).
11.5.1.1 Pathologically confirmed studies
A multicentre study of PET in dementia with diagnostic
verification by 3-year clinical follow-up (Silverman et al.,
2001) concluded that regional brain metabolism was a sen-
sitive indicator of AD. In the same study, PET predicted a
pathologically confirmed diagnosis of AD with a sensitivity
of 94% (91 out of 97 subjects) against a specificity of 73%
(30 out of 41 subjects) against other patients presenting with
symptoms of dementia. Azzn overall diagnostic accuracy of
89% was achieved for a subset of 55 patients who presented
at the time of PET with questionable or mild dementia.
A PET study in a group considered ‘diagnostically
challenging or difficult to characterize by clinical criteria’
(Hoffman et al., 2000) produced sensitivity and specificity
values of PET against a histological diagnosis at autopsy of
AD of 93% and 63%, respectively. For comparison, clini-
cal diagnosis of probable AD had sensitivity and specificity
values of 63% and 100%, respectively, concluding that the

overall diagnostic accuracy of PET at 82% was better than
clinical diagnosis at 73%. Two comparable SPECT studies
with pathological verification of AD reported sensitivities of
86% and 63% (43 dementia patients versus 11 healthy elderly
controls) against specificities of 73% and 93% (70 demen-
tia patients versus 85 healthy elderly controls), respectively
(Bonte et al., 1997; Jagust et al., 2001). In a perfusion SPECT
study of 49 patients coming to autopsy, (Bonte et al., 2006)
found specificity for a diagnosis of AD with and without
Lewy bodies of 89.5%, against a mixed group of patients
with FTD, and sensitivity of 86.7% (Bonte et al., 2006).
Cerebrospinal fluid (CSF) biomarkers are equally found
to be associated with regional metabolic changes (Ceravolo
et al., 2008; Arlt et al., 2009).
11.5.2 VASCULAR DEMENTIA
Typical findings in VaD are multiple small areas of reduced
perfusion and metabolism extending over cortical and sub-
cortical structures and a high diagnostic accuracy has been
reported for the discrimination of probable AD and VaD
using this characteristic metabolic pattern (Mielke and
Heiss, 1998). In addition, frontal lobes including cingulate
and superior frontal gyri have been reported to be more
affected in VaD than in AD (Lee et al., 2001). On the other
hand, temporal-parietal brain regions have been said best
to discriminate AD from VaD with sensitivities reported as
high as 90% and 82% against 80% and 82% specificity respec-
tively (Butler et al., 1995; deFigueiredo et al., 1995). SPECT
has been reported to differentiate AD from multi-infarct
dementia (MID) in a study with a 77% correct classification
rate, compared with structural MRI which correctly classi-
fied only 50% in the same subject group (Butler et al., 1995).
11.5.3 FRONTOTEMPORAL DEMENTIA
Highly significant metabolic abnormalities have been
reported for PET in fronto-temporo-parietal association
cortex, limbic area, basal ganglia and thalamus in FTD
compared with normal volunteers. In particular, bilateral
frontal hypoperfusion is a strong predictor of FTD versus
AD in SPECT, with sensitivity and specificity estimated at
88% and 79%, respectively (Sjogren et al., 2000). Medial
temporal lobe reduction has been suggested as a marker
to separate AD from FTD (Sjogren et al., 2000). In a MRI
study using ASL, AD patients had reduced CBF values
relative to FTD patients in posterior brain regions, such
as posterior cingulate and parietal lobes, whereas FTD
patients had reduced CBF values in frontal regions relative
to AD patients. The combined use of grey matter atrophy
and perfusion values improved the discrimination between
FTD patients and healthy controls, yielding a correct clas-
sification value of 74% (71% sensitivity, 76% specificity).
In addition, the combination of grey matter and CBF val-
ues improved the differential diagnosis between FTD and
Functional brain imaging and connectivity in dementia 111
AD patients with 87% correctly classified (90% sensitiv-
ity, 83% specificity) (Du et al., 2006). Fluorodeoxyglucose-
PET (FDG-PET) in behavioural variant FTD (bvFTD) was
able to identify almost 50% of patients not diagnosed with
structural MRI (Kerklaan et al., 2014).
11.5.4 DEMENTIA WITH LEWY BODIES
AND DIFFERENTIAL DIAGNOSIS
WITH DEPRESSION
An autopsy-confirmed PET study of the differential diag-
nosis of DLB and AD subjects found occipital metabolic
reductions as a potential ante-mortem marker to distin-
guish DLB from AD, with sensitivity and specificity values
determined at 90% and 80% respectively (Minoshima et al.,
2001). SPECT studies have confirmed occipital reduction
in perfusion as an indicator of DLB (Lobotesis et al., 2001).
Medial temporal and cingulate reductions in metabolism
were significantly more pronounced in AD compared to
DLB (Imamura et al., 1997), while the occipital deficit in
DLB appears irrespective of clinical severity (Okamura et
al., 2001). There is, however, significant overlap between the
imaging phenotypes of AD and DLB (Chiba et al., 2015).
SPECT has been reported to be a useful tool for the differ-
ential diagnosis of AD and depression, with perfusion deficits
in depression lying between those of controls and AD and a
reported sensitivity of 52% (against 94% with controls) using
parieto-occipital perfusion as a marker (Stoppe et al., 1995).
11.5.5 SPECT VERSUS PET
A direct comparison (Herholz et al., 2002) of SPECT and
PET produced an overall significant correlation of abnor-
mal tracer uptake between PET and SPECT across the entire
brain (r = 0.43) with better correspondence achieved in the
temporo-parietal and posterior cingulate association cor-
tices. Using quantitative statistical parametric mapping
(SPM), the same study reported that PET discriminated
between healthy volunteers and AD with greater reliabil-
ity than SPECT, since PET was less sensitive to statistical
threshold effects. Clinical utility, e.g. predictive validity, of
FDG-PET appears to be higher than SPECT in small pre-
liminary studies (Ishii and Minoshima, 2005), although
opinions differ (Yuan et al., 2009). In a small study directly
comparing F-18-FDG-PET and IMP-SPECT in patients
with DLB, reductions of tracer uptake were found in poste-
rior parietal and to a lesser extend in occipital cortex, with
PET appearing to be more sensitive to changes (Ishii et al.,
2004). A recent systematic review concluded that although
studies suggest superiority of PET over SPECT, the evidence
base for this is limited (Davison and O’Brien, 2014). SPECT
studies reported sensitivities of 65%–85% for diagnosing
AD and specificities (for other dementias) of 72%–87%, PET
studies sensitivities of 75%–99% for AD and specificities of
71%–93% (Davison and O’Brien, 2014).
112 Dementia
11.5.6 METHODOLOGICAL ISSUES
FOR ESTABLISHING
DIAGNOSTIC TOOLS
PET and SPECT images can be analysed qualitatively using
visual inspection methods or quantitatively using a variety
of semi-automated methods (Morbelli et al., 2014; Perani
et al., 2014).
For quantitative ROI analysis, the brain is divided into
areas often approximating underlying structural anatomy.
Mean values of functional activity are then averaged within
these regions and compared with a data set of controls
(Defebvre et al., 1999). More objective methods have been
developed recently, such as an automated multi-ROI pro-
gramme 3DSRT (Kobayashi et al., 2008), statistical para-
metric mapping (Friston et al., 1995), discriminant function
analysis (O’Brien et al., 2001) and neural network analysis
(Chan et al., 1994). Three-dimensional stereotactic surface
projection images improve the accuracy of visually detect-
ing AD with PET (Burdette et al., 1996). Finally, a combina-
tion of structural MRI or computed tomography (CT) and
functional imaging improves the accuracy of diagnostic
classification (O’Brien et al., 2001).
11.6 THE CUTTING EDGE: BRAIN
FUNCTION AND CONNECTIVITY
IN DEMENTIA
The first cognitive deficit in AD is often associated with epi-
sodic memory loss, which corresponds to early reduction in
perfusion of the posterior cingulate gyrus and precuneus
(Desgranges et al., 1998). The semantic memory impair-
ment common in early AD and even MCI (Lonie et al.,
2009) occurs when neurodegenerative changes extend to
the adjacent temporal neocortex. Short-term memory per-
formance is correlated with metabolism in the temporo-
parietal association cortex, with the left hemisphere for
verbal and right for spatial memory respectively (Haxby et
al., 1990b; Trollor and Valenzuela, 2001). If attention is the
next domain to be affected, the anterior cingulate is thought
to be involved (Matsuda, 2001). This is consistent with the
clinical picture – it is thought that attentional impairment
is responsible for those problems in activities of daily living
that occur at an early stage.
Patients often have problems with task performance
which makes the interpretation of group differences in
imaging studies difficult. This does not apply to resting
state fMRI (rs-fMRI) (Fox and Raichle, 2007). During an
rs-fMRI study, participants lie in the scanner without task
or stimulation. Brain regions showing a strong connectivity
(temporal coherence) are defined as ‘resting state networks’
(RSNs) and reflect properties of functional brain organiza-
tion. RSNs have been consistently observed across subjects
(Damoiseaux et al., 2006), sessions (Chen et al., 2008) and
imaging modalities (fMRI, PET, electroencephalography
[EEG]) (Raichle et al., 2001; Goldman et al., 2002). The use
of rs-fMRI data has been of great interest, particularly in
those with or at risk of developing neurodegenerative disor-
ders (Greicius et al., 2004; Sorg et al., 2007).
11.6.1 COGNITIVE ACTIVATION STUDIES
IN DEMENTIA AND PRECLINICAL
STAGES
Functional activation studies have shown that in mild-to-
moderately severe AD, a cognitive or sensory challenge task
can cause nearly normal levels of activation in areas that
are hypometabolic or hypoperfused at rest. However, with
increased disease severity the degree of activation declines
(Devous, 2002). Furthermore, excessive activation may be
required in AD patients who perform a task, or activation
of additional brain areas, which are not activated by healthy
controls (Cardebat et al., 1998). It has been hypothesized that
functional plasticity may be responsible for such additional
recruitment of new brain regions in patients. Because the
medial temporal lobe (MTL) complex, and the hippocampus
in particular, is the brain region to show earliest pathologi-
cal signs in AD, and because of its involvement in memory
processes, most fMRI studies of AD patients have used mem-
ory paradigms to investigate disease-related effects on brain
activity. fMRI studies using encoding and retrieval memory
tasks have consistently reported decreased activation in hip-
pocampus and parahippocampus of patients compared with
healthy volunteers (Rombouts et al., 2000). More controver-
sial are reports for other neocortical brain regions, such as
prefrontal cortex, where both decreased (Small et al., 1999)
and increased (Sperling et al., 2003) activation have been
observed in AD patients. Such increased activation in pre-
frontal cortex has been interpreted as compensatory reorga-
nization (plasticity) or as a dedifferentiation (mass activation)
process (Prvulovic et al., 2005). Functional abnormalities
have been also observed in brain regions not directly affected
by AD in the early stages of the disease, such as sensory motor
cortex (Buckner et al., 2000). Other neurodegenerative dis-
eases, such as FTD, DLB and VaD, have been less extensively
studied. An fMRI activation study compared patients with
early AD and FTD during a working memory task in order
to identify group-related differences. During performance of
the task, there was reduced activation in the frontal, tempo-
ral and cingulate cortices in the FTD group compared with
the AD group. There was, however, the opposite effect in the
cerebellum, a region less consistently activated in functional
working memory imaging studies. This cerebellar activation
in FTD may reflect successful working memory specific com-
pensation, since test performance of FTD patients were not
different from the AD group (Rombouts et al., 2003).
FMRI has been advocated to detect early functional brain
changes in patients with MCI, where memory symptoms are
still isolated, and before more wide-spread structural atro-
phy observed in AD patients has become manifest. fMRI
studies in MCI subjects have focused on detecting brain
functional abnormalities within the MTL complex using

memory-based tasks. Results are less consistent than in AD
studies, showing either increased (Dickerson et al., 2005) or
decreased (Machulda et al., 2003) activation in MTL regions
compared with healthy subjects. It has been suggested
that MCI subjects may show increased MTL activation to
compensate for incipient structural damage. Accordingly,
where MCI subjects were divided into two groups, those
less impaired and those more impaired in an associative
memory task, the less impaired group showed increased
activation, whereas the more impaired group showed hip-
pocampal decreased activation, compared with a group of
healthy subjects (Celone et al., 2006).
11.6.2 RESTING FMRI STUDIES IN
DEMENTIA AND PRECLINICAL
STAGES
The value of rs-fMRI has been examined in several clinical
studies (Greicius et al., 2004; Greicius et al., 2007; Sorg et al.,
2007). The most commonly investigated RSN, the ‘default
mode network’ (DMN) (Raichle et al., 2001), includes brain
regions, such as prefrontal cortex, anterior and posterior
cingulate and lateral parietal extending to medial temporal
cortex, that overlap with amyloid plaques and grey matter
atrophy (Sperling et al., 2009). Reduced functional con-
nectivity in the DMN has been reported in AD relative to
healthy controls, and is associated with faster disease pro-
gression (Raichle et al., 2001; Greicius et al., 2004; Zhang
et al., 2010; Binnewijzend et al., 2012; Zamboni et al., 2013).
Reduced DMN connectivity has also been observed in
MCI (Sorg et al., 2007), unaffected relatives in familial AD
(Chhatwal et al., 2013) and volunteers with memory com-
plaints (Wang et al., 2013). Moreover, a disproportionate
reduction in DMN connectivity with advancing age has
been found in subjects carrying the apoprotein E (APOE)
ε4 allele, reflecting the increased vulnerability of ε4 carriers
to late-life pathology and cognitive decline (Sheline et al.,
2010; Machulda et al., 2011).
Reduced connectivity in the ‘salience’ network has been
consistently observed in FTD patients (Whitwell et al., 2011b;
Filippi et al., 2013). This network includes brain regions
such as the dorsal anterior cingulate and the insular cortices
bilaterally and it is largely involved in guiding behaviourally
salient events (Seeley et al., 2007). Reduced connectivity in
a network including motor regions, basal ganglia nuclei and
cerebellar areas has been observed in patients with pro-
gressive supranuclear palsy (PSP) (Whitwell et al., 2011a;
Gardner et al., 2013), which is clinically characterized by
motor symptoms and cognitive impairment.
11.6.3 STRUCTURAL CONNECTIVITY IN
AD AND OTHER DEMENTIAS
Decreased white matter integrity (increases in MD/
ADC and decreases in FA) are a feature of normal ageing
(Charlton et al., 2006), and histopathological studies show
Functional brain imaging and connectivity in dementia 113
that this may be due to a loss of myelinated fibres (Tang
et al., 1997). Studies demonstrating a negative correlation
between FA and performance on cognitive tasks lend sup-
port to the hypothesis that white matter deterioration can
underlie cognitive decline.
White matter hyperintensities are common in AD,
increased ADC and decreased FA have been reported
throughout the temporal, frontal and parietal lobes in
patients with AD (Chua et al., 2008), and several authors
have related white matter deficits to neuropsychological
measures of cognitive decline (Bozzali et al., 2002). Reduced
FA has also been reported in patients with early AD (Choi et
al., 2005), MCI (Rose et al., 2006) and in healthy carriers of
the APOE ε4 allele (Persson et al., 2006). Although reduc-
tions in FA and increases in ADC are not specific to AD,
these studies suggest that white matter degradation begins
early in the disease process.
Although white matter abnormalities have been
described in many areas of the brain in AD, there is some
suggestion that the regional pattern of impairment may
distinguish AD from other dementias; for a recent review
see Suri et al. (2014). Zarei et al. (2009) used TBSS to distin-
guish AD from VaD. Relative to controls, patients with AD
had reduced FA in the temporal lobe, whereas patients with
VaD had more widespread reductions in FA in frontal and
parietal areas. They identified a small region in the genu of
the corpus callosum that was significantly more impaired
in patients with VaD relative to those with AD. Zhang
et al. (2011) reported that patients with FTD have more
widespread abnormalities of white matter than patients
with AD. Like the patients with VaD in the previous study,
patients with FTD have significantly lower FA and higher
ADC in the genu of the corpus callosum (Zhang et al.,
2009), as well as in the uncinate fasciculus (Mahoney et al.,
2014). These studies suggest that there are more extensive
impairments of white matter integrity in patients with VaD
and FTD relative to those with AD. There is also evidence
for regional differences in white matter microstructure
between AD and DLB patients. Using a tractography-based
approach, Kiuchi et al. (2011) found that despite similar
severity of dementia, DLB patients show greater reduc-
tions in FA in temporo-occipital projection tracts relative
to healthy controls than patients with AD. Damage to these
tracts may underlie the visual deficits commonly observed
in DLB patients.
11.6.4 LONGITUDINAL STUDIES
A number of functional imaging studies have investigated
cognitive functioning over time. These have shown that
patients with more severe perfusion or metabolic deficits
in the temporo-parietal cortex at initial evaluation show
a more rapid cognitive decline over time (Devous, 2002).
With regard to MCI, significant bilateral regional CBF
(rCBF) decreases are seen in the posterior cingulate, pari-
etal and precuneus regions of those who later meet criteria
for AD. Subsequently, at the stage of a clinical diagnosis of
114 Dementia
AD, additional rCBF abnormalities are seen in the hippo-
campus and parahippocampus (Minoshima et al., 1997).
For individual patients, the particular neuropsychologi-
cal pattern that develops during the progression of AD can
be predicted by early metabolic asymmetries in the asso-
ciation cortices (Haxby et al., 1990a). This would indicate
that there is a functional reserve in the brain, so that neu-
ropsychological dysfunction is likely to follow rather than
co-occur with rCBF changes.
More recently, longitudinal functional imaging studies
have been proposed to assess the response to treatments for
AD (Alexander et al., 2002). Such activation studies are of
particular interest, as they can help in identifying poten-
tially reversible tissue damage.
Conversion from MCI to AD can be predicted with
functional scans (Drzezga et al., 2005; Borroni et al., 2006;
Nobili et al., 2009), and hypometabolism is even found in
cognitively normal subjects at increased risk of AD (Reiman
et al., 2004; Mosconi et al., 2007).
11.7 CONCLUSIONS FOR THE
CLINICIAN
One of the authors’ central tenets is that the ‘gold stan-
dard’ of all imaging work has to be the patients’ clinical
state. By implication, ‘predictive validity’ is the concept of
greatest interest: imaging results should predict patients’
prognosis and in particular whether they are going to
respond to a treatment. This does not contradict the basic
notion that diagnosis has to be at the beginning of effec-
tive treatment, but it reflects the observation that brain
pathological changes are not always specific to a particu-
lar illness; that there is a substantial overlap of pathologi-
cal changes even with health, and that pathological illness
‘entities’ are likely to be caused by a varying admixture
of genotype–environment interactions: AD is really a
collective term for a number of conditions resulting in
dementia, plaques and tangles. Histological diagnoses
merely reflect recognizable final common pathways for
a collection of pathological conditions and therefore do
not necessarily predict treatment response or prognosis.
In evaluating the usefulness of imaging methods, direct
comparisons should be made with clinical outcome mea-
sures – histopathological follow-through studies are of
interest, but will always be confounded by selection bias,
intervening illness and other artefacts. The utility of any
imaging biomarker depends on its specificity and sen-
sitivity for differential diagnosis, their ability to detect
disease early or their response to treatment (Dubois et
al., 2014). Although most imaging modalities described
here have clinical relevance, it is likely that the individual
measurements will be most useful in combination. One
of the binds we encounter is that useful data on sensitiv-
ity and specificity, and more particularly positive and
negative predictive value, require representative clinical
cohorts. If the introduction of a new imaging method is to
be evidence-based in a National Health Service and good
evidence is only available after the establishment of a ser-
vice, the creation of pilot services is necessary that are not
technology driven, i.e. that are centred in a normal clini-
cal set-up that will generate results transferable to the ser-
vice in general (Elias et al., 2014). The theoretical appeal of
imaging methods, after all we believe that the dementias
are brain diseases, holds out the promise of visualizing
brain changes that are relevant to illness outcome and
treatment response.
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Molecular brain imaging in dementia
VICTOR L. VILLEMAGNE AND CHRISTOPHER C. ROWE
12.1 MOLECULAR IMAGING IN
DEMENTIA
Molecular neuroimaging techniques such as positron
­emission tomography (PET) have been used for the in vivo
assessment of molecular processes at their sites of action,
permitting detection of subtle pathophysiological changes
in the brain at asymptomatic stages, when there is no evi-
dence of anatomic changes on computed tomography (CT)
or magnetic resonance imaging (MRI). The development
of molecular imaging methods for non-invasively assess-
ing disease-specific traits such as beta-amyloid (Aβ) or tau
in Alzheimer’s disease (AD) is allowing early diagnosis at
presymptomatic stages, more accurate differential diagnosis
as well as, when available, the evaluation and monitoring
of disease-modifying therapy (Table 12.1) (Villemagne and
Okamura, 2014; Rowe and Villemagne, 2011).
12.2 MOLECULAR IMAGING
RADIOTRACERS
Therapies, especially those targeting irreversible neuro-
degenerative processes, have a better chance of success if
Table 12.1 Potential roles for Aβ and tau imaging in Alzheimer’s disease
• Accurate diagnosis of Alzheimer’s disease
• Prediction (Aβ) and monitoring (tau) of disease progression
• Early diagnosis of Alzheimer’s disease, allowing intervention when minimally impaired
• Investigate the spatial and temporal pattern of Aβ and tau deposition over a period of time, their interplay as well as
their relation to genetic and epigenetic factors, onset of phenotype, cognitive decline, brain volumetrics and other
disease biomarkers
• Subject selection for disease-specific therapeutic trials
• Monitor the effectiveness of anti-Aβ or anti-tau therapy
• Predict response to disease-specific therapy
12
applied early. So early detection of the underlying patho-
logical process is important. Since Aβ plaques and tau
­neurofibrillary tangles (NFT) are the hallmark brain lesions
at the centre of AD pathogenesis, several pharmacological
agents aimed at reducing Aβ and tau levels in the brain
are being developed and tested, many efforts have focused
on generating radiotracers that allow Aβ and tau imaging
in vivo and are suited to widespread clinical application.
For a radiotracer to be useful as a neuroimaging Aβ
probe, a number of key general properties are desirable: they
should be lipophilic molecules that cross the blood–brain
barrier, preferably not to be metabolized, while reversibly
binding to Aβ in a specific and selective fashion (Villemagne
et al., 2008a). Furthermore, low non-specific binding to
white matter is desirable as Aβ deposition usually starts at
layers III and IV of the cortex (Thal et al., 2000) and spills
over from high non-specific binding in white matter mask
or reduces the ability to detect this early deposition.
The last two decades have been focused on developing
Aβ radiotracers to detect cortical Aβ deposition in vivo
and some of them have already been approved for clinical
use. Aiming at mirroring the achievements of Aβ imaging,
renewed efforts have been directed to the design of selec-
tive tau radiotracers (Klunk et al., 2004; Villemagne et al.,
2012a; Villemagne and Okamura, 2014). Stemming from
the tracer’s capacity to bind a particular target over other
119
120 Dementia
similar misfolded proteins has been used to classify them as
selective or non-selective (Villemagne and Okamura, 2014).
12.2.1 SELECTIVE Aβ IMAGING
RADIOTRACERS
Several compounds have been evaluated as potential Aβ
probes. Almost a decade after unsuccessful trials with
Aβ fragments, anti-Aβ antibodies and different dyes
(Villemagne et al., 2014a) Αβ imaging came to fruition with
the first report of successful imaging in an AD patient with
2-(l-{6-[(2-[18F]fluoroethyl)(methyl)amino]-2-naph-thyl}
ethylidene)malononitrile (18F-FDDNP), a tracer character-
ized for binding both plaques and NFT (Shoghi-Jadid et al.,
2002). Since then, human Αβ imaging studies have been con-
ducted in AD patients, normal controls and patients with
other dementias using C-11 labelled Pittsburgh Compound
B (11C-PiB) (Klunk et al., 2004), 11C-SB13 (Verhoeff et al.,
2004), 11C-ST1859 (Bauer et al., 2006), 11C-BF227 (Kudo et al.,
2007), 18F-florbetaben (Rowe et al., 2008a), [18F]flutemetamol
(Vandenberghe et al., 2010), 11C-AZD2138 (Nyberg et al.,
2009), 18F-florbetapir (Wong et al., 2010) and 18F-AZD4694
(Cselenyi et al., 2012) with PET and with 123I-clioquinol
(CQ) (Opazo et al., 2006) and 123I-IMPY (Newberg et al.,
2006) using single photon emission computed tomography
(SPECT) (Figure 12.1).
The focus on radiotracers for Aβ imaging in vivo
(Villemagne and Rowe, 2010) resulted in the development
of multiple compounds, some of which were successfully
tested in human clinical trials, including the most success-
ful and widely used radiotracer till date, 11C-PiB (Klunk
et al., 2004) (Figure 12.1). [11C]PiB is a derivative of the
NC CN
OH
CH3
18F
N H
CH3
18F-FDDNP
F O
O
11CH
3 11C-BF227
N 11
OH OH
H N
123I
11C-SB13
CI
123I-CQ
OH
11CH
2 18F-f lorbetaben
OH N
N 18F
123I
11C-ST1859 123I-IMPY
Figure 12.1 Chemical structure of Aβ ligands.
Αβ-binding dye thioflavin-T that shows both high affinity
and high specificity for fibrillary Aβ in plaques (Cohen et al.,
2012; Ye et al., 2005) as well as other Aβ-containing lesions
including cerebral amyloid angiopathy (CAA) (Lockhart
et al., 2007). Furthermore, no specific binding was found in
subcortical white matter (Fodero-Tavoletti et al., 2009) and
at tracer concentrations, [11C]PiB does not bind at detectable
levels to other misfolded proteins with a similar secondary
β-sheet structure such as α-synuclein (Fodero-Tavoletti et al.,
2007) or tau (Ikonomovic et al., 2012; Lockhart et al., 2007).
On visual inspection, cortical retention of [11C]PiB, regard-
less of disease severity, is markedly elevated in AD (Klunk
et al., 2004; Mintun et al., 2006; Rowe et al., 2007), being high-
est in frontal, cingulate, precuneus, striatum, parietal and
lateral temporal cortices (Figure 12.2). Post-mortem studies
using [11C]PiB revealed high correlations with regional Aβ
retention as measure at autopsy (Ikonomovic et al., 2012),
as well as with Aβ1-42 in cerebrospinal fluid (CSF) (Zwan
et al., 2014a). A handful of other C-11 labelled radiotrac-
ers have been tested in human studies, although low effect
sizes ([11C]SB13) (Verhoeff et al., 2004), small dynamic range
([11C]ST1859) (Bauer et al., 2006) or lack of selectivity ([11C]
BF-227) (Okamura et al. 2004) made them less favourable
for detection of cortical Aβ burden compared with 11C-PiB.
On the other hand, a couple of C-11 tracers, [11C]AZD2184
(Nyberg et al., 2009) and [11C]AZD2995 (Forsberg et al.,
2013) are detected projecting similar characteristics as [11C]
PiB. However, widespread clinical implementation of these
C-11 tracers is hampered by the short radioactive half-life of
C-11 (T½ = 20 min) requiring on-site production. To over-
come this limitation, various F-18 (T½ = 110 min) labelled
tracers were developed.
N H
N H
S N
11CH
3
H O N 11
11C-PiB 18 CH3
F
18F-NAV4696
N
N N
H S N 11CH
N 3
S CH3 11
C-AZD2184
N 18F
CH3
N H
N S
OH CH3
HN
18
F-f lutemetamol
18F
O
O O
HN
N
O
18
F-f lorbetapir N O O
 Molecular brain imaging in dementia 121

Figure 12.2 (See colour insert.) Typical pattern of 11C-PiB binding in AD. Representative sagittal and transaxial [11C]
PiB PET images overlayed on their respective MRI in a healthy elderly control subject (HC) (left) compared with an
Alzheimer’s disease (AD) patient (right). 11C-PiB retention is observed in frontal, temporal and parietal cortices as well as in
the posterior cingulate/precuneus areas, with relative sparing of occipital and sensorimotor cortex.

[18F]florbetapir ([18F]AV-45, Amyvid®), is a stilbene deriv-
ative synthesized by Kung and colleagues at the University of
Pennsylvania (Zhang et al., 2005a, 2005b) (Figure 12.1). [18F]
florbetapir showed a 96% agreement with neuropathology
(Clark et al., 2011) with a sensitivity of 92% and a specificity
of 100% for detection of cortical Aβ in vivo against moder-
ate to frequent Aβ plaque pathology at autopsy (Clark et al.,
2012). Furthermore, in direct comparison study, [18F]flor-
betapir was highly correlated with [11C]PiB (Landau et al.,
2014) and found suitable to discriminate AD from controls
(Wong et al., 2010). A multicentre study showed that, both
in at-risk subjects and AD patients, high cortical Aβ burden
was associated with worse cognitive performance (Sperling
et al., 2013) and these patients were predicted to face a
greater cognitive deterioration over 3 years (Doraiswamy
et al., 2012; Doraiswamy et al., 2014). Furthermore, high
cortical Aβ burden measure by 18F-florbetapir was associ-
ated with lower memory performance in clinical normal
elderly (Sperling et al., 2013). [18F]Florbetapir was the first
radiotracer approved by the Food and Drug Administration
(FDA; April 2012) and the European Medicines Agency
(EMA; January 2013) for detection of Aβ in vivo and is being
used for both patient selection and evaluation of treatment
response in several anti-Αβ drug trails (Sperling et al., 2011).
To date, it is regarded as the most widely used Aβ radio-
tracer after [11C]PiB.
[18F]florbetaben ([18F]AV-1, [18F]BAY-94-9172, Neuraceq®)
was also synthesized by Kung and colleagues (Zhang et al.,
2005a) and developed by Bayer Healthcare and Piramal
(Figure 12.1). [18F]florbetaben showed selective binding to
Aβ plaques with lack of binding to Lewy bodies or NFT
in post-mortem tissue at low nanomolar concentrations
(Fodero-Tavoletti et al., 2012). Global 18F-florbetaben reten-
tion showed excellent correlation with [11C]PiB retention
(Villemagne et al., 2011a). Furthermore, it was effective in
discriminating AD from clinically normal controls and
frontotempolar lobar degeneration (FTLD) patients with
high sensitivity and specificity to detect high Aβ burden
against clinical diagnosis (Rowe et al., 2008; Barthel et al.,
2011) and was able to detect the presence or absence of AD
pathology in a mixed population of cognitive impaired sub-
jects (Villemagne et al., 2011a). In mild cognitive impair-
ment (MCI) patients, [18F]florbetaben was correlated with
episodic memory and showed a predictive accuracy of 83%
for conversion to AD after 2 years and up to 94% after 4
years (Ong et al., 2015). Furthermore, a multicentre phase 3
trail confirmed that florbetaben PET was able to detect cor-
tical fibrillar Aβ plaques as assessed by visual reading with
100% sensitivity and 92% specificity against post-mortem
silver-staining and immunohistochemistry (Sabbagh et al.,
2012). [18F]florbetaben received FDA and EMA approval for
clinical use in February and March 2014, respectively.
[18F]flutemetamol (GE-067, Vizamyl ®) is the [3]-fluoro-
derivative of [11C]PiB developed by GE Healthcare for
detection of cortical Aβ deposition (Figure 12.1). A histo-
pathology study showed high concordance and strong cor-
relation between [18F]flutemetamol PET retention and Aβ
burden measure by a monoclonal antibody in brain biopsy
122 Dementia

tissue and at autopsy (Ikonomovic et al., 2012). In addition,
[18F]flutemetamol retention is highly correlated with [11C]
PiB across the spectrum of AD (Vandenberghe et al., 2010)
and phase II and III trails confirmed that [18F]flutemetamol
can differentiate between AD and controls with a sensitivity
and specificity of 93% (Nelissen et al., 2009; Vandenberghe
et al., 2010). Furthermore, [18F]flutemetamol PET has addi-
tive value to MRI for diagnostic classification and prediction
of conversion in MCI subjects (Thurfjell et al., 2012; Duara
et al., 2012). [18F]flutemetamol received FDA approval in
October 2013 and EMA approval in September 2014 under
the brand name of Vizamyl®.
[18F]NAV4694 (also known as [18F]AZD4694) is a radio-
tracer developed by Astra-Zeneca and Navidea (Figure
12.1). Direct comparison with [11C]PiB revealed that [18F]
AZD4694 showed similar binding kinetics, dynamic reten-
tion range and low non-specific binding to white matter
with an excellent correlation between [18F]AZD4694 and
[11C]PiB cortical retention (Rowe et al., 2013b). Furthermore,
[18F]AZD4694 clearly identified AD patients from healthy
controls both by quantitative measure and visual inspection
(Rowe et al., 2013b; Cselenyi et al., 2012).
For visual inspection of Aβ imaging studies, high radio-
tracer retention in the cortical and subcortical grey matter
is synonymous of a high Aβ burden (Zwan et al., 2014b)
(Figure 12.3). In contrast to [11C]PiB or [18F]NAV4694, [18F]
florbetapir, [18F]florbetaben and [18F]flutemetamol (Figure
12.3) show the presence of relatively high white matter
uptake. In the case of [18F]flutemetamol, similar cortical
tracer retention than [11C]PiB is accompanied by higher
white matter uptake, whereas in the cases of [18F]florbetapir
and [18F]florbetaben (Landau et al., 2014; Villemagne et al.,
2011a), lower cortical retention than [11C]PiB is accompa-
nied by a similar white matter uptake. This results in a very
sharp contrast between grey and white matter in those cases
with low or no detectable Aβ deposition in the brain and
loss of this normal grey–white matter demarcation has been
proposed for the correct identification of high Aβ burden
with these F-18 tracers.
While all of the aforementioned tracers bind with vary-
ing degrees of success to Aβ fibrils and brain homogenates
of AD patients, Congo Red and thioflavin T – and some
of their derivatives – have been shown to also bind to the
soluble oligomeric forms of Aβ (Maezawa et al., 2008). On
the other hand, Aβ soluble species reportedly represent less
than 1% of the total brain Aβ (McLean et al., 1999) and the
reported affinity of PiB for these soluble oligomers seems
to be significantly lower than for Aβ fibrils (Maezawa et al.,
2008). Until highly selective radiotracers are developed to
bind the Aβ soluble species, the contribution of these oligo-
mers to the Αβ imaging PET signal in sporadic AD from
tracers such as 11C-PiB is considered to be negligible (Mathis
et al., 2007).
Preliminary studies with SPECT Aβ radiotracers (Figure
12.1) shows limited utility for the evaluation of Aβ burden
in AD (Newberg et al., 2006). New SPECT radiotracers
labelled with 123I or those that could be potentially labelled
with 99mTc are being evaluated (Lin et al., 2009).

Figure 12.3 (See colour insert.) Aβ imaging in Alzheimer’s disease. Representative parametric sagittal, transaxial and
coronal PET images of Alzheimer’s disease (AD) patients assessed with either [11C]PiB, [18F]florbetaben, [18F]flutemetamol,
[18F]florbetapir or [18F]NAV4694. All AD patients harboured high Aβ burdens in the brain, reflected in marked radiotracer
retention in cortical and subcortical grey matter areas. [18F]Florbetapir (Amyvid®); [18F]flutemetamol (Vizamyl®) and [18F]
florbetaben (Neuraceq®) have already been approved for clinical use by the FDA and EMA.
 Molecular brain imaging in dementia 123

12.2.2 SELECTIVE TAU IMAGING
RADIOTRACERS
In AD, the prevalent ultrastructural conformation of tau
aggregates is PHF, therefore, most of the focus has been
directed at developing selective tau imaging radiotracers for
PHF-tau. Notwithstanding, some of these tracers recognize
other conformations of tau aggregates found in non-AD
tauopathies. The development of novel selective tau ligands
(Figure 12.4) has led to successful first-in-human tau imag-
ing PET studies. While several potential tracers have been
proposed by research groups working on anti-tau therapeu-
tics (for review see Villemagne and Okamura, 2014), only a
few tau tracers amenable to radiolabeling made the transi-
tion into human trials (Chien et al., 2013; Maruyama et al.,
2013; Okamura et al., 2013).
For more than a decade, Kudo and colleagues at Tohoku
University, Sendai, Japan, have been designing, developing
and screening small binding molecules targeting misfolded
proteins (Okamura et al., 2005, 2013). The first candidate,
[18F]THK523 (Figure 12.4) showed low nanomolar affinity
to tau fibrils, a 12-fold selectivity for tau over Aβ, and sig-
nificant in vivo tracer retention in a tau transgenic mouse
model (Fodero-Tavoletti et al., 2011). In vitro studies dem-
onstrated that while [18F]THK523 bound selectively to
PHF-tau (Harada et al., 2013), it did not bind to α-synuclein
deposits (Fodero-Tavoletti et al., 2014) nor other non-AD tau
lesions. Initial PET studies showed significantly higher [18F]
THK523 retention in hippocampi, temporal, parietal and
orbitofrontal regions of AD patients, but because cortical
retention was significantly lower than white matter reten-
tion it was impossible to discriminate tracer retention by
visual inspection of the images (Villemagne et al., 2014b).
Notably, in healthy controls with high Aβ burden as assessed
by [11C]PiB, while cortical [18F]THK523 retention was low,
[18F] THK523 retention in hippocampus and insula was
similar to the one observed in AD (Villemagne et al., 2014b).
Two improved derivatives, [18F]THK5105 and [18F]THK5117
(Figure 12.4), were developed and tested (Okamura et al.,
2013). Both tracers displayed higher binding affinity to tau-
rich AD brain homogenates than [18F]THK523 (Okamura
et al., 2013). Initial human PET studies with [18F]THK5105
and [18F]THK5117 demonstrated a substantially lower
retention in subcortical white matter and cortical reten-
tion in AD patients analogous to the pattern of tau depos-
its described by Braak and Braak (1997) or Delacourte et al.
(1999), ­leading to a robust visual and quantitative separation
between AD patients and healthy controls, while also corre-
lating with dementia severity and brain atrophy (Okamura
et al., 2014a) and showing a different pattern of retention
between tau and Aβ imaging with PiB (Okamura et al.,
2014b; Okamura et al., 2014a). [18F]THK5351, a new addition

N 18F O NC CN

N N CH3
H H 18F
N N
18F N
H
18
F-THK-523 CH3
18F-T807
18F-FDDNP
OH
18
F O
N

N N N N
CH3 N O
18F N S N
18F-THK-5105
CH3 N
18F-T808 11CH
3 O
OH 11 CF3
C-N-Methyl lansoprazole
F
18
O

H N N
H
OH S N
H F-THK-5117
18

CH3 N O
N
S N
N H311C N
11C-PBB3
OH CH3
18F O O
18 C18F3
N F-N-Methyl lansoprazole
H
N N
18F-THK-5351
CH3

Figure 12.4 Chemical structure of tau imaging ligands.

124 Dementia
to the THK series (Figure 12.4), has been recently evaluated
in young and elderly volunteers as well as in AD patients
(Okamura et al., 2014c). The preliminary evaluation of [18F]
THK5351 showed that it has faster tracer kinetics and higher
signal-to-noise ratios than [18F]THK5105 and [18F]THK5117,
­suggesting [18F]THK5351 might be a superior tau tracer
(Okamura et al., 2014c).
Kolb and colleagues, first at Siemens and then at Avid/
Lilly have developed [18F]AV1451 ([18F]T807) and [18F]T808
(Figure 12.4) two novel benzimidazole-pyrimidines deriva-
tives with nanomolar affinity and more than a 25-fold selec-
tivity for PHF-tau over Aβ (Chien et al., 2013; Xia et al.,
2013; Chien et al., 2014). Initial human PET studies showed
very low [18F]AV1451 white matter retention and cortical
retention in AD that followed the known distribution of
tau deposits in the brain, retention that was also associated
with disease severity (Chien et al., 2013). Prof Johnson and
Dickerson at the Massachusets General Hospital in Boston
are conducting the largest series of head-to-head [18F]AV1451
and [11C]PiB PET studies in AD and non-AD tauopathies
as well as controls (Johnson et al., 2013a; Dickerson et al.,
2014). On preliminary evaluation, [18F]T808 displayed faster
tracer kinetics than [18F]AV1451, reaching steady state dur-
ing the scanning period (Chien et al., 2014). Unfortunately,
substantial defluorination was observed in some cases
(Chien et al., 2014).
Due to its in vitro binding affinity to PHF-tau, lansopra-
zole was assessed as a potential tau imaging tracer. A series
of lanzoprasole derivatives with subnanomolar affinity for
tau fibrils were radiolabelled with 11C (Shao et al., 2012)
and more recently, 18F (Fawaz et al., 2014) (Figure 12.4).
Preclinical mice studies showed no entry of 11C-N-methyl-
lanzoprasole into the brain, effect that was reversed after
inhibition of the permeability-glycoprotein 1 transporter
with cyclosporine (Shao et al., 2012). In contrast, non-
human primate studies with either the 11C and 18F versions
of the tracer showed unencumbered entry into the brain
(Shao et al., 2012; Fawaz et al., 2014). No human studies
have been reported till date with these tracers.
More recently, Maruyama and colleagues from the
National Institute of Radiological Sciences, Chiba, Japan,
described the preclinical and initial clinical characteriza-
tion of a novel C-11 labelled selective tau tracer, [11C]PBB3
(Maruyama et al., 2013; Hashimoto et al., 2014) (Figure
12.4). The comprehensive preclinical evaluation involved in
vitro autoradiography, two-photon laser scanning fluores-
cence microscopy and small animal PET studies, showing
higher PBB3 binding in the spinal cord of a tau transgenic
mouse model (Maruyama et al., 2013). Although 70% of
unchanged [11C]PBB3 was found in mice brain homog-
enates, metabolite analysis showed that only 2% of the par-
ent compound remained in plasma at 5 min after injection
(Hashimoto et al., 2014). Preliminary clinical studies with
both [11C]PBB3 and [11C]PiB in healthy controls and AD
patients showed a distinct pattern of brain retention between
the two tracers suggesting that and despite marked [11C]
PBB3 retention in the venous sinuses, [11C]PBB3 selectively
binds tau at high specific activities (Maruyama et al., 2013).
A completely different [11C]PBB3 regional retention pattern
was observed in a CBS patient, suggesting [11C]PBB3 might
also bind other non-PHF tau conformations. Development
of more selective and fluorinated derivatives will further
confirm the usefulness of the PBB scaffold.
12.2.3 NON-SELECTIVE PAN-AMYLOID
IMAGING RADIOTRACERS
[18F]FDDNP is a naphthol derivative synthesized and
characterized by Barrio and colleagues at UCLA (Barrio
et al., 1999). [18F]FDDNP was initially reported to bind
non-selectively to both extracellular Aβ plaques and intra-
cellular NFT (Shoghi-Jadid et al., 2002; Smid et al., 2013)
and has been applied to the evaluation of a wide spec-
trum of neurodegenerative conditions such as AD (Small
et al., 2006), CTE (Small et al., 2013), Down syndrome
(Nelson et al., 2011), Gerstmann–Straussler–Scheinker
disease (Kepe et al., 2010), Creutzfeld–Jakob disease (CJD)
(Bresjanac et al., 2003), FTLD and progressive supranu-
clear palsy (PSP) (Kepe et al., 2013). Human PET studies
showed [18F]FDDNP has a very narrow dynamic range
(Small et al., 2006; Tolboom et al., 2009b), to correlate with
CSF-tau (Tolboom et al., 2009a), whereas in vitro assess-
ments in concentrations similar to those achieved during a
PET scan showed limited binding to both Aβ plaques and
NFT (Thompson et al., 2009). Given is a non-selective pan-
amyloid tracer, [18F]FDDNP counterbalances its inability
to identify the misfolded protein responsible for a specific
phenotype by using the regional retention of [18F]FDDNP
in the brain as to discriminate amid different neurodeagen-
erative conditions.
12.3 Aβ IMAGING
On visual inspection, as well as in quantitative and semi-
quantitative PET studies of different Aβ radiotracers, there
is a robust difference in tracer retention between AD patients
and age-matched controls (Rowe et al., 2007; Klunk et al.,
2004; Jack et al., 2008), with more than 90% of AD patients
(Figure 12.3) showing cortical tracer retention higher in
frontal, cingulate, precuneus, striatum, parietal and lat-
eral temporal cortices, while occipital, sensorimotor and
mesial temporal cortices are much less affected. These PET
images present a pattern of radiotracer retention that seems
to replicate the sequence of Aβ deposition found at autopsy
(Braak and Braak, 1997), but also similar to the anatomy of
the ‘default network’ (Sperling et al., 2009b). The regional
distribution of these tracers varies with the characteristics
of Aβ distribution among the different genotypes and phe-
notypes. For example, carriers of mutations associated with
familial AD (Klunk et al., 2007; Villemagne et al., 2009a),
subjects with posterior cortical atrophy (Ng et al., 2007;
Tenovuo et al., 2008) or CAA (Dierksen et al., 2010; Johnson

et al., 2007) present a different pattern of tracer retention to
the one observed in sporadic AD (Klunk et al., 2004; Rowe
et al., 2007).
While the accuracy of clinical assessments for the diagno-
sis of AD ranges between 70% and 90%, the regional reten-
tion of Aβ radiotracers is highly correlated with regional
Aβ plaques as reported at autopsy or biopsy (Ikonomovic
et al., 2008; Wolk et al., 2011; Sojkova et al., 2011; Clark et al.,
2011), with higher Aβ burden in the frontal cortex than in
hippocampus, consistent with previous reports (Naslund
et al., 2000).
About 25%–35% of cognitively unimpaired elderly sub-
jects present with high Aβ burden (Mintun et al., 2006;
Villemagne et al., 2008b; Aizenstein et al., 2008; Rowe
et al., 2010; Rowe et al., 2007) (Figure 12.3), are in perfect
agreement with post-mortem reports (Davies et al., 1988;
Morris and Price, 2001) and likely to reflect preclinical AD
(Morris and Price, 1999). While neuropsychological exami-
nation show that individuals with high Aβ burden perform
within the normal limits, they do perform worse and have
a higher risk for disease progression than those with low
Aβ burden (Rowe et al., 2013a; Sperling et al., 2013). The
detection of Aβ pathology at the presymptomatic stage is
of crucial importance because if this group truly represents
preclinical AD (Thal et al., 2004; Morris and Price, 1999),
it is precisely the group that may benefit the most from
therapies aimed at reducing or eliminating Aβ from the
brain (Sperling et al., 2011). Furthermore, one of the most
important conclusions to be drawn from all the Aβ imag-
ing studies conducted is that, the likelihood of a cognitively
unimpaired individual with low Aβ burden in the brain
developing AD dementia is extremely small (Villemagne
et al., 2011b; Rowe et al., 2013a). Aβ imaging has proven
useful in identifying AD pathology in about 50%–70% of
individuals fulfilling criteria for MCI (Winblad et al., 2004;
Petersen, 2000; Kemppainen et al., 2007; Pike et al., 2007;
Forsberg et al., 2008; Mormino et al., 2009). Most ­studies
reported that subjects classified as non-amnestic MCI –
and more specifically those classified as non-amnestic
single domain MCI – show low Aβ burden in the brain,
consistent with a non-AD underlying pathological process
(Pike et al., 2007; Villemagne et al., 2011b). Although, at the
early MCI stages Aβ and hippocampal volume have inde-
pendent effects on cognition (Ong et al., 2013), at the late
MCI stage, it is believed that the Aβ-related impairment is
mediated by hippocampal atrophy (Mormino et al., 2009;
Ong et al., 2015) and modulated by cognitive reserve (Rentz
et al., 2010; Roe et al., 2008).
Both post-mortem (Bennett et al., 2006; Price and
Morris, 1999) and Aβ imaging studies (Jack et al., 2013;
Villemagne et al., 2013) indicate that Aβ deposition starts
decades before dementia phenotype is manifested and non-
demented individuals with high Aβ burden in the brain are
at a much greater risk of cognitive decline (Resnick et al.,
2010; Villemagne et al., 2008b; Villemagne et al., 2011b;
Rowe et al., 2013a), highlighting the clinical relevance and
potential impact in patient management of Aβ imaging
Molecular brain imaging in dementia 125
(Wolk et al., 2009; Forsberg et al., 2008; Okello et al., 2009;
Villemagne et al., 2011b). The fact that high Aβ burden
relates to episodic memory impairment in non-demented
individuals and that it is associated with a significant higher
risk of cognitive impairment, emphasizes the non-benign
nature of Aβ and supports the hypothesis that Aβ deposi-
tion occurs well before the onset of symptoms, further sug-
gesting that early disease-specific therapeutic intervention
at the presymptomatic stage might be the most promising
approach to either delay onset or halt disease progression
(Sperling et al., 2011). On the other hand, the prevalence
of high Aβ deposition among non-demented individu-
als, added to the absence of a strong association between
Aβ deposition and measure of cognition, synaptic activ-
ity and neurodegeneration in AD, suggesting that Aβ is an
early and necessary, though not sufficient cause for cogni-
tive decline in AD (Villemagne et al., 2008b; Sojkova and
Resnick, 2011), indicates that other – Aβ-dependent or inde-
pendent – factors, such as acceleration and/or spreading of
tau aggregation beyond the MTL, lead to synaptic failure
and eventually neuronal loss in cortical association areas
which play a crucial role in cognitive decline and disease
progression. Other factors such as age, years of education,
IQ, occupational level and brain volume among others
appear to play a modulatory role between Aβ deposition
and cognition (Roe et al., 2008; Chetelat et al., 2010).
With regard to some of these environmental variables,
age is the strongest risk factor in sporadic AD, with the
prevalence of the disease increasing exponentially with
age. These risks are increased in the presence of the most
consistent genetic risk factor associated with sporadic AD,
the ApoE ε4 allele (Farrer et al., 1997). The presence of the
ApoE ε4 allele has been associated with onset of the dis-
ease at an earlier age and a gene dose dependent on higher
risk of developing AD (Farrer et al., 1997). Examination of
ApoE ε4 allele status revealed that, independent of clinical
classification, ε4 carriers present with significantly higher
Aβ burdens than non-ε4 carriers, further emphasizing the
crucial role ApoE plays in Aβ metabolism (Reiman et al.,
2009; Morris et al., 2010; Rowe et al., 2010). Although ApoE
ε4 carriage is associated with higher Aβ burdens and early
disease onset, it has no effect on the rates of Aβ deposition
(Villemagne et al., 2013). Aβ imaging is also proving useful
in the characterization of autosomal mutations in APP or
presenilin 1 or 2 genes that lead to the overproduction of Aβ,
where mutation carriers present with abnormal Aβ deposi-
tion up to 25 years before the onset of dementia (Benzinger
et al., 2013; Bateman et al., 2012) has been noticed. These
studies are helping validate the relevance and change over
a course of time of several biomarkers (Fagan et al., 2014;
Benzinger et al., 2013), assessments that are being applied to
better-targeted disease-specific therapeutic strategies (Mills
et al., 2013).
Aβ imaging has also been applied to a wide spectrum
of neurodegenerative conditions. Although lower than
found in AD, similar patterns of Aβ deposition are usu-
ally observed in dementia with Lewy bodies (DLB) (Rowe
126 Dementia

et al., 2007; Gomperts et al., 2008; Maetzler et al., 2009)
(Figure 12.5). There is usually no detectable Aβ burden
in patients with sporadic CJD (Villemagne et al., 2009b)
(Figure 12.5) or those diagnosed with FTLD (Rowe et al.,
2007; Drzezga et al., 2008; Rabinovici et al., 2007) with the
exception of patients presenting with logopenic aphasia that
do have high Aβ burden in the brain, and are thought to
represent a language-onset variant of AD (Leyton et al.,
2011; Rabinovici et al., 2008) (Figure 12.5). In contrast to
FTLD and as confirmed by autopsy and Aβ imaging studies,
more than half of DLB patients show signs of high Aβ depo-
sition (McKeith et al., 2005; Rowe et al., 2007) (Figure 12.5).
Therefore, differential diagnosis from AD can be better
accomplished by assessing the integrity of the dopami-
nergic nigrostriatal terminals (Villemagne et al., 2012c).
Aβ imaging has also facilitated differential diagnosis in

PiB- HC

Misfolded
proteins PiB- MCI

PD

α-syn

PiB- DLB

PiB+ HC

PiB+ MCI

Aβ PiB+ DLB

AD

tau

FTLD

PrPsc spCJD

Figure 12.5 (See colour insert.) Aβ imaging in ageing and dementia. Representative 40–70 min post-injection trans-
axial 11C-PiB images along the spectrum of some of the misfolded proteins associated with neurodegenerative diseases,
encompassing the different patterns of 11C-PiB retention in the brain, with – from top to bottom – a 73-year-old healthy
PiB-negative control (PiB-HC) subject (mini mental state examination [MMSE] 30), 83-year-old PiB-negative subject with
mild cognitive impairment (PiB-MCI) (MMSE 28), 61-year-old PiB-negative Parkinson’s disease (PD) patient (MMSE 27),
69-year-old PiB-negative patient with dementia with Lewy Bodies (DLB; MMSE 24), 77-year-old PiB-positive healthy
control (PiB+ HC) subject (MMSE 28), 82-year-old PiB-positive subject with mild cognitive impairment (PiB+ MCI) (MMSE
28), 78-year-old PiB-positive DLB patient (PiB+ DLB) (MMSE 19), 76-year-old Alzheimer’s disease (AD) patient (MMSE 21),
59-year-old patient with frontotemporal lobe degeneration (FTLD; MMSE 20) and 59-year-old PiB-negative patient with
confirmed sporadic Creutzfeldt–Jakob disease (spCJD). PET images show clear differences when comparing cortical PiB
retention in PiB-negative HC, MCI, PD, spCJD and FTLD with PiB-positive HC, MCI, DLB or AD patients. Only non-specific
PiB binding in white matter is observed in PiB-negative HC, MCI, PD, spCJD and FTLD compared with PiB binding in corti-
cal areas of AD and DLB patients. All images are scaled to the same standardized uptake value ratio (SUVR) maximum.
 Molecular brain imaging in dementia 127

cases of inpatients with atypical presentations of dementia
(Ng et al., 2007; Wolk et al., 2012).
Another rapidly expanding area is the examination of
potential association between fluid and imaging biomark-
ers of pathology or neurodegeneration and how these bio-
marker constructs are used to establish the criteria for the
different stages of the disease (Thal et al., 2006; Clark et al.,
2008; Albert et al., 2011; McKhann et al., 2011; Storandt
et al., 2012; Morris et al., 2005).
Clear criteria for appropriate use of Aβ imaging has been
established emphasizing the need to integrate the result of
Aβ imaging with a comprehensive cognitive and clinical
evaluation performed by a clinician experienced in the eval-
uation of dementia, to ensure a positive impact on patient
management (Johnson et al., 2013b). The criteria clearly
stipulates the specific cases Aβ imaging should be used, such
as patients with persistent or progressive unexplained cog-
nitive impairment, progressive atypical or unclear clinical
presentation of dementia, or dementia onset in i­ndividuals
65 years old or younger (Johnson et al., 2013b). It also out-
lines the inappropriate use of Aβ ­imaging, such as cases
of probable AD with typical age of onset or to determine
dementia severity, asymptomatic i­ndividuals or uncon-
firmed cognitive complaint, a family history of dementia or
presence of the ApoE ε4 allele, as well as non-medical use
found in litigation for insurance purposes (Johnson et al.,
2013b).
Aβ imaging is also assisting the evaluation of anti-Aβ
therapies in several ways, allowing better subject selec-
tion, assessing target engagement and evaluating treat-
ment response of patients for therapy trials and providing a
means to measure their impact on Aβ burden (Rinne et al.,
2010; Ostrowitzki et al., 2011; Salloway et al., 2014).
12.4 TAU IMAGING
Tau imaging is a recent addition to the arsenal of tools for the
non-invasive assessment of neurodegenerative conditions.
While several international groups are implementing and
applying tau imaging for the evaluation of AD (Figure 12.6)
and non-AD tauopathies, little has been communicated or
published beyond the in vitro and initial human proof of
mechanism studies assessing novel tau tracers. However,
these initial studies have furnished enough information to
allow some clearer speculation on the potential applications
of this new technique. Although most of the potential appli-
cations are similar to those of Aβ imaging, there are some
that seem more appropriate or better suited for tau imaging.
Given the critical and stereotypical pattern of tau deposi-
tion and in contrast with CSF studies, tau imaging studies
can assess both the quantity and regional brain distribu-
tion of tau deposits, features that can be potentially used for

HC AD

18F-flutemetamol 18F-flutemetamol
L R R L L R R L

PET-SUVRpons PET-SUVRpons
1.2 1.2
0.9 0.9
RT.LAT LT.LAT SUP INF RT.LAT LT.LAT SUP INF
0.7 0.7
0.4 0.4

RT.MED LT.MED POST ANT RT.MED LT.MED POST ANT

18F-THK5117 18F-THK5117
L R R L L R R L

PET-SUVRCbCtx PET-SUVRCbCtx
2.0 2.0
1.6 1.6
RT.LAT LT.LAT SUP INF RT.LAT LT.LAT SUP INF
1.2 1.2
0.8 0.8

RT.MED LT.MED POST ANT RT.MED LT.MED POST ANT

Figure 12.6 (See colour insert.) Aβ and tau imaging in ageing and dementia. Surface display PET images of the respective
Aβ ([18F]flutemetamol, top row) and tau ([18F]THK5117, bottom row) burden in an age-matched healthy control (HC) and an
Alzheimer’s disease (AD) patient.
128 Dementia
staging the disease. Given the tight association between tau
deposition, cognition and neurodegeneration, tau imaging
might prove essential for assessing disease progression.
The combination of tau with Aβ imaging studies will help
ascertain if Aβ accelerates and/or triggers the spread of tau
deposition outside the mesial temporal cortex and if this initial
dissemination into cortical association areas is manifested as
incipient and insidious objective cognitive impairment occurs
known as MCI (Price and Morris, 1999; Delacourte et al.,
2002). Further spreading into the remaining cortical areas is
usually accompanied by severe cognitive deterioration and
dementia (Price and Morris, 1999; Delacourte et al., 2002). This
sequence of events might help explain the preliminary results
from combined Aβ and tau imaging studies (Johnson et al.,
2013a; Villemagne and Okamura, 2014) and is one of the essen-
tial issues to be tackled by the in vivo imaging of tau deposits.
Aβ imaging studies have shown that the actual amount of Aβ
in the brain is more relevant than the regional Aβ distribution
as an early driver of cognitive decline. Post-mortem and initial
tau imaging PET studies indicate that, not only the amount
of tau deposition, but also – or mainly – their topographical
distribution in the brain (Royall, 2007; Delacourte et al., 1999)
might be more relevant and robustly associated with neuro-
degeneration and cognitive decline. Furthermore, this extra
dimension is not limited to the AD spectrum but essentially to
all tauopathies where the regional distribution of tau deposits
is pathognomonic for each specific condition.
12.5 SUMMARY
The introduction of radiotracers for the non-invasive in
vivo quantification of Aβ in the brain has revolutionized the
approach in the evaluation of AD. Frank et al. (2003) proposed
that an ideal biomarker for AD should be disease-specific,
non-invasive, with sensitivity and specificity above 80%. Αβ
imaging already fulfills these criteria. Aβ burden as measure
by PET matches histopathological reports of Aβ distribution
in ageing and dementia, it appears more accurate than FDG
for the diagnosis of AD and is an excellent aid in the differen-
tial diagnosis of AD from FTLD. ApoE ε4 status is associated
with higher Aβ burden. As new treatments in clinical trials
are aimed at preventing or slowing AD progression, either
by preventing Aβ generation or deposition, or increasing the
clearance of Aβ, the role of imaging and quantifying Aβ bur-
den in vivo is becoming increasingly crucial. Although these
treatments are aimed at AD, the available data suggest that
they may have value in other dementias such as DLB, where
Aβ deposition is present.
Despite the development of promising new and reliable
Aβ and tau imaging ligands labelled with isotopes with
longer radioactive half-lives (Rowe et al., 2008b; Serdons
et al., 2009; Sundgren-Andersson et al., 2009; Sperling et al.,
2009a; Chien et al., 2014; Okamura et al., 2013), population
screening is unlikely to involve neuroimaging approaches
and despite the unreliability of plasma assays till date
(Zetterberg and Blennow, 2006), a simple blood test assess-
ing central features of the disease (Burnham et al., 2014) as
well as the use of near-infrared Αβ dyes (Raymond et al.,
2008) should soon be available to permit widespread screen-
ing of the population at-risk. On the other hand, molecu-
lar neuroimaging can provide highly accurate, reliable and
reproducible quantitative statements of Aβ and tau burden,
essential for therapeutic trial recruitment and for the evalu-
ation of disease-specific treatments directed at removing or
slowing the brain deposition of either Aβ or tau.
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Services for people with dementia
SUBE BANERJEE
13.1 INTRODUCTION
We have come a long way in the past decade. From obscu-
rity in terms of policies, dementia is now almost universally
acknowledged as one of the most common and serious dis-
orders faced by the human population. It is the most feared
illness in older people and the most expensive common
condition. One-third of people aged over 65 live and die
with dementia (Brayne et al., 2006). The need for action to
improve care for people with dementia has been acknowl-
edged by international organizations like the World Health
Organization (WHO, 2012) and the G8 dementia summit
(Department of Health [DH], 2013). The ‘diagnosis gap’ in
dementia where less than a half of those with dementia ever
attract a diagnosis of dementia, is a global phenomenon
(Alzheimer’s Disease International [ADI], 2012). Dementia
is a challenge at international, national, regional and local
levels as well as at the personal level.
In the last decade it has become clear that there are
multiple positive interventions that can promote indepen-
dence and give people with dementia and their family car-
ers a good quality of life. Things that can enable individuals
and their friends and families to adapt to the challenges
of dementia and steer a course in the 7–12 years that they
might be living with dementia, avoiding crises and harm
and promoting wellbeing for all involved are proposed.
However, it has also become clear that the large majority of
people with dementia and their family carers do not benefit
from these positive interventions and supports. This makes
dementia a real priority issue and challenge for service plan-
ning and delivery. Services are built on how policies are
delivered; services are the vehicles that enable practitioners
to deliver care. Developing and delivering services for those
with dementia is more complicated than they are in other
health conditions such as cancer and heart diseases, because
dementia does not respect the silos we erect between health
and social care, between what families do and what the state
13
of the disease does to them, and between the state, private
and voluntary sectors.
Services for people with dementia are necessarily com-
plex and include primary healthcare, specialist services in
mental health (e.g. old age psychiatry), care provided in gen-
eral hospitals (e.g. geriatrics and neurology), as well as social
care commissioned and provided by both local authorities,
the voluntary and independent sectors and business out-
lets of home care and care homes. Most important of all is
the unpaid care provided by families. There are examples
of excellent dementia care provided by all of these agencies
and also problematic issues while caring within each of the
sectors. Strategy and policy evolves and with the growth of
evidence base the last decade has seen a growing acknowl-
edgement and understanding of the challenge posed by
dementia and the need for service improvement. This chap-
ter aims to look critically at some of the major issues in the
development of services for people with dementia through
the prism of the provision of memory assessment services
and the service challenge posed by multimorbidity and
complexity in dementia.
13.2 MEMORY ASSESSMENT SERVICES
In terms of service provisions for dementia, one major issue
is that, in current systems, less than a half of those suffer-
ing from the illness are ever diagnosed with dementia. Such
diagnosis and contact only occurs in the later stages of the
illness or in crisis and very often not at all. In economically
developed countries, between 50–80% of dementia cases
are unrecognized (Alzheimer’s Disease International, 2011;
Alzheimer’s Society [AS], 2012). This ‘diagnosis gap’ and
the consequent ‘treatment gap’ is even greater in economi-
cally developed and underdeveloped countries, with 90%
unidentified cases in India. If these data are extrapolated
worldwide, 28 million (78%) of the 36 million people with
135
136 Dementia
dementia who have not received any diagnosis and there-
fore, do not have access to treatment, care and organized
support can be provided a formal diagnosis inclusive of all
these.
Much is shared between countries about the challenges
posed by dementia, and while different countries need solu-
tions that fit and exploit local levers for change, it is strik-
ing that strategies have emerged in health systems as diverse
as those in Japan, Australia, France, Denmark, Taiwan, the
United States and the United Kingdom who all share a com-
mitment to early diagnosis in dementia (http://www.alz.
co.uk/alzheimer-plans). The fourth objective of the French
Plan for Alzheimer is ‘improving access to diagnosis and
care pathways’. In the United States, early diagnosis of
Alzheimer’s disease is one of the six main purposes of the
U.S. National Alzheimer’s Project Act (NAPA) which was
passed with bipartisan support and brought into force by
President Obama in January 2011.
The purpose of memory assessment services is to turn
people with worrying symptoms into people who know
what is going on, turning toxic uncertainty into empow-
ered knowledge and enabling access to effective care, sup-
port and treatment (Banerjee, 2015a). For many illnesses
there are clear and simple ways in which one becomes
aware that there is a problem (e.g. central crushing chest
pain or a generalized seizure). This is not the case in
dementia where the onset is insidious, where there may
be a lack of insight and where there are misconceptions
about the disease that result in inactivity. Public and
professional misconceptions act to impair help seeking
and help offering. In the National Dementia Strategy for
England (Department of Health, 2009; Banerjee, 2010),
three such barriers are identified: stigma, the misbelief
that the symptoms of dementia as a normal part of ageing
and the misbelief that there is nothing that can be done
for dementia patients. These factors act together to gener-
ate the systems that we have worldwide where a person
with dementia is more likely not to have had their condi-
tion diagnosed than it is for them to have had that diag-
nosis made.
A common element of health strategies to improve the
quality of care of people with dementia is the i­njunction
that diagnosis rates should be increased and that d ­ iagnosis
should be made ‘early’, ‘earlier’ or in a ‘timely’ f­ashion
(Department of Health, 2008;Nuffield Council on Bioethics,
2009; Burns and Buckman, 2013). In the last couple of
years, there has been debate and discussion about issues
surrounding the diagnosis of dementia with questions
raised as to the balance of benefits and harms of a d­ iagnosis
or an early diagnosis in dementia, with even the ­suggestion
of a ‘curse of diagnosis’ (Le Couteur et al., 2013). There are
some who state that in the absence of definitive positive evi-
dence as to the benefit of receiving an early and accurate
diagnosis, services to deliver this should not be funded.
This statement is made on the basis of a lack of evidence
rather than evidence of dis-benefit. There are strands of
both therapeutic nihilism and medical paternalism in this
construction. The assumption often made is that ‘igno-
rance is bliss’ or that ‘it is best for them not to know, it
would be too upsetting’. These have major similarities with
the excuses made for not telling people they had cancer 40
years ago. Alzheimer’s Disease International in their 2011
World Alzheimer Report reviewed in detail all the data
available and generated a useful categorization of the ratio-
nale for early diagnosis at an individual level into nine
broad themes (Box 13.1).
BOX 13.1: World Alzheimer Report 2011:
Nine reasons for early identification and
treatment of dementia
1 Optimizing current medical management
2 Relief gained from better understanding of
symptoms
3 Maximizing decision-making autonomy
4 Access to services
5 Risk reduction
6 Planning for the future
7 Improving clinical outcomes
8 Avoiding or reducing future costs
9 Diagnosis as part of human right
In a simpler world there would be an easy diagnostic
test that could be done quickly and simply that would tell
us if we had dementia and diagnose the particular ­subtype.
Despite fantastic work in this area, it is still not the case
yet. In that desired world there would also be an efficient
screening test that would work across populations to iden-
tify a group with a high likelihood of dementia who could
then undergo a diagnostic procedure to generate a defini-
tive diagnosis. Again, this is not the case in the complex
world of dementia. In the absence of a technical fix, we
are left with an entirely clinical task of making a careful
broad-based diagnosis based on multidisciplinary assess-
ment and formulation of a synthesis of history, examination
and investigation. Tests can help us make decisions about
absence or presence of the syndrome of dementia and the
accurate diagnosis of the subtype or cause for dementia, but
the results cannot make those diagnoses for us. The chal-
lenge then is how to generate a system that can achieve this.
Memory assessment services place this function as their
core service (Feldman et al., 2003; Banerjee et al., 2007,
Brodaty et al., 2011, Banerjee, 2015a).
13.3 DEVELOPMENT OF MEMORY
CLINICS AND MEMORY SERVICES
Memory Clinics were first established in the United States,
in the 1970s, in specialist centres interested in carrying out
research in Alzheimer’s disease and other dementias. These

clinics offered outpatient diagnostic treatment and advice
for people concerned about their memory. In addition to
general research into the types of dementia, Fraser (1992),
describing these early services, identified four core functions:
1. To forestall deterioration in dementia by early diagno-
sis and treatment
2. To identify and treat disorders other than dementia
that might be contributing to the patient’s problems
3. To evaluate new therapeutic agents in the treatment of
dementia
4. To reassure people who are worried that they might
be losing their memory, when no morbid deficits are
found
The thing that set these memory clinics apart from nor-
mal neurological, neuropsychiatric or old age psychiatric
clinics was their specific focus on dementia. Part of their
rationale was the identification of ‘treatable’ forms of or
causes for dementia. None was a full-time operation; most
were exactly what they said they were, a clinic or a room
in a specific hospital where once or twice a week there was
a specific focus on dementia. The term ‘memory’ seems
to have been used in order to avoid the negative connota-
tions of the word ‘dementia’ as well as to indicate a broad
interest in cognition in a way that might be understood by
referrers. The first memory clinic in the United Kingdom
was probably opened at St. Pancras Hospital in London in
1983. The numbers of such clinics grew with the passage of
time so much so that it was possible to identify 20 clinics in
1995 (Wright and Lindesay, 1995) and 102 clinics in 2002
(Lindesay et al., 2002) with the authors noting that the ori-
entation of these clinics was moving from being research
bases to ways of providing a diagnostic service for demen-
tia. The term ‘memory service’ was probably first used in
naming the Croydon Memory Service (Banerjee et al.,
2007) when the term was coined to describe a new team
working in south London. There were two reasons for the
coinage of this term. Firstly, they wanted to indicate that
this should be a service dedicated to serving people with
dementia and their carers rather than a clinic organized for
the convenience of service providers to meet their interests
or needs (e.g. to recruit research participants or to pursue a
clinical interest). Secondly, these service providers wanted
to stress that such services were not about whether they
represented ‘the clinic’ but were instead about what they
did (for people with dementia and their carers) ‘the service’.
There is a lack of clarity of definition of what constitutes a
memory assessment service, a memory service and a mem-
ory clinic. What they all share in common is an interest and
skill in the diagnosis of dementia and particularly, in the
early diagnosis of dementia. A simple statement of what a
memory service is for (i.e. its primary aim) is given in the
National Dementia Strategy for England:
Good-quality early diagnosis and intervention
for all.
Services for people with dementia 137
This requires the service to do three things:
1. To provide a good quality diagnosis in the early stages
of illness
2. To provide good quality early diagnosis and interven-
tion in dementia
3. To provide this good quality service for all that might
need it in a given population
So a service without the skills to diagnose the cause or
subtype of dementia and to have a high degree of clini-
cal certainty so much so that when a person diagnosed
with dementia is not misguided and vice versa, would not
meet these criteria. Equally, the service needs to have the
skill to identify that small group where there is real clinical
uncertainty, even after a full multifaceted multidisciplinary
assessment and where a longitudinal approach to diagnosis
is needed to be sure of the consequences. Using these tests,
a service that provides diagnosis but not treatment would
also be seen as a failure.
Finally, there is the stipulation that this service should
work for all in a given population. This is based on equity
and access; these should not be services for the lucky few,
as many memory clinics have been in the past. They need to
have the capacity to deal with all incident cases in the area
they serve. An average UK Clinical Commissioning Group
(CCG) population has 50,000 people over the age of 65 in its
catchment area. To meet the needs of all, the memory ser-
vice would need to see people of all ages not just those over
the age of 65, but the number over 65 is the best population
denominator to make a broad assessment in terms of capac-
ity needed, given the exponential increase in the prevalence
and incidence of dementia in this age group. If we take the
incidence rate of dementia in this group at 2% per year, then
this means that there will be 1000 new cases per year in that
area. If a 70% diagnosis rate is aimed for (allowing for indi-
viduals to opt out of referral and for those who die inciden-
tally in the first year) and we apply the 64% rate of dementia
in those referred by and found in the Croydon Memory
Service (Banerjee et al., 2007), then this means that the ser-
vice needs be able to see around 1100 people a year. If the
threshold for referral is lowered or the target for diagnosis is
increased then this number would also increase. This would
not be possible with the traditional once-a-week memory
clinic (Wright and Lindesay, 1995; Lindesay et al., 2002) that
sees only a couple of new cases per week.
Such services are potentially powerful local agents and
function as engines for change. They are there to empower
people with dementia and their carers by providing them
the benefits that come from good quality early diagnosis and
treatment. They are also there to enable the whole health
and social care system to work well for dementia. Memory
services are, therefore, at the heart of a win-win scenario
where there is quality and value improvement for people
with dementia and carers for health services as well as social
services. While ambitious, the establishment of services
those are able to see 1000 to 1500 new patients a year pro
138 Dementia
rata for a catchment area including 50,000 over 65-year-old
patients, is not impossible. The Croydon Memory Service
Model evaluation (Banerjee et al., 2007) is a proof of concept
and there are an increasing number of well-resourced mem-
ory services that run on most days of the week in the United
Kingdom that have the ability to deliver quality assessment
at the proposed rate (Doncaster et al., 2011). The paucity of
current provision and counsels of despair with respect to
funding should not limit our ambition.
13.4 ROLE OF PRIMARY CARE IN
DIAGNOSIS OF DEMENTIA
There is an important set of questions concerning the role
of primary care in the diagnosis of dementia and in par-
ticular, early dementia. There should not be a conflict about
professional protectionism between specialities or cost con-
tainment. Instead, there should be a discussion about the
value brought by different approaches to the person with
dementia and their carers, primarily and secondarily to the
system as a whole. The equation will vary between countries
in terms of what can and should be done in primary care
and what is best done in secondary care. Different systems
have different training available and different time packages
that can be spent in assessment. What is vital is that those
who are charged with providing such services should have
the skills needed to do this and do it well. What is possible
in Canada may not be possible in France.
13.5 SERVICES FOR THOSE WITH
NEUROPSYCHIATRIC COMPLEXITY
IN DEMENTIA – SPECIALIST
PEOPLE’S MENTAL HEALTH
SERVICES
One important element in good quality care for people with
dementia is specialist older people’s mental health services.
The rationale for such services being separate from those
for adults of working age is based upon the need to have
the skills in meeting the special needs of the elderly which
include the following:
●● Dementia
●● A pattern of multiple pathology
●● Complex co-morbidity of physical and mental health
with social care needs
●● Different patterns of social care and family support
If the system as a whole is to work well for dementia,
this requires effective specialist expertise. There are strong
arguments for services that have a role that extends beyond
dementia, to include responsibility for older adults with
schizophrenia, depression and mania so that they have the
capacity and skills to provide the range of care needed for
people with neuropsychiatric complexity in dementia. The
separation of ‘organic’ and ‘functional’ disorders is in many
ways a false dichotomy for specialist mental health service
provision and one that is likely to disadvantage people with
dementia and their family carers with complex needs. The
natural history of dementia denotes a substantial propor-
tion of those affected will develop challenging behaviour,
including symptoms, such as depression, hallucinations and
delusions. Where these are severe and complex, they may
benefit from specialist older people’s mental health services
care. For the system as a whole to work for people with
dementia and their carers, these services need to be effective
and available. The focus of these teams could be conceptual-
ized as the ‘serious mental illness’ element of older people’s
mental health dealing with urgent and complex disorders
providing assessment and treatment in the community for
older people with functional and organic disorders. The role
of memory services is a complementary one, of early inter-
vention and harm prevention in dementia.
13.6 SERVICES FOR THOSE WITH
MULTIMORBIDITY IN DEMENTIA –
DEMENTIA AS AN EXAMPLE
OF INTEGRATIVE HEALTHCARE
SERVICES
In the case of older people with multimorbidity, their
healthcare needs and the extent to which they are met well
or met badly are sharp exemplars of the challenges faced by
healthcare systems across the world in the twenty-first cen-
tury (Banerjee, 2015b). The increase in longevity in devel-
oped and underdeveloped economies alike is a testament to
the success of twentieth century medicine as well as eco-
nomic and social development. Research, policy and action
has transformed our ability to prevent infant mortality, pre-
vent and treat infectious diseases and more recently, to pre-
vent and treat the great killers of middle-aged people, such
as heart diseases and cancer. This is a fantastic success. It
shows we can make a profound positive difference towards
individual and world health. But, with this success comes
consequences of the success. With increasing longevity
comes multimorbidity (people with two or more long-term
conditions) and with multimorbidity comes complexity.
While multimorbidity is not just a problem of older adults,
its prevalence is much higher in older age groups with 65%
of those aged 65–84 and 82% of those aged 85 or more
affected (Barnett et al., 2012).
Dementia provides a concrete example of a disorder that
illustrates the complexities of the challenges of multimor-
bidity and the implications of not addressing them in a
systematic fashion. People with dementia have the highest
level of multimorbidity with data from the Scottish School
of Primary Care (Guthrie et al., 2012) suggesting, that
only 5.3% of people diagnosed of dementia have no other

long-term condition and that they have, on an average, 4.6
of the prior mentioned conditions. In an analysis of primary
care data from Wishard Health Services in the United States
(Schubert et al., 2006), people with dementia similarly had,
on an average, four chronic medical conditions and were
prescribed 5.1 medications; 82% had hypertension and 39%
diabetes mellitus.
As in other disorders, multimorbidity in dementia pre-
dicts poor outcomes and poor quality service response.
People with chronic illness and dementia report fewer
symptoms (McCormick et al., 1994) and undiagnosed but
treatable medical diseases have been reported in almost
half of those with dementia (Larson et al., 1984). So why
do people with multimorbidity in general and those with
dementia receive poor quality care? A large part of the
answer would seem to lie in the fact that health systems
are providing twentieth century medicine to a twenty-first
century patient population. General hospitals are increas-
ingly filled with older people with multimorbidity admit-
ted in the emergency ward; this is the twenty-first century
patient population. United Kingdom Hospital Episode
Statistics show that people over 65 consist of 60% of the
admissions, 70% of occupied bed days, 85% of delayed
transfers and 65% of emergency readmissions. Those over
65 of age make up 17% of the UK population but more than
2 million unplanned admissions per year, of people over 65,
account for 68% of hospital emergency bed days and the
use of more than 51,000 acute beds at any one time (Imison
et al., 2012). Almost a quarter of the older people in general
hospitals may have dementia and people with dementia in
general hospitals have worse outcomes in terms of length
of stay, mortality rate and institutionalization. The major-
ity of these patients are not known to specialists providing
dementia services and are undiagnosed. General hospitals
are particularly challenging environments for people with
memory and communication problems, with cluttered ward
layouts, poor signage and other hazards.
These twentieth century services were generally designed
for people, often young or middle aged, with one ailment
and often with a discreet episode of illness. Research, policy
and health systems in the developed world, particularly,
have evolved in the past 50 years to generate increasing spe-
cialization and increasingly deliver technical treatments for
individual conditions. This paradigm of uni-disciplinary
technical super-specialism has grown to dominate policy,
research, practice and education. It casts a dense shadow,
acting to devalue and impair the growth of the generalized
and integrative focus of much of primary care and geriatric
medicine. The siloed services that it generates in hospitals
are those that often fail the frail elderly populations with
multimorbidity who are the large majority of current patient
populations and who find services to be confusing, imper-
sonal and challenging (Mason et al., 2014). Conditions other
than that of the specialty, with dementia as a good example,
are often seen as a complication, ignored or managed by
multiple specialist referral which may be both inefficient
and ineffective (Wolff et al., 2002; Starfield et al., 2005). In
Services for people with dementia 139
hospitals, the impression given to patients and families of
people with dementia is often, that, the patient has failed by
not fitting the service.
In terms of treatment, the working assumption is that the
optimal treatment of someone with conditions A, B and C
is treatment A + treatment B + treatment C. Clinical guide-
lines for chronic illnesses almost always focus on single
disorders even though most with those disorders will have
multimorbidity symptom (Guthrie et al., 2012). Questions
can be raised as to whether treatments and services that are
developed on otherwise healthy people work for people with
multiple problems as well. Therapeutic and adverse effects
may differ in those with multimorbidity. Dementia provides
good example in this regard. In those, with multimorbidity
of depression and dementia at the same time, antidepres-
sants that work well appear to have no effect on those with-
out dementia (Rosenberg et al., 2010; Banerjee et al., 2011).
In terms of serious adverse effects, the use of antipsychotic
medication in those with dementia has been shown to have
a greater mortality rate than in those without dementia,
with an estimated 1400 extra deaths attributable to their
usage in the United Kingdom in 2009 (Banerjee, 2009).
What works for a single disorder does not necessarily work
in multimorbidity subjects; what is safe for a single disorder
is not necessarily safe in multimorbidity patients. We need
to ensure that national data systems collect data in a way
that enables an understanding of the burden, management
and outcomes of those with multimorbidity. We need better
research to understand multimorbidity from the biological
perspective through applied health and social care research.
Equally, we need to ensure that evaluative research includ-
ing randomized controlled trials (RCTs) are conducted in
real life clinical populations that include multimorbidity so
that the data generated can be generalized to those that will
be treated.
The education that we provide our healthcare staff from
all professional backgrounds does not prepare them well for
the challenges of multimorbidity or long-term conditions of
dementia. Current clinical experience is delivered through
a series of discreet, time-limited clinical placements in acute
and primary care settings. This provides students with a
snapshot of different illnesses in different patients with an
emphasis on the acute phase of illness. An example of what
might be done in this education is the Time for Dementia
Programme (TFD). Funded by Health Education England,
Kent, Surrey, Sussex, TFD is a longitudinal clerkship to help
students to develop an understanding of the emerging chal-
lenges presented by the ageing population, multimorbidity
and long-term conditions using dementia as an exemplar
condition. TFD has been included in the core curricula for
the 2014 cohort of medical students starting their second
year at Brighton and Sussex Medical School and nursing
and paramedic students in their first year at the University
of Surrey. All students visited an assigned patient and fam-
ily every 3–4 months for 24 months from January 2015. The
focus was on the health and care experience of the person
with dementia and their family members. It was located in
140 Dementia
people’s own houses facilitated by the Alzheimer’s Society
rather than in a health service and running the programme
over a 2-year period helped students to gain a long-term
perspective. The programme’s aim was to support an
empathetic relationship between students and people with
dementia to enhance their understanding of dementia itself,
the health, social and family care of people with dementia,
what it is like to be ill and old in society, the progression of a
long-term condition and chronic disease management from
a patient/family viewpoint.
So what would a twenty-first century healthcare that
works for those with dementia and physical multimorbid-
ity look like? It should be multidisciplinary and integra-
tive, valuing generalist skills as well as technical ones. It
would be patient-centred, focussed in what works for the
patient not what works for the service. It would draw on the
insights and expertise of specialists but deliver them in a
balanced and seamless manner. The core of the challenge
is the increasing complexity of our clinical population with
dementia as a marker. As Mencken (1982) reminds us, we
need to be wary of simple answers to complex problems that
are wrong. Any solution to these complex set of problems is
likely to be complex in itself, it will require us to continue
with the technical innovation and scientific advancements
that has characterized twentieth century medicine and use
this along with new ways of organizing to deliver services
and make the system work for people with multiple disor-
ders as they do for those with single illnesses.
At a national level there is a need for political imagina-
tion, courage and will in re-engineering cherished current
systems and services. The clinical and financial pressures
imposed by our current system should, however, be the
impetus to moving decisively and quickly on this mat-
ter. The tendency to generate systems to fight the last war
rather than the current one is no less a characteristic of
healthcare systems than it is of defence forces. We need
to develop our services to meet the actual needs of our
patients in the present century, not just those of the last
century. This means a system that works for multimor-
bidity. This means making multimorbidity everybody’s
business and creating policy, commissioning, services,
research and education tools to deliver good quality care
to those suffering from more than one illness. One way
of testing if the methods are successful will be to observe
how well these services work for those suffering from
dementia.
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Family carers of people with dementia
KATRIN SEEHER AND HENRY BRODATY
14.1 FAMILY CAREGIVING
Family caregiving can be defined in many ways. Schulz and
Martire (2004) describe caregiving as:
… the provision of extraordinary care, exceeding
the bounds of what is normative or usual in family
relationships. Caregiving typically involves a sig-
nificant expenditure of time, energy and money
over potentially long periods of time; it involves
tasks that may be unpleasant and uncomfortable
and are psychologically stressful and physically
exhausting (p. 240).
According to the National Long-Term Care Survey
(NLTCS), caregiving is the ‘assistance with at least one
activity of daily living (ADL)’ (Stone et al., 1987; Kasper
et al., 1994), while the American Association of Retired
Persons (AARP) defines caregiving as ‘any assistance pro-
vided for any physical ADL or two or more instrumental
activities of daily living (IADLs)’ (Wagner, 1997).
Other researchers have interpreted caregiving as ‘a con-
cern for, and taking responsibility for, the well-being of
others’ (Resource Implications Study Group, 2000), or sim-
ply as ‘a continuum ranging from normal social exchanges
between fully independent people through various mixes of
assistance’ (Lawton et al., 2000).
14.1.1 WHO ARE FAMILY CARERS?
Alzheimer’s Disease International estimated that in 2013
there were 44.4 million people with dementia worldwide
(Alzheimer’s Disease International, 2013). For approxi-
mately 75%–80% of people with dementia who live in the
community, care is provided informally by unpaid carers
(Schulz and Martire 2004; Alzheimer’s Association, 2014),
142
14
typically family members, also friends and neighbours
(World Health Organization and Alzheimer’s Disease
International, 2012; Alzheimer’s Association, 2014). At least
15 million people in the United States were caring for a
friend or family member with Alzheimer’s disease (AD) or
other dementia in 2013 (Alzheimer’s Association, 2014).
Family carers, also referred to as caregivers, are the ‘cor-
nerstone of support for people with dementia’ (Ferri et al.,
2005). In the developed world, up to 50% of care-associated
costs are attributable to informal care provided by family
members (Hurd et al., 2013; Alzheimer’s Association, 2014),
rather than direct costs for medical or professional nurs-
ing care (Jelic et al., 2000). The role of family carers is even
more pivotal in low and middle income countries (LMIC),
where they account for 58%–65% of care costs due to low
rates of institutionalization and a lack of community ser-
vices (World Health Organization and Alzheimer’s Disease
International, 2012).
In the United States, most dementia carers are spouses
or adult children (72%) (Bouldin and Andresen, 2010).
Women outnumber men, accounting for 60%–70% of
dementia carers (Bouldin and Andresen, 2010; Fisher et al.,
2011; Alzheimer’s Disease International, 2014), although
the number of male carers have has nearly doubled since
1996 (Alzheimer’s Association, 2008). The 10/66 Dementia
Research Group (a collective of researchers from the devel-
oping and developed worlds) assessed the care arrange-
ments of 706 people with dementia in South East Asia,
China, India, Latin America, the Caribbean and Nigeria
(Prince and the 10/66 Dementia Research Group, 2004). The
rates of female carers in LMIC ranged from 59% in China
and South East Asia to 95% in Nigeria. As in high-income
countries, wives were most often the primary carers (21% in
China and South East Asia to 45% in Nigeria), followed by
daughters (15% in India to 40% in Nigeria) and daughters-
in-law (3% in Latin America and the Caribbean to 24% in
India and South Asia). In India and South Asia daughters-
in-law were the second largest group of carers after wives.

Persons with dementia in LMIC tend to live in larger mul-
tigenerational households than those in countries such as
the United States and the United Kingdom (World Health
Organization and Alzheimer’s Disease International, 2012).
14.1.2 WHY DO THEY CARE?
Informal carers are motivated to provide care for their
loved ones for several reasons, some of which are positive
and beneficial and others not. Positive reasons include a
sense of love or reciprocity, spiritual fulfilment and feel-
ings of mastery and accomplishment (Eisdorfer, 1991;
Sanders, 2005). Carers who identify these reasons experi-
ence less burden, better health, more positive relationships
and more social support (Cohen et al., 2002). Less positive
reasons include, for instance, family responsibility, emo-
tional obligation or ‘having no choice’ (Australian Institute
of Health and Welfare, 2012). Carers who are motivated by
these reasons are more likely to suffer psychological dis-
tress, burden and anxiety and to institutionalize the person
with dementia (Pyke and Bengston, 1996; Camden et al.,
2011). While the negative aspects of caregiving generally
receive more attention in the literature, between 55% and
90% of carers identified positive motivations for caregiv-
ing, including spiritual and personal growth, increased
faith, accomplishment and mastery (Sanders, 2005).
A number of variables influence the way carers view
their role. More positive feelings towards caregiving have
been associated with lower educational level, greater social
resources, satisfaction with social participation, better
physical health status, being non-Caucasian and being
older (Haley et al., 1996; Kramer, 1997; Rapp and Chao,
2000). African Americans identified more traditional, col-
lectivist reasons for providing care than White Americans
(Dilworth-Anderson et al., 2004, 2005). With the increasing
prevalence of male carers, gender differences may be of par-
ticular interest, but research to date is lacking and requires
further refinement (Baker and Robertson, 2008).
14.1.3 HOW DO THEY CARE?
Family carers can be differentiated not only by their rela-
tionship or living arrangements with the person with
dementia (i.e. co-residing or not) but also by their level of
care input. They can be care providers, who facilitate the
day-to-day hands-on care, or care managers, who organize
the care delivered by others (World Health Organization
and Alzheimer’s Disease International, 2012).
Providing care for a person with dementia is very
demanding. Primary carers typically spend large propor-
tions of their day assisting and supervising care recipients
with ADLs (e.g. bathing, toileting) and IADLs (e.g. shop-
ping, food preparation). According to a systematic lit-
erature review, carers spend on average 1.6 hours helping
with ADLs, 2.1 hours on IADLs and 3.7 hours on general
supervision (Wimo et al., 2007). Female carers are more
than twice as likely to provide more hours of care than men,
Family carers of people with dementia 143
and they also care for a longer period of time (Alzheimer’s
Disease International, 2014).
In a study of 1181 UK and European carers (a ­random sam-
ple from Alzheimer Europe’s member organizations fairly
evenly distributed between Germany, Poland, Spain, France
and Scotland), 44% reported spending at least 10 hours a day
assisting the person with dementia (Georges et al., 2008).
The Australian Survey of Disability, Ageing and Carers
identified that 65% of ~12,000 primary dementia carers spent
40 hours or more per week in their caregiving role (Australian
Institute of Health and Welfare, 2007). Dementia severity
is the strongest predictor of hours spent on providing care
(Alzheimer’s Disease International, 2009). Other variables
include time since onset and the amount of instrumental
support available to the carer (Taylor et al., 2008).
Estimates of informal care time typically only reflect
the time spent by the primary carer. Including the input of
other carers increases the total estimate conservatively by
more than 10% (Neubauer et al., 2008) which may still be
an underestimate.
The demands of caregiving in LMIC are comparable to
the developed world. On average, carers in LMIC spend
between 2 and 7 hours assisting the person with dementia
(Alzheimer’s Disease International, 2009). Fifty per cent of
carers from LMIC spend between 3 (India, China, South
and South East Asia) and 9 (Nigeria) hours per day assisting
the person with dementia (Prince and the 10/66 Dementia
Research Group, 2004). Living in multigenerational house-
holds is very common in these countries, but does not
decrease carer burden. While there may be a number of
care managers involved, typically only one care provider
performs most of the hands-on care. Additionally, if the
primary carer does not live with the care recipient, hav-
ing more people involved appears to create additional ten-
sion and conflict (Prince and the 10/66 Dementia Research
Group, 2004). In some developing countries, particularly
African countries, there is a weakening of traditional kin-
ship and support systems. Economic hardship, migration
of younger generations from rural areas and shifting val-
ues and priorities have meant that families are less able or
willing to provide care in traditional ways for older people
(Aboderin, 2004; Okojie, 2004).
14.2 EFFECTS OF DEMENTIA ON
CARERS
The consequences of dementia caregiving are diverse,
ranging from adverse effects on carers’ mental and physi-
cal health, compromised immune function, as well as
financial and social disadvantages (Schulz and Martire
2004; Alzheimer’s Association, 2014) to positive effects
such as uplifts, personal gain, role satisfaction and rewards
(Kramer, 1997).
The most widely studied negative outcomes for demen-
tia carers are carer burden (Pinquart and Sörensen, 2003a;
144 Dementia
Torti et al., 2004; Etters et al., 2008; van der Lee et al., 2014) and
increased levels of depressive symptoms or distress (Pinquart
and Sörensen 2003a, 2003b; van der Lee et al., 2014).
14.2.1 CARER BURDEN
Carer burden refers to the subjective burden specific to the
experiences of carers. The Zarit Burden Interview (ZBI)
(Zarit et al., 1980) is the most widely used measure of carer
burden in dementia carers (Knight et al., 2000; O’Rourke
and Tuokko, 2003; Bachner and O’Rourke, 2007). Scores
range from 0 to 88 with higher scores reflecting greater bur-
den and statistically derived cut-points of 24/26 out of 88
indicating high burden (Schreiner et al., 2006).
Bachner and O’Rourke (2007) pooled ZBI data across
138 studies and reported a mean ZBI score of 33.6 (stan-
dard deviation = 12.1). The 10/66 Dementia Research Group
also found high levels of carer burden in population-based
samples from LMIC, with mean ZBI scores ranging from
17 to 28 (Prince et al., 2012).
14.2.2 PSYCHOLOGICAL MORBIDITY
The strain of caregiving can manifest as psychological mor-
bidity, particularly depression and anxiety (Cooper et al.,
2006; Campbell et al., 2008; Gaugler et al., 2008). In devel-
oped countries, rates of depression among dementia carers
range from 23% to 85% (Adkins, 1999; Clare et al., 2002;
Schoenmakers et al., 2010a). According to a systematic litera-
ture review, 22% of dementia carers meet diagnostic criteria
for major depressive disorder, with rates for individual studies
ranging from 15% to 32% (Cuijpers, 2005). The rates of anxi-
ety vary between 16% and 45% (Schulz et al., 1995; Livingston
et al., 2005; Cooper et al., 2006, 2007). In developing coun-
tries rates of psychiatric morbidity range from 40% to 75%
(Prince and the 10/66 Dementia Research Group, 2004).
Compared to other carers, dementia carers experience
higher levels of psychological distress and lower levels of
self-efficacy and subjective well-being (Schulz and Martire
2004). These differences are even larger when compared to
non-carers (Pinquart and Sörensen, 2003b; Schoenmakers
et al., 2010a) with effect sizes on meta-analysis ranging from
0.40 (95% confidence interval [CI]: 0.32–0.42) for subjective
well-being to 0.66 (95% CI: 0.49–0.84) for clinician-rated
depression (Pinquart and Sörensen, 2003b).
14.2.3 PHYSICAL MORBIDITY
Carers report more health problems and worse perceived
overall health compared to controls, with meta-analytic
effects ranging from 0.15 (95% CI: 0.09–0.22) for objec-
tive to 0.20 (95% CI: 0.12–0.28) for subjective health
measures. Dementia carers compared to other carers or
non-carers reported particularly poor physical health
(B = 0.15, p < 0.001) (Pinquart and Sörensen, 2003b).
Dementia caregiving has also been associated with nega-
tive objective health measures such as greater medication use
and a 23% higher level of stress hormones and a 15% lower
level of antibody responses than non-carers (Vitaliano et al.,
2003). The rates of higher numbers of chronic conditions,
greater health service utilization, compromised immunity,
cardiovascular and metabolic diseases were small and did
not reach statistical significance but given the large num-
ber of caregivers in the population have important implica-
tions (Vitaliano et al., 2003). The reasons for poorer health
may be physiological or because carers are less likely to
engage in preventative health behaviours such as exercise,
and are more likely to smoke, drink alcohol and soft drinks,
eat fast food, and have poor sleep patterns, thereby placing
themselves at risk of further health problems (Schulz and
Williamson, 1997; Hoffman et al., 2012).
14.2.4 SOCIAL ISOLATION
About one-third of dementia carers report feeling socially iso-
lated (Alzheimer’s Association, 2014) as they tend to sacrifice
their leisure pursuits and hobbies, restrict time with friends
and family and give up or reduce employment (Brodaty and
Hadzi-Pavlovic, 1990; LoGiudice et al., 1999; Leong et al.,
2001). Distance from family and friends can compound carer
isolation. In one study, half the carers had contact with some-
one outside their household once per week or less and 13%
had no personal contacts outside the home in the previous 2
weeks (Brodaty and Hadzi-Pavlovic, 1990). Social isolation,
on the other hand, is a risk factor for carer burden (Adelman
et al., 2014) and depression, particularly for female carers
(Alzheimer’s Association, 2014). Interventions may assist in
decreasing/preventing social isolation in carers by increasing
the number of support persons for carers, their satisfaction
with their support network, and the assistance they receive
with caregiving (Roth et al., 2005).
14.2.5 FINANCIAL IMPACT
In 2013, the monetary contribution of informal carers
to the overall costs of dementia in the United States was
$220 billion (Alzheimer’s Association, 2014). Almost 60%
of U.S. dementia carers are also employed of whom two-
thirds reported that they missed work and 8% reported
that they turned down promotion opportunities. Up to
31% had given up work to attend to caregiving responsi-
bilities (Alzheimer’s Association and National Alliance
for Caregiving, 2004; Alzheimer’s Association, 2007).
In Australia, 56% of all dementia carers are employed,
although rates are lower among primary dementia car-
ers (39%) (Australian Institute of Health and Welfare,
2012). The most common reason for leaving the work-
force, stated by 74%, is a lack of alternative care arrange-
ments (Australian Institute of Health and Welfare, 2012).
Female carers are almost seven times more likely than
men to reduce their employment from full-time to part-
time; and more than twice as many female carers give up
work entirely or lose job benefits compared to male carers
(Alzheimer’s Association, 2014).
 Family carers of people with dementia 145

In the developing world, the costs of dementia in com-
parative terms represent a greater burden than in the devel-
oped world, and the economic disadvantage associated with
caregiving is significant (Prince and the 10/66 Dementia
Research Group, 2004). On average, 32% of carers in LMIC
cut back on paid work to care for a family member with
dementia and very few were able to access compensatory
financial support such as government pensions. While
healthcare services are cheaper in absolute dollars than in
developed countries, in relative terms these families spend
a greater proportion of their income on healthcare for the
person with dementia. Paradoxically, despite their eco-
nomic disadvantage, carers from poorer countries tend to
use the more expensive services of private doctors as public
services are unsatisfactory (Prince and the 10/66 Dementia
Research Group, 2004).
14.3 PREDICTORS OF AND
PROTECTORS FROM CARER
DISTRESS
Several characteristics of the carer and/or care-recipient
have been linked to increased levels of depression, carer
burden or other negative outcomes in those caring for
family members with dementia (Torti et al., 2004; Etters
et al., 2008) or mild cognitive impairment (Seeher et al.,
2013).
Negative carer outcomes are best analyzed in the context
of multidimensional stress development models (Brodaty
and Donkin, 2009; Noyes et al., 2010). A recent systematic
literature review (van der Lee et al., 2014) identified four
theoretical frameworks that are used most consistently in
the literature to explain the development of carers’ stress:
the Transactional Model of Stress and Coping (Lazarus
and Folkman, 1984); the Stress Process and Coping Model
(Haley et al., 1987, 1996); the Two-Dimensional Model of
Psychosocial Morbidity (Poulshock and Deimling, 1984); and
the Stress Process Model of Alzheimer’s Disease Caregiver’s
Stress (Pearlin et al., 1990). These frameworks have in com-
mon that they incorporate both patient characteristics and
dementia-specific measures on one side and carer charac-
teristics and carer resources on the other.
As an example, Pearlin’s Stress Process Model (Pearlin
et al., 1990) is depicted schematically in Figure 14.1. The
model proclaims six distinct groups of stressors: (1) contex-
tual or background variables (i.e. patient and carer sociode-
mographic details, relationship characteristics; caregiving
context); (2) objective primary stressors (i.e. impairment
indicators such as patient cognition, function and behav-
iour); (3) subjective primary stressors (i.e. carer’s subjective
appraisals of objective stressors); (4) secondary role strains
(i.e. family conflict, job-caregiving conflicts, economic
problems, constrictions of social life. Secondary stressors
are no less potent than primary stressors, but merely result
from trying to ­balance primary stressors and other non-
dementia-related conflicts/conditions); (5) intrapsychic/
intrapersonal strains (i.e. low self-esteem, poor mastery,
role captivity, poor health); and (6) mediators of stress/pro-
tective factors (i.e. coping, social support).
The scientific evidence (mainly based on meta-analyses
and systematic reviews) for each of these areas of stress is
summarized next.

Context / background of stress

PWD: Demographic details, disease duration

Carer: Demographic/relationship characteristics
Direct effects
Primary objective stressors Indirect/mediated effects
Moderated effects
PWD: Cognition, function, behaviour

Primary subjective stressors

Carer: Appraisal of objective stress, role

Protective factors

overload, relational deprivation

Secondary role strain Coping

Social support
Carer: Family conflict, job-caregiving
conf licts

Intrapersonal strains
Carer: Self-esteem, mastery, loss of self, role captivity,
competence, gain

Outcome of stress

Carer: Depression, anxiety, yielding of role, physical health etc.

Figure 14.1 The stress process model. PWD: person with dementia (Adapted from Pearlin, L.I. et al., The Gerontologist,
30, 583–594, 1990.)
146 Dementia
14.3.1 CONTEXT OF BACKGROUND OF
STRESS
Meta-analytic and pooled evidence consistently suggest
that female carers report worse carer outcomes than men,
including but not limited to higher levels of depression,
anxiety and carer burden (Pinquart and Sörensen, 2003a,
2006a; Schoenmakers et al., 2010a). Likewise, older carer
age and being a spousal carer have been linked to more
negative carer outcomes (Pinquart and Sörensen, 2003a;
Schoenmakers et al., 2010a; Pinquart and Sörensen, 2011).
Mixed evidence exists for living arrangements, with some
studies reporting positive associations between living with
the person with dementia and more negative carer outcomes
while others do not find such a link (Schulz et al., 1995).
Providing care for a male person with dementia has been
linked to greater burden (Torti et al., 2004; Rosdinom et al.,
2013), but not consistently (Abdollahpour et al., 2012). At
the same time, younger patient age is associated with greater
carer depression (Covinsky et al., 2003) and higher levels of
burden (Torti et al., 2004). This is most likely due to higher
levels of burden reported by carers of people with young-
onset dementia (YOD), although the evidence is not conclu-
sive (van Vliet et al., 2010). Similarly, carers of people with
frontotemporal dementia (FTD) experience significantly
higher levels of burden than AD carers (Reidijk et al., 2006),
while carers of people with AD, vascular or Lewy body
dementia report similar levels of stress (Draper et al., 1992;
Lowery et al., 2000). However, these generalizations are not
undisputed and effects may in fact be mediated by other
important stressors such as patient problem difficult.
14.3.2 PRIMARY OBJECTIVE AND
SUBJECTIVE STRESSORS
Negative carer outcomes are most consistently and strongly
linked to the presence of behavioural and psychological
symptoms of dementia (BPSD). Moderately strong associa-
tions with carer burden and depression have been reported
in meta-analyses and systematic reviews (Schulz et al., 1995;
Pinquart and Sörensen, 2003a; Black and Almeida, 2004;
Etters et al., 2008; Schoenmakers et al., 2010a; Ornstein and
Gaugler, 2012; van der Lee et al., 2014).
The evidence is less conclusive for patients’ cogni-
tive symptoms. Links are generally weaker than for BPSD
(Schulz et al., 1995; Pinquart and Sörensen, 2003a; Etters
et al., 2008; Schoenmakers et al., 2010a) or may not be pres-
ent at all (van der Lee et al., 2014).
The same is true for patients’ functional dependency.
Only 36% of carer burden studies and 21% of carer
depression studies reported a significant association with
patients’ functional dependence (van der Lee et al., 2014).
If associations are found, they are generally weaker than for
BPSD (Schulz et al., 1995; Pinquart and Sörensen, 2003a;
Schoenmakers et al., 2010a). In addition, carers’ nega-
tive appraisal of primary stressors has strong detrimental
effects on their mental health and psychological well-being
(Kinney and Stephens, 1989; Goode et al., 1998; Lévesque
et al., 1998).
14.3.3 SECONDARY STRESSORS
Secondary carer strains include conflicts within the fam-
ily; struggling with balancing work, family and caregiving
demands; economic problems; constrictions to one’s social
life, but also carer characteristics such as low self-esteem,
poor mastery or role captivity.
Carers who have multiple roles (e.g. being a working
mother also looking after a parent with dementia) are more
likely to experience negative carer outcomes (e.g. Stephens
et al., 2001; Edwards et al., 2002).
Likewise, carers who report high levels of neuroticism,
low optimism and negative expressed emotion, and who
have insecure attachment styles experience higher levels of
distress (Schulz et al., 1995; Nomura et al., 2005; Campbell
et al., 2008; Cooper et al., 2008) and more burden (van der
Lee et al., 2014). Recently, carer neuroticism, particularly in
adult children, has been linked to greater cognitive decline
in the PWD (Norton et al., 2013). At the same time, better
the person with dementia and secure attachment style are
protective against distress and burden (Cooper et al., 2008;
Lopez and Crespo, 2008). Similarly, high levels of mastery
are linked to lower levels of depression (Schulz et al., 1995)
and reduced stress reactions (Roepke et al., 2008). However,
mastery has been shown to deteriorate for some AD car-
ers (Aneshensel et al., 1995; Skaff et al., 1996; Pearlin et al.,
2007) and a lack of mastery or confidence in one’s ability in
the caregiving role is associated with increased strain and
burden for carers (Campbell et al., 2008). Role captivity, or
feeling ‘trapped’ in one’s role as a carer predicts burden levels
and psychological ill health as it erodes the carer’s sense of
self and subsequently causes feelings of resentment towards
the patient (Pearlin et al., 1990; Campbell et al., 2008).
14.3.4 MEDIATORS OF STRESS
Dysfunctional and immature coping strategies (largely
emotion-based strategies such as escape avoidance) are
mildly to moderately associated with increased anxiety
and greater distress for carers (Cooper et al., 2006, 2007;
del-Pino-Casado et al., 2011; van der Lee et al., 2014). The
pooled weighted mean correlations derived from a recent
meta-analysis are 0.39 (95% CI: 0.28–0.50) and 0.46 (95%
CI: 0.36–0.56), respectively (Li et al., 2012). Greater levels
of emotional support and acceptance-based coping were
mildly protective, with the weighted mean correlation rang-
ing from −0.22 (95% CI: −0.26 to −0.18) for carer anxiety to
−0.20 (95% CI: −0.28 to −0.11) for depression (Li et al., 2012).
Problem/solution-focused coping strategies (largely cogni-
tively based strategies such as positive reframing) can mitigate
distress for carers (Lazarus and Folkman, 1984; Kneebone
and Martin, 2003; Cooper et al., 2007; del-Pino-Casado et al.,
2011; van der Lee et al., 2014). However, this effect did not
withstand meta-analytic scrutiny. The pooled effects on carer

anxiety and depression were 0.10 (95% CI: −0.02–0.21) and
−0.04 (95% CI: −0.11–0.04), respectively (Li et al., 2012). Some
cognitive coping styles, such as cognitive confronting were
even associated with higher levels of anxiety, while others,
such as ‘planful problem-solving’ and ‘cognitive confronting’
showed inconsistent results (Cooper et al., 2007).
Carer support can be formal or informal and can come
in the form of instrumental, emotional or informational
support. Formal support is provided by organizations such
as community services or aged care facilities while informal
support is provided by family and friends. Instrumental
support includes help with daily living needs and house-
work; emotional support provides a ‘shoulder to cry on’; and
informational support includes information and knowledge
from both health professionals and other carers who have
experienced similar situations.
The evidence for receiving support is mixed, but support
is generally regarded as being protective (Schulz et al., 1995;
Shrout and Bolger, 2002; Kneebone and Martin, 2003; van
der Lee et al., 2014) as it provides a buffer against burden and
stress for carers by increasing the perception that resources
are available to handle stress (Cohen, 2004). However, not all
support is beneficial; inappropriate or unwelcome support
can be more stressful than helpful (Edwards and Cooper,
1988). Satisfaction with social support requires the percep-
tion by the carer that the right type of support is available at
the desired level (Drentea et al., 2006). Carers who were more
satisfied with their social interactions showed fewer nega-
tive psychological ­symptoms (Serrano-Aguilar et al., 2006).
14.4 NURSING HOME ADMISSION AND
CARERS
Carers may choose to place the person with dementia in a
nursing home as the illness progresses, usually when the care-
giving demands become overwhelming (Gaugler et al., 2009).
While institutionalization reduces the direct obligations on
the carer and can provide relief and reduced stress (Brodaty
and Hadzi-Pavlovic, 1990; Aneshensel et al., 1995), it does not
necessarily remove distress. Following nursing home admis-
sion, carers may experience increased guilt, anger, anxiety,
depression, loss of self and financial difficulties (Tornatore
and Grant, 2002; Schulz et al., 2004). These can persist for up
to several years following institutionalization (Gaugler et al.,
2007). It was hypothesized that distress would be less for car-
ers if the person with dementia was placed in group homes
that had smaller numbers, more informal daily routines and
more decision-making involvement of residents and informal
carers, compared with traditional nursing homes. However,
there were no significant differences between carers of 67
care recipients in group homes and of 97 in nursing homes
on measures of competence, psychopathology and burden (te
Boekhorst et al., 2008).
Demographic and psychosocial factors predict nursing
home admission. Persons with dementia are more likely to
Family carers of people with dementia 147
be institutionalized, if their carers are employed and balanc-
ing too many demands, unemployed and financially unsta-
ble, feel burdened by the carer role, have difficulty dealing
with behavioural manifestations of dementia, are in a poorer
relationship with the person with dementia or have poorer
physical and psychological health (Brodaty et al., 1993; Tun
et al., 2007; te Boekhorst et al., 2008; Gaugler et al., 2009).
14.5 CARER INTERVENTIONS
A plethora of interventions, therapies and services have been
devised to buffer family carers from the negative effects that
dementia caregiving has on their health and well-being (Zarit
and Femia, 2008). Interventions can be broadly categorized
into psychological interventions including psychoeduca-
tion and psychotherapy such as skills training, provision of
structured information, cognitive behavioural therapy (CBT)
and/or counselling; educational/information interventions
which purely involve information provision and demen-
tia education; or support interventions including support
groups, home visits and social support. Often interventions
involve psychological and support components (Parker et al.,
2008; Zarit and Femia, 2008). Traditionally, interventions
have been delivered face-to-face in individual or group set-
tings. However, Internet-based interventions have become
more common and may be beneficial for some but not all
carers (Powell et al., 2008). Alzheimer Associations are
another important form of help and support for dementia
carers. Support organisations for people with dementia and
their carers exist in over 85 countries worldwide (www.alz.
co.uk). These are discussed further in Chapter 36. Referral of
families to Alzheimer Associations is part of the clinician’s
therapeutic armamentarium. Respite care and community
services also offer support to carers. These are discussed in
Chapter 15.
Table 14.1 lists meta-analyses and systematic literature
reviews that have analyzed the efficacy of carer interven-
tions in improving measures of carer mental health and
psychological well-being. Intervention effects on patient
symptoms and the ability to delay nursing home placement
are summarized in Table 14.2. Generally, there is no ‘one
size fits all’ solution in improving carer mental health or
patient symptoms. The efficacy of interventions depends
highly on the outcome one seeks to improve.
Depressive symptoms of dementia carers respond best
to CBT (Pinquart and Sörensen, 2006b; Vernooij-Dassen
et al., 2011) and psychoeducational group interventions
(Thompson et al., 2007), both showing moderately strong
effects (Table 14.1). The effects of decreased carer anxiety
are more modest (effect size around −0.21) with the best
evidence currently existing for CBT (Vernooij-Dassen
et al., 2011). Carer burden is more difficult to improve,
with effects generally being small or not statistically sig-
nificant possibly because studies do not always distinguish
between objective and subjective burden (Brodaty et al.,
148 Dementia

Table 14.1 Overview of the meta-analytic and systematic review evidence for the effectiveness of interventions on carer
outcomes

Psych. Subj.
Reference morb. Depression Anxiety Burden stress Know­ledge Coping SE SWB/QoL Other

Any psychosocial (between 5 and 98 interventions)

Pinquart and −0.24z −0.12 0.46 0.31
Sörensen (2006b)a
Brodaty et al. (2003)a 0.31 0.09 0.51 Any: 0.32

Psychoeducation (between 4 and 34 interventions)

Pinquart and −0.27 −0.15 0.46 0.21
Sörensen (2006b)a
Thompson et al. −0.71 −2.15
(2007)a
Selwood et al. (2007)b n/e n/e n/e

CBT (between 1 and 15 interventions)

Pinquart and −0.70 −0.36 1.12 0.37
Sörensen (2006b)a
Vernooij-Dassen et al. −0.66 −0.21 0.14 −0.24 0.64
(2011)c
Schoenmakers et al. 0.03 −2.94
(2010b)a

Counselling/case management (between 2 and 7 interventions)

Pinquart and −0.20 −0.50 0.43 0.42
Sörensen (2006b)a
Thompson et al. −0.21 0.37
(2007)a
Schoenmakers et al. −0.32
(2010b)a

Coping skills training (between 2 and 5 interventions) DFC PC

Li et al. (2012)ad 0.39d 0.28
Selwood et al. (2007)b m.d.n.

Meditation (between 5 and 8 interventions)

Hurley et al. (2014)b 5/7e+1fU 3/5eg 3/4ef

Technology based (Internet, computer, telephone) (between 2 and 6 interventions)

Thompson et al. 0.62
(2007)a
Schoenmakers et al. 0.07
(2010b)a
Boots et al. (2014)b 1/2e 2/3e 2/4eh 2/4i n.s. 5/6e n.s.
Powell et al. (2008)b 1/5e 0/1e 0/4e 1/1e Social: 0/3e

Information provision services (e.g. dementia advisory services, AA) (between 1 and 4 interventions)
Corbett et al. (2012)a −0.87 0.23–0.43

Support groups (between 2 and 19 interventions)

Pinquart and 0.05 0.01 0.29 2.03
Sörensen (2006b)a
Chien et al. (2011)a −0.44 −0.40 −0.23 −0.44 Social: 0.40
Thompson et al. −0.40
(2007)a
Selwood et al. (2007)b n/e n/e n/e
(Continued )
 Family carers of people with dementia 149

Table 14.1 (Continued ) Overview of the meta-analytic and systematic review evidence for the effectiveness of interventions
on carer outcomes

Psych. Subj.
Reference morb. Dep­ression Anxiety Burden stress Know­ledge Coping SE SWB/QoL Other

Physical activity (between 2 and 4 interventions) Obj

burden:
Orgeta and Miranda- −0.17 −0.22 −0.22−0.43j –0.18 −0.22
Castillo (2014)a

Behaviour management interventions for carers (between 3 and 17 interventions)

Brodaty and 0.15
Arasaratnam
(2012)a
Selwood et al. (2007)b ++k n/e
ind 6+
Selwood et al. n/e n/e
(2007)bind <6/G

Dyadic interventions (up to 20 interventions)

Van’t Leven et al. 3/9e(0 to 13/17e(−1.19 7/10e
(2013) b −0.98) to 0.31) (−0.15 to
0.92)

Respite (between 2 and 12 interventions)

Pinquart and Sörensen −0.12 −0.26 −0.06 0.27
(2006b)a
Schoenmakers et al. 0.30l
(2010b)a
Maayan et al. (2014)c n/d n/d 1m

Training of the care recipient (between 2 and 8 studies)

Pinquart and 0.01 −0.17 −0.12 0.42
Sörensen (2006b)a

Pharmacological treatment of the care recipient (between 4 and 8 interventions) Carer time:
Schoenmakers et al. −0.27 −42 min/d
(2009)a
Lingler et al. (2008)a −0.18 0.15

Notes: Bold values are statistically significant pooled effects; shaded effects are the strongest significant effect for the respective carer outcome;
effects are pooled standardized mean differences; effect size 0.2: small effect; effect size 0.5: moderate effect; effect size ≥0.8: strong effect.
Abbreviations: AA, Alzheimer’s Associations; CBT, Cognitive behavioural therapy; DFC, dysfunctional coping; ind 6+, therapies for individuals
with six or more sessions; ind<6/G, therapies for individuals with less than six sessions or group therapy; m.d.n, possibly beneficial,
more data needed; n/e, not effective; n/d, no data; NH, nursing home; n.s., not significant; Obj, objective; PC, positive coping; Psych.
Morb., psychiatric morbidity; QoL, quality of life; SWB, subjective well-being, including quality of life; SE, self-efficacy; Sx, symptoms.
a Meta-analysis.

b Systematic literature review.

c Cochrane review.

d Meta-analysis of interventions that significantly improved carer depression to analyze the extent to which they also changed coping styles.

Counterintuitively, these interventions increased dysfunctional coping.

e x/y: Ratio of significant effects to the total number of studies that investigated such effect.

f Follow-up.

g Post-treatment.

h One additional study found significant positive effects for high-frequent users of the programme.

i x/y: Reported increase in x of y studies.

j Based on studies using the same measure (i.e. SCB, Screen for Caregiver Burden).

k Short term/long term.

l Favouring controls.

m Negative.

++,effective.
150 Dementia

Table 14.2 Overview of the meta-analytic evidence for the effectiveness of interventions on patient outcomes

Reference BPSD Mood ADL/IADL QoL NH placement

Any psychosocial carer intervention (between 5 and 98 interventions)

Pinquart and Sörensen (2006b)a −0.17 0.72
Brodaty et al. (2003)a 0.68

Psychoeducation of carer (between 4 and 34 interventions)

Pinquart and Sörensen (2006b)a −0.15 1.09

CBT for carer (between 1 and 15 interventions)

Pinquart and Sörensen (2006b)a −0.29 n/d
Vernooij-Dassen et al. (2011)b n.s.

Carer counselling/case management (between 2 and 7 interventions)

Pinquart and Sörensen (2006b)a −0.33 n/d

Behaviour management interventions for carers (between 3 and 17 interventions)

[Brodaty and Arasaratnam 0.34
(2012)]a

Information provision services (e.g. dementia advisory services, AA) (1 to 4 interventions)

Corbett et al. (2012)a −1.48 n.s.

Carer support groups (between 2 and 19 interventions)

Pinquart and Sörensen (2006b)a 0.07 0.89

Dyadic interventions (up to 20 interventions)

Van’t Leven et al. (2013)c d3/8 3/6
d 5/10
d 4/8
d

(−0.66 to 0.27) (−0.47 to 0.34) (−1.46 to 0.23) (−0.26 to 1.27)

Training of the care-recipient (between 2 and 8 interventions)

Pinquart and Sörensen (2006b)a −0.35

Respite (between 2 and 12 interventions)

Pinquart and Sörensen (2006b)a −0.08 0.76
Orgeta and Miranda-Castillo n/d
(2014)b
Notes: Bold values indicate significant pooled effects; effects are pooled standardized mean differences, except effects on nursing home
placement which are odds ratios; effect size 0.2: small effect; effect size 0.5: moderate effect; effect size ≥0.8: strong effect.
Abbreviations: ADL, activities of daily living; BPSD, behavioural and psychological symptoms of dementia; BPSD dis, carer distress associated
with BPSD; IADL, instrumental activities of daily living; n/e, not effective; NH, nursing home; QoL, quality of life; Sx, symptoms.
a Meta-analysis.

b Cochrane review.

c Systematic literature review.

d x/y, ratio of significant effects to the total number of studies that investigated such effect

2003). However, one meta-analysis yielded moder-
ately strong effects for counselling or case management
(Pinquart and Sörensen, 2006b). Physical activity interven-
tions may also provide relief from carer burden, although
these results are based on two interventions only (Orgeta
and Miranda-Castillo, 2014). Carer knowledge is best
improved by psychoeducational interventions (Pinquart
and Sörensen, 2006b), while carers’ subjective well-being
benefits most from support group interventions (Chien et
al., 2011). Non-pharmacological interventions for patients
with BPSD which are delivered through the carer at home
significantly decrease patient BPSD (ES (effect size) = 0.34,
95% CI: 0.20–0.48; see Table 14.2) and the associated carer
distress (ES = 0.15, 95% CI: 0.04–0.26; Table 14.1) (Brodaty
and Arasaratnam, 2012).
Past carer intervention studies were often limited in their
design and methodology, contributing to the modest effects
traditionally obtained (Zarit and Femia, 2008). More recent
studies have addressed these shortcomings by ensuring that:
carers’ needs are clarified, the treatment is relevant to car-
ers’ needs, the methodology meets the treatment goal and
the heterogeneity of carers is taken into account (Zarit and
Femia, 2008). A selection of carer interventions is briefly
described below.
The Seattle Protocols (Reducing Disability in Alzheimer’s
disease, RDAD) are a systematic and structured, yet

individualized approach to training family carers to reduce
behavioural and psychiatric disturbances in persons with
dementia. The protocols teach carers to monitor problems,
identify possible events that trigger disturbances and develop
effective responses (Teri et al., 2005). They have been effective
at improving carer quality of life, reducing reactive responses
to problem behaviours, improving burden levels (Teri et al.,
2005) and depression, agitation and sleep disturbance (Teri
et al., 1997, 2000; McCurry et al., 2005). The programme
was successfully rolled out by chapters of the Alzheimer’s
Association in the United States, showing a significant reduc-
tion in carers’ unmet needs and care-efficacy strain in the
67% of completers (n = 219) (Menne et al., 2014).
The Resources for Enhancing Alzheimer’s Carer Health
(REACH) multisite, multicomponent project using a variety
of interventions is a 6-year study conducted over six loca-
tions in the United States (Belle et al., 2006). The follow-up
study, REACH II, was conducted over five sites with 692
Latino, Caucasian and African American carers divided into
intervention and control groups (Stevens et al., 2009). The
intervention group received a comprehensive programme
including provision of information, didactic instruction,
role playing, problem solving, skills training, stress manage-
ment and telephone support (Belle et al., 2006). Compared
to controls, significant improvements in depression, bur-
den, care recipient problem behaviours, self-care and social
support were found for Caucasian and Hispanic carers, but
not for African Americans (Belle et al., 2006). Since then,
REACH II has been implemented by community agencies
(Lykens et al., 2014; Cheung et al., 2015; Altpeter et al., 2015)
showing significant reductions in depression and carer bur-
den in completers of the intervention (Lykens et al., 2014;
Cheung et al., 2015). However, high rates of non-completion
(up to 64%) due to institutionalization or death of the per-
sons with dementia or other reasons (Lykens et al., 2014)
abate the enthusiasm for the programme somewhat.
The New York University Caregiver Intervention (NYUCI)
is a carer programme involving individual and family coun-
selling sessions focusing on carer skills training, behaviour
management techniques and carers’ communication strate-
gies with the PWD; weekly support group participation; and
availability of ad hoc telephone counselling. The intervention
has been proven to be successful in improving carer well-
being by reducing depressive symptoms; improving reactions
to memory and behaviour problems; and increasing the size
and satisfaction with support networks (e.g. Roth et al., 2005;
Mittelman et al., 2006). The NYUCI also significantly delayed
nursing home placement (Mittelman et al., 2006; Gaugler
et al., 2013) and reduced the level of carer burden following the
institutionalization (Gaugler et al., 2010). Community imple-
mentations (Mittelman and Bartels, 2014) and multinational
adaptations of the NYUCI also yielded promising results
(Burns et al., 2010). A randomized controlled trial (RCT) of
five NYUCI sessions conducted in Manchester, New York and
Sydney significantly reduced carer depression (Mittelman
et al., 2008) and reduced time to nursing home placement
but only at the Australian site (Brodaty et al., 2009). Possible
Family carers of people with dementia 151
reasons for varying effects on nursing home admission across
the three countries were differences in aged care systems and
financial disincentives to institutionalization and differences
in the amount of counselling provided (more ad hoc counsel-
ling was provided in Sydney) (Brodaty et al., 2009).
In general, multidimensional, flexible carer interventions
that involve follow-up and an ongoing relationship between
helper and carer are more likely to delay nursing home
placement (Brodaty et al., 2003; Pinquart and Sörensen,
2006b). A 10-day structured carer intervention programme
delayed institutionalization of care recipients over 7 years
with concurrent improvement in the psychological health of
carers, without increasing use of health services or demen-
tia drugs, and with significant cost savings over the first
3 years (Brodaty and Gresham, 1989; Brodaty and Peters,
1991; Brodaty et al., 1997).
Developing countries rely primarily on families to pro-
vide support to people with dementia as health services
are often ill-equipped to meet their needs (Dias et al.,
2008). Family carers in LMIC face additional challenges as
awareness and understanding about dementia are lacking;
symptoms may be perceived to be part of normal ageing, or
denied because of the stigma attached to the illness (Patel
and Prince, 2001; Senanarong et al., 2004; Dias et al., 2008).
Effective interventions addressing issues and needs relevant
to these carers are required and have been trialled as part of
the 10/66 Dementia Research Group network.
An RCT conducted in Goa, India, evaluated a home-
based intervention consisting of basic education about
dementia and common behaviour problems, strategies for
managing problem behaviours, support to carers in ADLs,
referral to psychiatrists or other medical professionals for
assistance with BPSD, networking to assist the carers to
form support groups and advice on government provisions
for the elderly (Dias et al., 2008). The intervention led to sig-
nificant improvements in carer mental health and perceived
burden for the 41 carers in the treatment group (compared to
40 controls). There were also reductions in the behavioural
disturbances and improvements in the functional abilities
of the PWD, but these were not statistically significant (Dias
et al., 2008). The programme used local health and human
resources, making it affordable and easily accessible.
A 6-month group counselling intervention was tri-
alled with 50 carers (half each assigned to the treatment
and control groups) in Thailand (Senanarong et al., 2004).
Counselling, support, education and strategies for manag-
ing problem behaviours formed part of the intervention. At
6 months, the neuropsychiatric symptoms of the PWD had
significantly declined. Carer distress associated with these
symptoms declined over time compared with the control
group, but not significantly.
An RCT in Moscow, Russia, involving a 5-week course
covering basic education about dementia and specific train-
ing on managing problem behaviours, resulted in statisti-
cally significant reductions in carer burden and increases in
quality of life that were close to significant (Gavrilova et al.,
2008). The effect sizes for these were in the moderate range
152 Dementia
(0.64 and 0.52, respectively), and larger than those typically
seen in interventions undertaken in high-income coun-
tries (Brodaty et al., 2003; Gavrilova et al., 2008). Thus, an
intervention focusing on education and training might be
particularly beneficial in a setting where community aware-
ness of dementia and appropriate formal care services are
lacking (Gavrilova et al., 2008). Carer psychological mor-
bidity and the severity of, and the distress caused by BPSD
did not improve significantly as a result of the intervention
(Gavrilova et al., 2008).
For all three studies small sample sizes limited the statis-
tical power and possibly explained the lack of significance
in some of the results. Additionally, the follow-up periods
may have been too short to demonstrate an effect, or to show
whether the intervention had a long-term impact on carer
and care-recipient well-being.
14.6 SPECIAL CATEGORIES OF CARERS
There are certain groups of carers who may experience
additional challenges beyond those directly related to
caregiving. These include (but are not limited to) carers of
younger people with dementia; carers of people who iden-
tify as gay, lesbian, bisexual, transsexual or transgender; and
carers of people with intellectual disabilities (World Health
Organization and Alzheimer’s Disease International, 2012).
People with YOD and their carers face additional prob-
lems as they are more likely to be working and have depen-
dent children (World Health Organization and Alzheimer’s
Disease International, 2012). Sometimes, these carers are
the affected person’s parents; their challenges are poignant.
Carers are often unprepared for the task and have fewer
appropriate services available to them (Chaston et al., 2004;
Arai et al., 2007; van Vliet et al., 2010). Formal services such
as respite are usually designed for older people and are con-
sidered inappropriate for people with YOD (Withall 2013;
Withall et al., 2014). Informal social support may be fewer as
family and friends are likely to be working and have depen-
dents themselves, and are unable to empathize with the
carer’s experience. Two systematic literature reviews have
summarized the evidence for negative mental health effects
of YOD carers (van Vliet et al., 2010; Svanberg et al., 2011).
There is strong evidence that YOD carers experience high lev-
els of burden, depression, distress and psychiatric symptoms
(van Vliet et al., 2010; Svanberg et al., 2011), with 50% or more
meeting cut-off scores for psychiatric caseness on global dis-
tress measures (Svanberg et al., 2011). When systematically
compared to carers of people with late-onset dementia, YOD
carers experience potentially higher levels of burden but the
evidence is less conclusive (van Vliet et al., 2010). The impact
of FTD on carers appears greater than for carers of people
with other types of dementia; with FTD carers reporting
higher levels of burden, depression and distress associated
with behavioural symptoms despite similar levels of behav-
ioural symptoms (Kaiser and Panegyres, 2007; Svanberg
et al., 2011). As with late-onset dementia, female carers report
higher levels of psychological morbidity than their male
counterparts (van Vliet et al., 2010; Svanberg et al., 2011).
Systematic research focusing on the impact of dementia
and the needs of homosexual men and women and their car-
ers remains largely inadequate (Price, 2008). Homosexual
partners of PWD may feel that the existing interventions
and support services do not meet their needs (Birch, 2009)
and that the issues they face (for instance next-of-kin rights)
are not well understood or addressed especially in residential
and acute care settings. Homosexual carers also experience
prejudice and insensitivity in their interactions with health
services; lack social and emotional support due to efforts to
maintain privacy in their nontraditional relationship; were
unable to use employee benefits to assist their partner with
dementia; faced opposition from employers when attempting
to take compassionate leave; and faced legal difficulties with
estate planning (Moore, 2002). Country-specific legislations
such as the Mental Capacity Act 2005 for England and Wales
(Department for Constitutional Affairs, 2007) promise
important legal changes for homosexual patients and their
carers concerning advance care planning and power of attor-
ney (Price, 2008; Birch, 2009) (see below for more details).
Increasingly, people with Down syndrome and other
intellectual disabilities (ID) are living to an age where they
become susceptible to developing dementia (Evans et al.,
2013). Persons with Down syndrome are likely to develop
Alzheimer pathology by their fourth decade, and clinical
symptoms by their fifth or sixth decades (Margallo-Lana
et al., 2007). Carers of people with ID and dementia, mostly
parents who have been the primary carer for decades, face
unique challenges (Haley and Perkins, 2004). Aside from
the prolonged caregiving experience, parental carers are
now facing age-related diseases themselves and anxieties
arise about who will care for their dependents if these par-
ents become disabled or die.
When a care recipient is in a second (or later) marriage,
particularly when there are children from a previous mar-
riage, disputes are more likely to arise about legal and
guardianship issues. When people marry close to the time
that one begins to dement, further issues can arise regard-
ing capacity to marry, the partner’s motivation (Peisah
and Bridger, 2008) and possible issues to do with less well-­
developed feelings of reciprocity and obligation.
14.7 LEGAL ASPECTS
Legal aspects concerning advance care planning (ACP), liv-
ing wills, enduring guardianship or power of attorney (POA)
are particularly relevant to family carers (for more details see
Chapters 30 and 32 in this book). Living wills or advance
care directives specify personal preferences for future medi-
cal care. Enduring guardians are appointed to make lifestyle,
health or personal welfare decisions on a person’s behalf once
the person is deemed no longer competent to do so. A POA

authorizes a person to make financial or property decisions
on behalf of an individual if this person no longer has capac-
ity to do so (Mullick et al., 2013). In some jurisdictions prior
POA becomes invalid when the appointer becomes incom-
petent. This can be circumvented, if the PWD declares that
these proxy powers should endure even if he or she loses
competency (i.e. enduring, durable or lasting POA).
There is considerable variation in laws between countries
and even between jurisdictions within countries (Peisah
et al., 2009; Stoppe, 2009). In any case, the person’s right to
self-determination and to have his or her wishes respected
should be protected. In England, the Mental Capacity Act
provides a legal framework for people who lack capacity or
who want to make provisions for a time when they no longer
have capacity (Department for Constitutional Affairs, 2007).
Among healthy older community-dwellers, the hypo-
thetical onset of a dementing illness was stated as a trig-
ger for putting in place ACP arrangements (Samsi and
Manthorpe, 2011; Mitchell et al., 2014). They certainly
should be discussed with anyone who has dementia and
their family (Bisson et al., 2009). The sooner after a diag-
nosis ACP is considered the better, so that the person can
participate as fully as possible in the process (Alzheimer’s
Association, 2007; Raivio et al., 2008). The potential ben-
efits of advance care plans for patients and carers have
been demonstrated in an Australian RCT involving 309
elderly legally competent hospital inpatients, of whom 40%
received an ACP intervention. Patients with advance care
directives in place were more likely to have their end-of-life
wishes known and acted upon (86% compared to 30% in
the control group) (Detering et al., 2010). Having advanced
care directives in place was also associated with signifi-
cantly lower psychological morbidity in family members
and greater satisfaction with the end-of-life care after the
loved one’s death (Detering et al., 2010).
Despite these benefits, the rates at which advance care
directives, legal guardianships and financial POA are in
place vary widely from 0 to 71% depending on the coun-
try, the setting and demographic and clinical aspects of the
person with dementia and the carer (Ruggieri and Piccoli,
2003; Lingler et al., 2008; Raivio et al., 2008; Garand et al.,
2011; Astell et al., 2013). The main factor associated with
initiating an advance care directive or durable POA was
younger patient age (i.e. <65 years), moderated by disease
severity, male sex, having a spousal carer, a family history of
AD and the absence of major depressive disorder at baseline
(Garand et al., 2011). Other studies have identified older age
(Mitchell et al., 2014) or disease severity, behavioural prob-
lems and carer strain but not demographic factors as pre-
dictors of initiating advance care plans (Raivio et al., 2008).
Reasons for not having advance care plans in place are
lack of awareness and knowledge. Raising the awareness for
the importance of ACP and POA in particular has a posi-
tive impact on a person’s willingness to put a POA in place
(Mitchell et al., 2014). Meta-analytic evidence suggests that
one-on-one interactive interventions which encourage ques-
tions and offer practical help with completing forms are
Family carers of people with dementia 153
particularly effective in promoting ACP (Jezewski et al., 2007;
Bravo et al., 2008). General practitioners are often viewed to
be best suited to initiate first discussions about ACP and POA
(Samsi and Manthorpe, 2011; Mitchell et al., 2014).
Even if advance care plans are in place, the different con-
cepts are often poorly understood by carers (Ruggieri and
Piccoli, 2003; Astell et al., 2013). For instance, family mem-
bers often assume a POA takes immediate effect, while in
some countries (e.g. United Kingdom and New Zealand)
it only becomes effective once the person loses capacity.
(Astell et al., 2013; Mullick et al., 2013). In Australia, the
person taking out an enduring POA can specify under what
circumstances it becomes active (Mitchell et al., 2014).
Carers also have an important legal role in assisting
care recipients to make decisions about treatment and par-
ticipation in research. Informed consent is required before
prescribing medication, which requires the patient to
understand what the medication is for, the likely benefits,
possible adverse events and any alternatives (Brodaty and
Green, 2002). If the person with dementia lacks capacity the
carer may be called on to give proxy consent to initiate phar-
macotherapy, or to participate in a drug trial or other rel-
evant research. Jurisdictions vary regarding the legislation
and requirements for proxy consent. In some jurisdictions
in the United States, uncertainty has led to institutions dis-
allowing proxy consent for research (Kim et al., 2009). This
is despite broad public support for a policy of proxy (or sur-
rogate) consent for AD research. A 2006 survey of 1515 older
Americans (aged 51 and older) showed between 68% and
83% support depending on the scenario (Kim et al., 2009).
14.8 CONCLUSIONS
Dementia seldom afflicts just one person. Carers (or care-
givers) are an integral part of the dementia management
equation from symptom onset through diagnosis and
management to death. Carers, the ‘second patient’, deserve
attention in their own right. Those vulnerable to stress can
be identified and interventions can reduce carers’ distress
and improve their quality of life. This, in turn, can lead to a
better quality of life for persons with dementia and increase
their length of time living in the community.
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Dementia care in the community: Challenges
for primary health and social care
STEVE ILIFFE, JILL MANTHORPE AND VARI DRENNAN
15.1 INTRODUCTION
Dementia is one of the main causes of disability in later
life. Although the incidence of dementia in industrial-
ized countries may have reached its peak (Matthews, 2013;
Alzheimer’s Disease International [ADI], 2014), its impact
remains profound. In terms of the global burden of disease,
it contributes 11.2% of all years lived with disability; higher
than stroke (9.5%), musculoskeletal disorders (8.9%), heart
disease (5%) and cancer (2.4%) (World Health Organization,
2003). Nevertheless, in comparison with other areas of long-
term disease management, the care of people with dementia
currently constitutes only a small proportion of primary
care family doctors’ workload with only three to four new
cases a year handled by a doctor in a demographically aver-
age population. While family doctors may have few cases,
their engagement with those patients and their families is
likely to be over a long period, as the median length of time
from symptom onset to death is 10 years for those under 65
years old at diagnosis and 4 years for those over 80 years
at diagnosis (Xie et al., 2008). Even allowing for delays in
diagnosis, median survival from diagnosis is 3.5 years (Rait
et al., 2010). As populations rapidly age, this situation will
change. Healthcare systems in many countries are antici-
pating the need to develop new services and reconfigure
existing ones to respond to the increasing prevalence of
dementia.
In England, both the National Institute for Clinical
Excellence and Social Care Institute for Excellence (NICE/
SCIE) dementia guidelines (NICE, 2006) and the National
Dementia Strategy (Department of Health, 2009) proposed
a systematic approach to the continuing care of people with
dementia in the community, to correct the evident deficits
in care identified over a period of many years, by a range
of bodies such as, the Alzheimer’s Disease Society (1995).
15
The same phenomenon of un-integrated services is found
throughout Europe (Waldemar et al., 2007), the United
States (Dementia Initiative, 2013) and Australia (Grealish
et al., 2013).
Services for people with dementia must cross boundaries
between health and social care agencies, between second-
ary and primary care sectors and between the disciplines
of medicine, nursing, allied professions and social care. The
purpose of this chapter is to identify effective ways to cre-
ate such cross-boundary working in the sector where most
people with dementia will receive most services and sup-
port: in primary care. Different healthcare systems and
funding streams are unhelpful regarding a prescriptive
approach to the disease, nevertheless, we believe there are
key ideas, approaches and techniques that can cross cul-
tures and systems. To help this process of learning from
others’ experiences, we have adopted a polyglot terminol-
ogy. Following this terminology, caregiver is used to mean
family members, neighbours or friends who provide practi-
cal and emotional support to people with dementia and who
are called carers or informal carers in the United Kingdom.
Family doctors are primary care physicians (PCPs) in some
parts of the world and general practitioners (GPs) in other
parts. Primary care nurses include those nurses who work
alongside family doctors as well as specialist nurses work-
ing in the community (like the United Kingdom’s District
Nurses or Community Nurses), particularly those working
with older people. Social workers do different things in dif-
ferent countries, but they all seem able to recognize each
other and have a common practice base (Manthorpe and
Moriarty, 2007). Social care and support, on the other hand,
may be provided by commercial, local government or com-
munity, voluntary and religious organizations, be part of
healthcare systems or separately funded.
Underpinning our argument is the knowledge that pro-
posals for skill acquisition or service development rest on a
161
162 Dementia
weak evidence base, particularly for psychosocial interven-
tions. The systematic reviews that we cite make it clear that
the paucity of evidence arises from the quality of studies
rather than the number. Only with the cholinesterase inhib-
itor drugs can we be confident that the evidence of effective-
ness is grounded in large trials with realistic time-frames.
Dementia syndromes are progressive neurodegenerative
diseases which follow a variable but inexorable trajectory.
We have organized this chapter to follow that trajectory,
starting with early symptoms, moving to diagnosis and
early support, then mid-stage dementia and behavioural
and psychological disorders (BSPD). The chapter ends with
a discussion of better care at home and in long-term care
facilities such as care homes and nursing homes, including
end-of-life care. In each section we attempt to answer four
questions: (1) what is known about this subject? (2) what do
primary care practitioners need to learn? (3) how will they
know they are effective? and (4) what service developments
are needed?
15.2 EARLY RECOGNITION OF
DEMENTIA IN PRIMARY CARE
15.2.1 WHAT IS KNOWN ABOUT THIS
SUBJECT?
Although this is a surprisingly understudied subject (Le
Couteur et al., 2013), the perceived benefits of reaching a
diagnosis include ending uncertainty about the cause of
symptoms and behaviour change and promoting greater
understanding among family members with respect to
the problems experienced by the person suffering from
dementia. The aim is to increase access to helpful support
resources, to promote positive coping strategies and to facil-
itate planning and fulfilment of short-term goals (Bamford
et al., 2004). Using cholinesterase inhibitor medication to
modify symptoms in a worthwhile way for a minority of
people with dementia who have Alzheimer’s disease is a
further advantage (NICE, 2006).
Dementia is probably under-diagnosed and under-
treated. Wide variation in family doctors’ abilities and
confidence in diagnosing and managing dementia has
been consistently reported across different countries
(Pucci et al., 2004). There is also evidence that diagnosis
is sometimes delayed, with misattributed early symptoms
as part of the process of normal ageing by both people
with dementia and their families as well as professionals.
Carers and family members often prompt the seeking of
a diagnosis as they may recognize symptoms before the
person is affected, especially after a trigger event in the
patient’s life or health such as bereavement. Changes in
personality and/or mood may also lead family members to
ask family doctors to identify what is wrong. Community
nurses and social care practitioners may be some of the
first professionals to notice the changes that affect an
older person living on their own (Manthorpe and Iliffe,
2007) and suggest a consultation. However, the stigma of
such a diagnosis, a general lack of awareness of the condi-
tion and the impression that little can be done for some-
one suffering from an incurable disease may often block
the diagnostic pathway preventing the patient or others
from seeking medical help, because of embarrassment,
shame, fear or uncertainty (Bradford et al., 2009). This
delay occurs despite evidence that early cognitive impair-
ment is associated with increased frequency of consulta-
tions in primary care (Ramakers et al., 2007).
The presenting symptoms of dementia may vary and do
not always include memory loss. For example, in one study,
memory loss was the symptom that prompted help seek-
ing in 85% of new diagnoses of dementia, but 63% also had
other behavioural and psychological symptoms of dementia
(BPSD) (Shigematsu, 2011). Symptoms can also fluctuate,
complicating decision-making, especially in mild cognitive
impairment, when between 40%–70% of patients notice an
improvement in their symptoms or are found not to have
dementia when reviewed (Le Couteur et al., 2013, Mitchell
and Shiri-Feshki, 2009).
Some may make an initial, potentially inaccurate diag-
nosis of depression, although depression may coexist with
dementia.
Early recognition of dementia syndrome is an area of
practice where there is considerable potential for uncer-
tainty and confusion, including the difficulty in distin-
guishing between the (adverse) consequences of receiving
the diagnosis report of dementia and the problems that
occur while living with dementia. Studies of older people’s
experiences of the assessment ‘journey’ have found that
many report feelings of confusion, uncertainty and anxiety
over seemingly inexplicable time of waiting required in the
diagnosis (Samsi et al., 2014). Some may be highly critical of
the systemic process of assessment and diagnosis disclosure
although, generally positive of the practice of individual
professionals (Samsi et al., 2014).
15.2.2 WHAT DO PRACTITIONERS NEED
TO LEARN?
Although lack of insight may be an early feature of the
dementia syndrome, people with dementia may be more
aware of their diagnosis than is suspected, because older
people and the general public are now much informed about
dementia and its symptoms. Many primary care nurses and
social care staff are often asked if they think an older per-
son is showing symptoms of dementia. Some primary care
nurses might lack confidence in responding to these ques-
tions, so they need to be knowledgeable about early symp-
toms of dementia and also familiar with the locally agreed
first points of contact for people with such anxieties if they
are to answer such questions with confidence.
Professional development among family doctors should
aim to enrich the illness scripts that practitioners use to
recognize dementia, emphasizing the functional symptoms
 Dementia care in the community: Challenges for primary health and social care 163
that can occur early in the disease process and reducing the
reliance on subjective memory loss as a cardinal symptom.
Concerns about causing harm by over-zealous pursuit of
early diagnosis can be offset by reframing the task as one
of making timely diagnoses, in which changes in cognition
or behaviour that worry the individual or those around
them are taken seriously, investigated and clarified. This is
essentially a clinical judgement rather than one that can be
made (in primary care) by use of cognitive function tests,
although such tests are useful adjunct to clinical reasoning.
15.2.3 HOW WILL THEY KNOW THEY ARE
EFFECTIVE?
Enhanced skills in earlier recognition of dementia will
help to minimize misattribution and reduce the length of
time from symptom onset to diagnostic assessment, so that
specialist services will see a change in their case mix, with
fewer late presentations during crises and more early ones.
Clinical records will contain more entries about risks being
discussed and diagnostic hazards managed. These needs to
be shared with primary care nurses and social care prac-
titioners to ensure that mixed messages are not given to
the carers. Individuals will report processes that are clear,
person-centred and accommodate individuals’ preferences.
Professionals will provide accurate information, outline the
options and explain their relevance, including potential to
appoint proxy decision makers, draw up advance decisions
and communicate wishes and preferences. Their patient
record systems will contain such information and share
it with the consent of their patients or when in their best
interests.
15.2.4 WHAT SERVICE DEVELOPMENTS
ARE NEEDED?
Professional development across community-based dis-
ciplines is the first priority in our view, although in some
countries, such as England, the development of memory
clinics has overtaken this in terms of investment. In addi-
tion to this, mechanisms are required at local levels for
developing and disseminating agreed service access routes,
or care pathways for people with symptoms or concerns
across agencies. Without such ‘maps’, the potential for con-
flict, omissions and delay increases (Waldorff et al., 2001),
but such maps need to be accurate and updated (Samsi and
Manthorpe, 2014) and are no replacement for advice and
consideration of personal circumstances.
There is a growing consensus that prevention of demen-
tia is practical and feasible. Service commissioners and pro-
viders should strengthen public health initiatives that have
the potential to reduce dementia prevalence by modifying
vascular risk in particular. Cognitive function changes are
measurable in people with cardiovascular risk factors in
their middle age, making targeted primary prevention of
both heart and brain disease imperatives. There is the real
possibility that vigorous control of cardiovascular risks
at community level could postpone the onset of dementia
syndromes and there is already some evidence of this hap-
pening in the United States (Langa et al., 2008) and other
industrialized countries (ADI, 2014). Public health initia-
tives may be situated in health services but they are as likely
to take place in sport, culture, environmental and transport
services, where opportunities for exercise and social partici-
pation can be tuned to localities and populations.
15.3 DIAGNOSIS AND EARLY SUPPORT
15.3.1 WHAT IS KNOWN ABOUT THIS
SUBJECT?
The problem of under-diagnosis of dementia is probably not
due to lack of diagnostic skills, but rather due to the inter-
action of case-complexity, pressure on time and the nega-
tive effects of reimbursement systems (Stoppe et al., 2007;
Hinton et al., 2007). PCPs appear to adopt a watchful wait-
ing stance when it comes to people with potential demen-
tia symptoms (Bamford et al., 2007). This may be due to a
number of factors, including the tendency to assume that
such cognitive changes are merely due to ‘old age’ (Vernooij-
Dassen, 2005), limited access to specialist mental health ser-
vices and restrictions on the prescribing of cholinesterase
inhibitors in the early stages of the illness in some countries.
In dementia, diagnosis is not a single act but a stepwise
process. De Lepeliere et al. (2008) explored the variety of
techniques used for detection of dementia throughout
Europe and concluded that a systematic, stepwise strategy
could be employed to improve timely detection of demen-
tia; that referral pathways could be more effective than
specific guidelines; and that a strong, multidisciplinary
service infrastructure enables the diagnostic process. In
other words, diagnosis may depend on the availability of
‘­treatment’ – in the case of dementia this includes psycho-
social support for patients and their social networks as well
as medication.
Telling people their diagnosis does seem to be match-
ing with people suffering from dementia (Jha et al., 2001)
and younger professionals that their service provided is
valuable (Sullivan and O’Connor, 2001) is essential, but
this is knowledge gleaned from those who seek help, not
those who avoid it. The fear of triggering individual dis-
tress, denial and withdrawal from contact with services
is one factor that inhibits practitioners from discussing
dementia as a diagnosis (Iliffe and Wilcock, 2005) and
there appears to be a lack of clinical skill in managing this
diagnostic transition (Samsi et al., 2014). Disclosure of the
suspected or a certain diagnosis is rated by PCPs as one
of the most difficult areas in dementia management and
they are more likely than psychiatrists to use euphemisms
(Bamford et al., 2004). The use of such euphemisms com-
plicates relationships with other primary care practitio-
ners who may be uncertain about what the patient has
164 Dementia
been told and confused about whether to suggest the
patient to be in touch with a support group such as the
Alzheimer’s Society or otherwise and further exasperated
as to what to record in their own notes.
Counselling and support may preserve caregivers’ self-
rated health if they are already engaged in emotional or
practical care work (Mittelman et al., 2007). Psychosocial
interventions that include group activity can reduce care-
giver’s feelings of ‘burden’ and increase their satisfac-
tion (Andren and Elmståhl, 2008; Bunn et al., 2012). The
characteristics of effective psychosocial interventions are:
psycho-education (which addresses barriers to change);
a family system’s perspective; being multifaceted in solving
problems and being able to apply them in a flexible manner
to meet different needs in different families. Specialist nurs-
ing services that have an explicit focus on supporting care-
givers, such as Admiral Nurses in the United Kingdom, are
highly valued, although there is limited evidence of effect
on psychosocial impacts (Bunn et al., 2015).
15.3.2 WHAT DO PRACTITIONERS NEED
TO LEARN?
A person-centred approach may help alleviate four key
problems: fears associated with other people ‘finding out’
the diagnosis, rapid deterioration in abilities, socially
embarrassing behaviour and a loss of involvement in care
planning (Edwards et al., 2014). The techniques avail-
able to all practitioners in primary care include combi-
nations of reality orientation, memory strategies and
reframing. Reality orientation, for example, focusses on
the likely slow progression in early dementia and offsets
catastrophic fears that may be triggered by mild memory
lapses. Memory enhancement strategies include short-
term goal setting and maintaining social and family roles
that reinforce memory. Reframing dementia as a disabil-
ity that can be accommodated shifts the emphasis from
preoccupations with the diagnosis to not being perceived
as a fool and fosters understanding of the anger or frus-
trations associated with inabilities to perform daily tasks
(Robinson et al., 2010).
Reluctance to make use of services or support is not
uncommon, and practitioners need to remember that opt-
ing for services is a result of a complex decision-making
process often unrelated to objective circumstances. Conflict
theory provides useful insights into such decision-making,
particularly service avoidance (Markle-Reid and Browne,
2001), but we must remember that a number of services may
be inappropriate for people with early symptoms of demen-
tia and neither they nor their families may see them as good
quality services (Bunn et al., 2013).
Dementia is one domain where training is not often
needed for it may be confidence that is lacking rather than
knowledge, or the opportunities to learn new skills and to
then put them into practise. There is an advantage in using
adult learning methods across professions and for profes-
sionals to learn together. This can produce the added value
of shared understandings of professional practice and pres-
sures undergone by all (Iliffe et al., 2009). Learning in this
way can usefully include people who have experienced ser-
vices earlier, but it still may not be enough to change clini-
cal practice among family doctors in the absence of extra
resources (Wilcock et al., 2013).
15.3.3 HOW WILL THEY KNOW THEY ARE
EFFECTIVE?
People with dementia and their carers often report that
the breaking of the ‘bad news’ was handled as well as it
could be by others and that they did not feel abandoned.
Practitioners will know that the diagnostic process is
customized according to the people that they are seeing
if there is an evident reduction in depressive responses,
catastrophizing and if caregivers report less sense of aban-
donment. Reports from voluntary or third sector groups
are useful as feedback experiences and as a link in the qual-
ity assurance feedback chain. Feedback from other practi-
tioners would be that the process or transition has been
handled as well as possible and that, rather than avoiding
‘putting people through’ such a process they would have
confidence that it will be supportive. Care home manag-
ers, for example, could be asked about the experiences of
residents who may be showing signs suggestive of demen-
tia. Would such a manager see it as being in the resident’s
best interests to suggest mentioning this to the family doc-
tor? What is the experience of staff who may accompany
a resident to a memory assessment service or what is the
outcome of a visit from a memory assessment practitioner
to a resident?
15.3.4 WHAT SERVICE DEVELOPMENTS
ARE NEEDEED?
De Lepeliere et al. (2008) emphasizes the need for primary
and secondary collaboration in the diagnostic process
and there is a case for creating integrated dementia care
services (Bullock et al., 2007). Support groups for people
with newly diagnosed dementia seem to promote well-
being. These may be experiential group therapy allowing
people to explore the experience of dementia in a safe, sup-
portive and secure setting (Bunn et al., 2012) or have less
ambitious aims of peer support. Memory cafes are ways
in which social settings can be adapted or tailor-made for
people with dementia, although, they are mostly found
in urban areas. Other groups for older people may focus
on couples or particular groups, such as men in particu-
lar (Manthorpe and Moniz-Cook, 2008). Such efforts to
widen the menu of support rests on the evidence that many
caregivers of people with dementia make infrequent use of
services (Brodaty et al., 2005) because they do not think
they need those services. People with dementia may also
be reluctant to use services. The accessibility and quality of
many services have been low compounding the stigma and
negativism of dementia itself.
 Dementia care in the community: Challenges for primary health and social care 165
15.4 MID-STAGE DEMENTIA AND BPSD
15.4.1 WHAT IS KNOWN ABOUT THIS
SUBJECT?
Non-cognitive symptoms, from agitation and pacing around
to wandering and getting lost, are particularly distressing
for families and social care staff. These BPSD are ‘behaviour
that challenges’ and are common. Up to 20%–90% of people
with dementia will experience BPSD at some time, particu-
larly, in the middle and later stages of the illness (Robinson
et al., 2010). BPSD precipitate crises and hospital admissions
and are associated with abuse and neglect. Although, the
risks from BPSD are often not as high as many fear, BPSD
can lead to high levels of caregiver stress and curtailment
of the activities of the person with dementia and can be
the crucial factor that leads to a move to a long-term care
facility (Balestreri et al., 2000).
Individual behaviour management therapy can reduce
caregiver perceptions of problems, with a lasting effect
(Selwood et al., 2007). A recent systematic review (Livingston
et al., 2014) of non-pharmacological interventions for agita-
tion in dementia found that person centred care, communi-
cation skills training and adapted dementia care mapping
(observation of staff and resident interactions to improve
care responsiveness) decreased severe agitation in people
with dementia living in care homes immediately and this
was sustained for up to 6 months afterwards. Activities and
music therapy by protocol decreased overall agitation while
sensory interventions decreased clinically significant agita-
tion immediately.
There is widespread concern over the hazards of using
antipsychotic drugs in dementia (Schneider et al., 2006) and
these should be used sparingly for short periods and with
specialist advice. Recent positive evidence about the clinical
and cost-effectiveness of a manual based coping strategy has
been provided by Livingston et al. (2014) where adherence
to the START (STrAtegies for RelaTives) manual reduced
affective symptoms and case level depression among care-
givers. Caregivers’ quality of life also improved with this
intervention.
Literature on the role of GPs in dementia has focussed
mainly on early diagnosis, access, attitudes, education and
training, burden of workload and responsibility, but the
quality of medical care they deliver to people with dementia
in mid stage has been neglected. Although multiple comor-
bidities are equally common in older people with or without
dementia, people with dementia are less likely to report to
be diagnosed or to receive optimal care for other comorbidi-
ties (Connolly et al., 2013).
The responses to incontinence symptoms are one exam-
ple of this. Embarrassment may prevent the individual
from seeking help, supported by carers who are trying
to protect the individual’s integrity in the outside world
(Drennan et al., 2011), the patient gains confidence. There
is also evidence that health professionals have a nihilistic
view of incontinence in older people. Urinary inconti-
nence is more common in people with dementia than their
peers without dementia and those with both dementia and
urinary incontinence are more likely to be catheterized
(Grant et al., 2013).
There is some evidence to suggest that in the mid stage
only a very small number of people with dementia have
incontinence problems that cannot be treated or ame-
liorated (Harari and Igbedioh, 2009), but it is an under-
researched area (Drennan et al., 2012). A recent European
survey of 1181 family carers of people with dementia
reported that incontinence symptoms were more prob-
lematic rather than behavioural symptoms (Georges et al.,
2008). In part this may reflect the interface between loss
of independence and behavioural problems. Toileting dif-
ficulties described by carers include use of an inappropri-
ate receptacle or place, passive urinating or defecating
without active attempts to reach a toilet, hiding soiled or
wet clothing, inability to clean after defaecation and clean-
ing faeces off their hands inappropriately (Drennan et al.,
2011). Contributory factors for some of these behaviours
may include difficult access to the toilet, neuropsycho-
logical dysfunction, depression, fear and embarrassment
or medication side effects (Stokes, 2000). Caregivers have
reported primary care professionals’ responses as less
than helpful in these situations and in some instances
found solutions that have the potential to distress or harm
the person with dementia, such as restricting fluid intake
(Drennan et al., 2012). An absence of explicit discussion
has been noted regarding the needs of people with demen-
tia and their caregivers in best practiced incontinence and
service guidelines (Drennan et al., 2013). It has been sug-
gested that well contained incontinence should be consid-
ered as an objective in care planning and in supporting
caregivers (DuBeau et al., 2010). However, it is clear that
the multifactorial nature of the problems require a broad
repertoire of types of solutions and responses from profes-
sionals and services.
The broad objectives of primary care and social care
professionals at this point are: to maintain cognition and
daily living skills, to reduce excess disability and distress,
to maintain the quality of life of patient and carers and to
sustain living in the community. Assessment of care quality
for people at this stage is complex and context-dependent
(Zermansky et al., 2007), so a holistic approach is needed
(McMurdo and Witham 2007). Judgements passed about
the quality of care are necessarily subjective and any qual-
ity improvement should take into account not only the per-
spectives of the care providers but also of individuals and
their supporters (Orrell et al., 2008; Robinson et al., 2007 a).
Case management of people with dementia (includ-
ing systematic follow up, provision of brief psychological
therapy and medication management) has the potential to
provide a holistic approach and overcome service fragmen-
tation; it has been tested in the United States (Vickrey et al.,
2006; Callahan et al., 2006) and Europe (Eloniemi-Sulkava
et al., 2009).
166 Dementia
Case management for people with dementia can reduce
hospital and emergency admissions (Vickrey et al., 2006), mit-
igate embarrassment, isolation and relationship strain (Clark
et al., 2004) and caregiver stress (Callahan et al., 2006) as well
as delay relocation of the person with dementia to a care home
(Pinquart and Sorensen, 2006). However, few studies have
recorded large effects (Koch et al., 2012). The heterogeneity of
patients in dementia case management studies and the lack
of subgroup analyses make it difficult to identify the disease
stage at which patients and their carers most benefit. A recent
systematic review of randomized controlled trials (RCTs) of
case management for people with dementia and their carers
concluded that evidence for the efficacy of case management
remains equivocal (Pimouguet et al., 2010).
A modelling and feasibility study in four general prac-
tices in the United Kingdom (Iliffe et al., 2014) suggests that
case management of people with dementia, whether prac-
ticed by experienced nurses in dedicated sessional time,
or by a seconded social worker devoted exclusively to case
management, does not fit easily into practice routines.
15.4.2 WHAT DO PRACTITIONERS NEED
TO LEARN?
The strategies people with dementia and their immediate
caregivers develop to protect their external persona and dig-
nity may mean that the extent of problems and their con-
sequences are not disclosed to professionals without direct
appropriately worded enquiry. Training in simple methods
for recognizing, understanding and responding to BPSD,
stress and continence problems should be part of profes-
sional development across disciplines. Social care providers
need help to develop and sustain basic levels of understand-
ing and support from primary care teams. Opportunities
for them to develop skills can be delivered by co-working
rather than taking them away from care settings. Care
staff can benefit from opportunities for reflective practice
in supervision. Mentoring through opportunities to learn
from senior care staff is possible if such care practitioners
are not required to move away from care delivery. Night
staff and temporary or part-time workers need to be given
opportunities to develop their skills, particularly, given the
stresses of lone working or managing when staff is less in
number. Family doctors working at night or at weekends
need to be able to assist care staff or caregivers in difficulty,
if necessary and risky hospital admission is to be avoided.
Given the hazards of using antipsychotic medication, fam-
ily doctors need to understand the limits of medication as
a solution to BPSD and should be able to obtain specialist
advice quickly and easily.
15.4.3 HOW WILL THEY KNOW THEY ARE
EFFECTIVE?
Effective management of BSPD will be shown in preven-
tion and in symptom management if necessary. Fewer cri-
ses, fewer out-of-hours (OOH) contacts, reduced hospital
admissions and limited or short-term psychotropic drug
use will be signs that dementia risks are being addressed
effectively. Nevertheless, prevention may be a better solu-
tion. This may be assisted by tailor-made support plans,
the use of skilled and experienced staff who can under-
take diversionary and pleasurable activities and spot signs
of distress, access physical activities and stimulate sympa-
thetic environments as well as understand people’s wishes,
habits and patterns of activity and behaviour. Good care or
support planning will contain information that is transfer-
able but communication patterns need continual rehears-
ing. Audit and review can be the hallmark of support that is
seeking to be effective.
15.4.4 WHAT SERVICE DEVELOPMENTS
ARE NEEDED?
Investment in counselling, support planning and review
for people with dementia and caregivers and skill develop-
ment for community nurses, social workers and care home
staff may be more useful than investment in ‘memory clin-
ics’, unless they are able to undertake these support tasks
in a consistent way. Commissioners or funders of care
and support may be able to use budgets in a flexible man-
ner to bolster or reward good preventive strategies rather
than directing funds towards crises. Training and support
of front line workers may take much more of professionals’
time than individual case work, raising new challenges for
professionals to be in a position to demonstrate that their
input in supervision, training and prevention is effective
and efficient. Further, modelling studies are needed to clar-
ify the purpose of case management, to revisit the skills and
attributes required for case management, to embed deliv-
ery of case management in primary care and to establish
whether the illness trajectory of dementia case management
has maximum cost-effectiveness.
15.5 HIGHER INTENSITY AND END
OF LIFE CARE (AT HOME AND IN
CARE HOMES)
15.5.1 WHAT IS KNOWN ABOUT THIS
SUBJECT?
Specialist home care teams have (in some cases) demon-
strated greater flexibility and responsiveness to caregivers
than task-oriented care services and they may also reduce
caregiver stress and prevent crises. These outcomes depend
on the configuration of the service, including multidisci-
plinary health and social care services’ input, care worker
autonomy, continuous reassessment of client’s circum-
stances and capacity to develop long-term relationships
through care-worker continuity (Rothera et al., 2008). Poor
quality services, of course, often lead to poor quality out-
comes and it is rare for specialist services to be funded or
 Dementia care in the community: Challenges for primary health and social care 167
employed in the same way as standard services, with their
frequent problems of high staff turnover, short interven-
tions (e.g. 15 minutes to undertake personal care and meal
preparation) and inflexibilities. There are promising results
from ‘cash for care’ schemes in many parts of the developed
world where individual or personal budgets can potentially
provide much better support by responding to people’s
needs at the time necessary and supporting rather than
undermining family and other assistance (Moran et al.,
2014). However, the risk that these places additionally bur-
den caregivers with, needs to be recognized. In some coun-
tries, the effectiveness of community care polices enabling
people to stay at home means that people who do eventually
enter care homes are often very ill or frail. High intensity
care may be akin to palliative care.
The move to a care home may be determined by the
severity of cognitive impairment and functional loss, the
presence of depression in the person with dementia and (in
some but not all studies) incontinence (Thomas et al., 2004).
In the United Kingdom, the majority of people with
dementia live and die at home or in a care home rather than
in hospital (dying with dementia is rare in a hospice). There
are three ways in which people with dementia can die (Cox
and Cook, 2002). First, there are people who have been diag-
nosed of dementia, but their death is caused by another med-
ical condition (e.g. cancer or heart disease). Second, people
may die with interplay of another illness and dementia,
where the dementia has not impacted greatly on their func-
tioning. Third, there are people who are described as hav-
ing end-stage dementia, where the associated consequences
of the dementia impact upon all domains of their life and
they ultimately die of the complications of this condition.
Each of these different ways will directly influence the place
and experience of death for an individual and their fam-
ily members and primary care involvement. A recent study
talking to people with dementia living in care homes about
approaching end-of-life suggested that there was value in
creating opportunities to talk about these issues (Goodman
et al., 2013). There is, therefore, not a single experience and
some patients and carers live with dementia for years often
with different trajectories of functional decline and needs
(Mularski et al., 2007; Barclay et al., 2014).
Professional and policy guidance on care for people with
dementia nearing the end of life emphasizes the benefits
of advance care planning, coordinated working between
health and social care and the adaptation and use of pal-
liative care frameworks and clinical tools for people with
long-term conditions (Alzheimer Europe, 2008). However,
policy guidance and end-of-life initiatives, though laud-
able, have outstripped the available evidence on end-of-life
care for people with dementia and their caregivers that live
at home or in care homes (Goodman et al., 2010). There is
some evidence that processes and emphasis on commu-
nication and collaborative problem solving between fam-
ily doctors, care home staff and visiting specialist services
can improve the quality of end-of-life care and reduce costs
(Amador et al., 2014).
15.5.2 WHAT DO PRACTITIONERS NEED
TO LEARN?
Understanding the caregiver’s strengths and their rela-
tionship with the person suffering from dementia may be
an important guide to how support is offered and given.
Offering support early should become part of routine prac-
tice, but only if the professional knows where to signpost the
patient or caregiver. Local service maps are important so
that patients and carers do not face the frustration of being
passed from pillar to post. Professionals need to know the
best sources of information about their locality and how to
report unmet needs to those responsible for locality plan-
ning and service development. Sometimes, these may be
consolidated as part of dementia care pathways (Samsi and
Manthorpe, 2014), but like most information these need to
be updated from time to time to be accurate.
Compared with those with other conditions, people with
dementia are more likely to experience symptoms, includ-
ing persistent pain and are more likely to be untreated in
the last 6 months of life (McCarthy et al., 1997). The focus
of attention may be on other problems, like nutrition and
hydration, with pain being relatively neglected (Goodman
et al., 2010). This is a complex dilemma because of the
communication difficulties that are a feature of advanced
dementia and should, therefore, be the focus of professional
development for all practitioners who contribute to end-of-
life care. Early attention to such matters among those who
may wish to make plans for their future care and treat-
ment may be part of primary care consultations. In coun-
tries, such as England, there is evidence that more people
with dementia are moving into care facilities with proxy
decision-makers appointed and statements of wishes in
­
place (Manthorpe and Samsi, 2014), meaning, that, primary
care and care providers will need to share such information
and discuss its implications.
15.5.3 HOW WILL THEY KNOW THEY ARE
EFFECTIVE?
Good care homes and good home care services can reduce
fewer inappropriate hospital admissions and transfers as
well as out of hours contact. Good care homes will meet reg-
ulatory demands but there will also be confidence among
local communities and perhaps a sense of pride that a local
care home is part of the community. Care homes that work
with volunteers and are supportive of residents’ families
will become well known. Local professionals often know
which homes they would want to enter or where they might
wish a relative to live if the need arose. We will know care
homes are effective if they have limited staff turnover and
if there are (short) waiting lists for their services. The same
applies to home care services. Staff may be able to support
each other if this culture is fostered. They will then be more
able to offer support for families and other residents who
are bereaved. Fewer admissions to hospital and greater con-
fidence that people’s statements of wishes and any advance
168 Dementia
decisions will be respected can be indicators that end-of-life
care is being well managed. Audits of records and face to
face quality assurance data collection will prove that peo-
ple’s ability to make decisions and choices has been assessed
and respected.
15.5.4 WHAT SERVICE DEVELOPMENTS
ARE NEEDED?
The salience of flexibility, autonomy and responsiveness in
home care teams is an important lesson for other service
providers which might help others to learn lessons from
home care management’s style of functioning. End-of-life
guidelines should be reviewed and monitored to make sure
that they are realistic and do not add to a ‘tick box culture’.
Staff may need time to develop skills in this area and to pass
on these skills to new staff and to family members. The sup-
port services for staff in large organizations, such as, coun-
selling or access to in-house employment support services
should be thought about in small or medium care enter-
prises. Time for supervision and reflection should be built
into contracts for care services.
15.6 CONCLUSION
Kodner’s (2006) analysis of a successful model of inte-
grated care for frail older adults argues that provider net-
works which join together through standardized referral
procedures, service agreements, joint training, shared
information systems and even common ownership of
resources enhance access to services, provide seamless
care and maintain quality. In this chapter we have drawn
on this and other evidence to suggest ways to create such
cross-boundary work in the sector where most people with
dementia will receive most services and support/primary
care.
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Managing people with dementia in the
general hospital
ANDREW TEODORCZUK, ROWAN HARWOOD AND ELIZABETH SAMPSON
16.1 INTRODUCTION
In the United Kingdom, older people with dementia occupy
a quarter of the general hospital beds (Alzheimer’s Society,
2009). One out of three emergency medical admissions is
of an older person with cognitive impairment; someone
with dementia is up to four times more likely to be admit-
ted as an emergency case than someone without (Goldberg
et al., 2012) and severity of dementia independently predicts
hospitalization (Albert et al., 1999). Arguably, dementia
now represents ‘core business’ for general hospital clinical
practices.
The largest hospital medical speciality is geriatric medi-
cine, which espouse ‘comprehensive geriatric assessment’,
taking into account function, mental health, social and
environmental aspects alongside diagnosis and medical
management. Yet, current systems of care often presume
non-confused patients with a single acute illness, some-
times called the ‘acute medical model’ (Tullo et al., 2015).
This mismatch between hospital practices and the current
hospital demographic presents challenges to patients, fam-
ily or other carers and staff alike. Typically, staff have not
been trained to work with patients suffering from dementia
and find it difficult to implement good dementia care within
outdated work structures and expectations (Marshall, 1999,
2001; Clissett et al., 2014).
Patients with dementia are especially vulnerable in
acute hospital settings. Admission to hospital represents a
time of crisis usually caused by acute ill health or injury. In
addition to this, the setting forms a disruption to familiar-
ity and routine, which a person with dementia relies on to
enable them to cope successfully with daily activities. The
challenge, however, of improving dementia care also repre-
sents an opportunity. The elements of good dementia care
enable good care for those who are vulnerable for other
172
16
reasons, such as sensory impairment, learning disability, or
approaching the end of life (Inouye et al., 1999).
In this chapter, we explore the challenges of caring for
someone with dementia in the general hospital. Initially, the
epidemiology is detailed and issues of screening discussed.
The diverse clinical presentations and problems of physi-
cal health, complexities and uncertainties are outlined.
The chapter then considers specific areas of concern such
as pain suffered by the patient with dementia that may be
overlooked. Key transition points, such as admission and
discharge of patients are further described and the chapter
ends with potential solutions to the difficulties that patients
with dementia face in hospital, together with evidence-
based educational messages for hospital staff.
16.2 EPIDEMIOLOGY OF PEOPLE IN
HOSPITAL WITH DEMENTIA
It has been estimated that 25% of hospital inpatients in the
United Kingdom have dementia, but identifying those most
at risk can be challenging. Under-diagnosis of dementia in
the community, particularly in primary care, is common
and therefore, diagnosis often occurs at a time of crisis, for
example, after a fall, when the person comes into contact
with healthcare or social care services, and requires an
emergency hospital admission (Bourne, 2007).
However, even after general hospital admission, detec-
tion rates remain as low as between 37% and 46% (Harwood
et al., 1997; Joray et al., 2004; Sampson et al., 2009). Diagnosis
of dementia in the general hospital is made more complex by
concurrent delirium (see Chapter 71), the fact that patients
may be sleep deprived and unwell in a strange and disori-
entating environment and may have suffered an acute func-
tional decline. Assessing cognition in these circumstances
 Managing people with dementia in the general hospital 173

can be impossible. Delirium may occur in the absence of prior
dementia, but up to two-thirds of people with dementia in
hospital have superimposed delirium, recovery from which
may be slow or incomplete (Cole et al., 2009; Mukadam and
Sampson, 2011; Whittamore et al., 2014).
Screening for dementia in the community is controversial.
It has been argued that primary care doctors may not have the
specialist skills to make an accurate diagnosis and that offering
financial incentives to do this is unethical (Campbell-Taylor,
2014). However, routine assessment of cognition is necessary
for inpatients in general hospital: delirium (and underlying
medical causes) must be diagnosed and those with previously
known and unknown dementia identified in order to adjust to
meet their special needs (Goldberg et al., 2012). This includes
adapting communication and care approaches to enhance
understanding and minimize distress, communication and
engagement with family carers and other stakeholders, collec-
tion of medical and personal background information from
informants to enable decision making for patients lacking
mental capacity and to plan discharge and future care. Many
screening tools are available, but only the simple 10-point
Abbreviated Mental Test Score (AMTS) has been validated in
more than one study in general hospitals (Jackson et al., 2013).
This tool is shorter than alternative cognitive screening tests
such as the Mini-mental State Examination (MMSE) (Folstein
et al., 1975) and its use already is embedded in many hospitals.
For both clinical and research purposes, a two-step approach is
essential with initial screening and then more detailed cogni-
tive, functional and behavioural assessment is necessary. This
should include discussion with a carer or relative to acquire
collateral history and then applying diagnostic criteria, such
as Diagnostic and Statistical Manual of Mental Disorders,
Fourth Edition (DSM-IV) or International Classification of
Diseases, 10th Revision (ICD-10), or clinician’s judgement.
The frailty of patients and age of people admitted to gen-
eral hospitals reflects and then amplifies the prevalence of
dementia found in the community. Prevalence estimates
for severe dementia in medical inpatients, over the age of
65 years range from 9% to 50% in general hospital wards
(Feldman et al., 1987; Hickey et al., 1997) and from 63% to
80% in specialized geriatric medical wards (Adamis et al.,
2006; Torian et al., 1992). This illustrates how the preva-
lence of dementia is highest in older women and unlike
other criteria such as, ICD-10, the DSM-IV criteria does not
require 6 months duration of symptoms for diagnosis. Half
of the patients with hip fractures have cognitive impair-
ment (Holmes and House, 2000). For a summary of the
prevalence of dementia in general hospitals, see Table 16.1.

Table 16.1 Prevalence of dementia in older general hospital patients – clinical studies 2000–2014
Age (mean, Female Sample Assessment tools and Prevalence
Paper Setting SD) % size diagnostic criteria %

Mixed wards
Uwakwe (2000) Medical, surgical, >60 (69.9, 38.7 109 24 item Self Reporting 2.8
Nigeria gynaecological 8.4) Questionnaire (SRQ-24),
wards Geriatric Mental State
(GMS), MMSE, ICD-10
Wancata et al. (2003) Medical wards, >60 (75.9, 72.3 372 Clinical Interview Schedule 27.4
Austria general 8.4) (CIS), DSM-IIIR and at
hospital least 2/5 on global
severity scale
Travers et al. (2013) Medical, surgical, >70 (80.4, 58.4 493 MMSE 20.7
Australia orthopaedic 6.5) Informant Questionnaire of
wards Cognitive Decline
(IQCODE)
DSM-IV

Geriatric wards/hospital
Laurila et al. (2004) Acute geriatric >70 (not 71.7 219 MMSE, Digit Span, parts of 40.2
Finland wards (medical given) WAIS, operationalized
and surgical), 59.4% DSM-IV criteria
geriatric over 85
hospitals years
Marengoni et al. Geriatric wards >65 (79.4, 54.1 1221 DSM-IV 9.6
(2011) n/a)
Italy
Zekry et al. (2008) Geriatric hospital >75 (85.2, 76.0 349 MMSE, Short Cognitive 43.3
Switzerland 6.7) Evaluation, DSM-IVTR
(Continued )
174 Dementia

Table 16.1 (Continued) Prevalence of dementia in older general hospital patients – clinical studies 2000–2014
Age (mean, Female Sample Assessment tools and Prevalence
Paper Setting SD) % size diagnostic criteria %
Acute medical wards
Margiotta et al. Acute medical >65 (79.8, 58 330 MMSE, DSM-IV 26.1
(2006) unit 8.0)
Italy
Sampson et al. (2009) Acute medical >70 (83.0, 59 617 MMSE, DSM-IV 42.0
United Kingdom wards 7.3)
Specific populations
Frohnhofen et al. Inpatients with Male 79, 8 63 1621 MMSE 52
(2011) COPD Female 81, 8 Global Deterioration
Germany scale (GDS)
Nightingale et al. Orthopaedic >65 n/a 731 GMS/AGECAT 40
(2001) Hip fracture (n/a) MMSE
United Kingdom
Gruber-Baldini et al. Orthopaedic >65 77.5 674 MMSE 28
(2003) Hip fracture (81, n/a) Chart review
United States
Abbreviations: SD, standard deviation; MMSE, Mini-mental State Examination; ICD-10, International Classification of Diseases, 10th
Revision; DSM-IV, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; WAIS, Wechsler Adult Intelligence Scale;
COPD, chronic obstructive pulmonary disease; n/a, not available.

Epidemiological studies vary in their findings, depending
on the populations studied and the diagnostic tools used to
study the population.
16.3 CHARACTERISTICS OF PEOPLE
WITH DEMENTIA IN HOSPITAL
People with dementia in general hospitals are older by 5–9
years (Erkinjuntti et al., 1986; Lyketsos et al., 2000), more
likely to be female, with lower education level (Sands et al.,
2003; Joray et al., 2004), more impaired in activities of daily
living (Torian et al., 1992; Zekry et al., 2008) and more
likely to be admitted from nursing homes (Zekry et al.,
2008; Sampson et al., 2009). Among acute medical inpa-
tients, dementia has a marked and independent effect on
short- and longer-term mortality. Dementia significantly
increases the risk of death during the index admission even
after controlling severity of present illness considering the
age and multimorbidities. This increased risk is found both
in medical inpatients and in patients who have suffered hip
fracture (Sampson et al., 2009; Marengoni et al., 2011).
16.4 PHYSICAL HEALTH IN DEMENTIA
Multiple pathology is a defining feature of ill health in old
age. People with dementia often have other things wrong as
well and most of the patients are old. Moreover, dementia,
stroke and hip fracture all increase exponentially with age.
Arthritis, heart, lung and bladder problems, Parkinson’s
disease, poor vision and deafness are also common at this
stage. Functional problems (disability) represent a final
common pathway for the effects of these multiple diagno-
sis and the impact of the environment, aids and available
human help. People with dementia are prone to acute ill-
ness, injury, adverse drug effects and delirium (Box 16.1).
The experience and well-being of a person with dementia
is determined by symptoms more than their neurological
impairments. Personality, biography, other aspects of health
(physical and mental) and social environment are impor-
tant too (Kitwood, 1997). General physical health may be
more amenable to intervention than other aspects, but may
be neglected if the dementia diagnosis is overemphasized
(so-called ‘diagnostic overshadowing’).
The term ‘frail’ means the propensity to deterioration in
the face of a stressor, reflecting loss of physiological homeo-
stasis, functional reserve and social resilience. Following
this definition many people with dementia are ‘frail’ and
warrant proactive attempts to maintain health and pre-
vent illness. Examples include vaccination, vascular risk
and bone protection, careful drug review and physical and
social activity promotion.
Ultimately ill health will lead to death, more than half
of which occur in hospitals. This should be anticipated and
planned for, in terms of preferred place of care and some indi-
cation of preferences, beliefs and values with respect to health-
care interventions (such as tube feeding and resuscitation). As

BOX 16.1: Older people differ medically
from the young
Presentation is often non-specific or atypical. The
classical non-specific presentations are confusion,
immobility, falls and incontinence, or ‘inability to
cope’
Diseases are multiple
Lose abilities fast – so diseases can present with
their functional consequences
More prone to complications of disease and their
treatments
More dependent on the environment – someone
with an adverse environment will present
symptoms sooner, someone with a supportive
environment often later and presentation of
symptoms may be due to a change in the
environment rather than the person concerned
Need for explicit rehabilitation
the disease progresses, it is appropriate to de-prioritize pre-
ventative drugs and to emphasize comfort and dignity.
16.5 EMERGENCY ADMISSION TO
HOSPITAL
One of the most challenging times for people with demen-
tia is dealing with acute illness, injury or other crises. Not
all crises are medical and not all medical crises need hospi-
tal admission. The exact causes of crises in old age can be
difficult to disentangle. Medical, mental and social factors
may all be operating and their relative contributions may be
unclear. For example, the cause of hallucinations or delu-
sions may be delirium, physical illness, or the ability to cope
with a chronic medical condition may depend on the physi-
cal and social environment.
People come to hospital because of a crisis that is, or may
be, due to physical illness or injury, and where investigation,
treatment or nursing care requirements cannot be met in
another setting. In the face of such crises, general hospitals
are called upon to diagnose or exclude physical disease, to
understand and take account of mental and social factors
and to provide refuge and relative safety while the crisis is
resolved. Hospital beds are an expensive and scarce resource,
so must be used wisely; hospital stay should only continue if
necessary care cannot be delivered elsewhere. Hospitals must
integrate pathways of care with community or at-home reha-
bilitation provisions, primary care and community health
teams (including mental health) and care homes.
Crises that cause admission in hospitals are frequently
functional, including falls, immobility, pain, dehydration,
Managing people with dementia in the general hospital 175
breathlessness and incontinence. In dementia, the crisis
may also be due to a sudden worsening of confusion state,
or ‘behavioural’ problems, such as, wandering and getting
lost, aggression towards carers, or a grave misjudgement
of abilities. Among older patients admitted into hospitals,
delusions, hallucinations, agitation and aggression, each
of these symptoms have 10%–20% prevalence. A third of
the patients are anxious or depressed, apathetic or awake
at night (Goldberg et al., 2012). Propensity to delirium is a
key issue; this must be recognized, diagnosed, distressing
features addressed and opportunity allowed for rehabilita-
tion and recovery.
Sometimes the presentation is due to the progression of
dementia. This is especially the case with vascular dementia,
where the steps of progression can look like delirium and be
associated with problems, like, loss of balance or swallow-
ing difficulties, or dementia with Lewy bodies where motor
features, fluctuation, psychosis and drug sensitivity may be
responsible.
16.6 COMPREHENSIVE GERIATRIC
ASSESSMENT
Health problems may present itself with typical symptoms,
such as, pain or breathlessness, but also in terms of their
impact on everyday functions, such as, immobility, falls or
incontinence. The ‘Comprehensive Geriatric Assessment’
(Box 16.2) tries to understand these problems, at the level
of body parts or organs (so-called ‘impairments’, such as
weakness, dizziness, visual acuity or bladder function) to
identify underlying pathological diagnoses or syndromes.
From these specific treatments – pharmacological, surgi-
cal, or rehabilitation – can be applied. Psychological, social
and environmental contextual factors are also taken into
account and may themselves be the target of therapeu-
tic, adaptive or supportive interventions, for example, by
informing and educating family carers, or by resorting to
environmental aids and adaptations.
Medical care for people with dementia draws on a mul-
tiplicity of models (Box 16.3), often simultaneously, to
address the complex mix of multiple acute, progressive and
chronic problems, which impact function and well-being,
BOX 16.2: Dimensions of Comprehensive
Geriatric Assessment
Diagnoses
Function
Mental
Social
Environmental
176 Dementia

BOX 16.3: Models of health care for older people

Prevention Anticipatory intervention among high risk groups
Medical Diagnose, treatment
Rehabilitation Cycle of problem identification, analysis, multi-professional therapeutic intervention and
reassessment, directed at maximizing physical and social functioning
Palliative Meticulous management of symptoms, open communication, attention to psychological, social
and spiritual aspects
Person-centred care Value and respect for personhood, individualized care, empathic understanding,
communication and relationships to promote well-being and reduce distress
Recovery model Emphasize hope, set achievable goals, identify positive attributes and abilities, take risk, accept
failure
Social model Opportunities, environment and relationships adapted to personal abilities

in a varied and sometimes adverse social and physical envi-
ronment (e.g. frail or stressed carers, residence in a care
home, or an unadapted domestic environment).
16.7 ELECTIVE ADMISSION
People with dementia may also be admitted to hospital
for elective procedures. Special care is required to prevent
delirium, detect and treat it if it occurs. Attention must be
paid while dealing with the unavoidable disruption to rou-
tine, to ensure good communication with family or other
stakeholders, assessment of mental capacity and ability to
consent provision of appropriately skilled rehabilitation.
Problems may arise if previously undiagnosed dementia
is present; assessment prior to admission in the hospital
should specifically assess cognition.
16.8 PAIN
Persistent pain is found in up to half of people with demen-
tia in the community or in care homes, but is commonly
under-detected and under-treated. It has been reported that
some clinical staff believe that people with dementia actually
experience less pain (Scherder et al., 2009). Under-treatment
of pain causes distress and suffering for people with demen-
tia, their families included. In addition, pain increases the
risk of delirium (Inouye, 1993), slows recovery, worsens
functional decline and is associated with poor sleep and
appetite (Scherder et al., 2009). Poorly managed pain can
slow down a person’s rehabilitation or even increase the risk
of delirium. These are major drivers of prolonged hospital
stay and thus, raise the costs of care (Zwakhalen et al., 2006).
Under-detection of pain may occur because people with
dementia may not remember they have been in pain before.
Some can tell you about pain if asked, but others lose the
words required to describe it. Pain can be communicated in
different ways, through behaviours. When in pain, a person
with dementia may respond with agitation, often shouting,
restiveness to care, depression or withdrawal (Ryden et al.,
1999; Tosato et al., 2012). This association is, however, com-
plex. Some observational pain scales are sensitive in detect-
ing pain in people with dementia but have a high rate of false
positive alarm rate and may be detecting fear, frustration or
anger (Jordan et al., 2011). In the general hospitals, other
factors such as delirium and the confusing ward environ-
ment may increase the risk of behavioural and psychologi-
cal symptoms and these may also be communicating other
unmet needs such as fear and boredom (Ahn and Horgas,
2013).
The ‘gold standard’ for pain assessment is self-report.
Some people with moderate to severe dementia can report
pain if supported by using visual pain scales (Zwakhalen
et al., 2006). One study in a geriatric hospital found out
that only 44% of patients with severe dementia were able to
report that they were in pain (Pautex et al., 2005). Clinicians
assessing behaviours that might indicate pain need to look
purposefully for potential sources of pain, in particular
joints, pressure areas, the mouth, abdomen and pelvis. It is
helpful to observe people with communication difficulties
over a period of time, in motion, including transfers from
bed to chair or repositioning and at rest, but people differ
greatly in how they express pain and hospital staff may not
be aware of an individual’s pain indicators. Pain manage-
ment can be improved by contacting relatives or carers of
the person with dementia who may be aware of individual
responses to pain (for example, social withdrawal or gri-
macing). Few pain scales for people with dementia have
been validated in the general hospital, despite the fact that
this is a frail older population likely to suffer from painful
multiple morbidities.
In care homes, behavioural problems, particularly, verbal
aggression can be significantly reduced with systematic pain
management (Husebo et al., 2011). There have been no stud-
ies conducted of such interventions in the general hospitals.
However, a number of barriers to improving pain management
in hospitals have been identified, including poor knowledge

of how to respond when pain is detected, irregular adminis-
tration of ‘as required’ medications and concerns about the
side effects of some medications, particularly, opiates. Simple
interventions with regular analgesia such as paracetamol, can
be extremely effective (Zwakhalen et al., 2006).
16.9 DISCHARGING PATIENTS WITH
DEMENTIA
Discharging a person with dementia from hospital requires
planning and good communication. The person may be
able to cope well, or have well-established and satisfactory
support arrangements, but equally well progression of dis-
ease; the consequences of acute illness, slow recovery, or
inadequate previous care support mean that explicit new
provision is required. The usual goal will be to return the
person to the accommodation from which they were admit-
ted. About a quarter of people with dementia admitted in
general hospitals are residents of care homes (Goldberg
et al., 2012). About a quarter will not return home, 10% die
in hospital and a quarter will be newly placed in a care home
within the next 6 months of their discharge. Readmissions
are common (18% within 30 days and nearly half within
6 months) (Bradshaw et al., 2013; Jencks et al., 2009). People
with dementia (and delirium) may be denied opportuni-
ties to recover and regain function in intermediate care and
other rehabilitation centres.
The goal of a safe discharge is to relocate a patient to
accommodation in accordance with their preferences and
wishes that can meet their care needs and those of fam-
ily carers as well as other stakeholders. Efficient services
aim to minimize length of stay and readmissions in hos-
pital and use of expensive resources such as care homes,
while accepting that these are sometimes the right option
for individuals. Studies seeking to understand what leads
to a safe discharge suggest that it is dependent on patient
and hospital characteristics, social environment and
clinical practice (Westert et al., 1993; Martin and Smith,
1996). Important patient characteristics include age, care-
giver burden, comorbidity and polypharmacy. Social fac-
tors that affect patients include availability of social care,
levels of poverty, provision of nursing homes and family
support.
Tailored discharge planning does reduce length of stay
and readmission rates (Shepperd et al., 2010), but the extent
to which discharge planning impacts on other health out-
comes including mortality is unclear. Important risks for
readmission include demographic factors such as, low
socio-economic status, health literacy, reduced social net-
work. Clinical factors that increased risk of readmission
include discharges against medical advice; polypharmacy
(over five medications) and having more than six chronic
conditions. Specific conditions such as, chronic obstructive
pulmonary disease, diabetes, heart failure, stroke, cancer
and depression all increase risk of readmission.
Managing people with dementia in the general hospital 177
Considerable uncertainty often surrounds the likely
success of a discharge. Attitude to risk vary greatly, among
patients (when suffering from dementia or when they had
mental capacity), families, care homes and hospital staff.
Risk is often unavoidable and important functions are
to identify it, mitigate it where possible and then follow a
decision-making process to decide whether to take it up or
not. There is little evidence that discharge to a care home is
‘safer’. A ‘trial of discharge’ to a person’s own home is often
warranted, sometimes as part of a process of establish-
ing that institutional care is truly required (Stewart et al.,
2005). The process is sometimes called ‘risk enablement’
(Manthorpe and Moriaty, 2010).
There is relatively little evidence on successful discharge
specific to patients with dementia. This reflects on the fact
that there are limited available reliable data, especially in
the United Kingdom. However, the evidence suggests that
the greatest variation in discharge processes and outcomes
is in older patients (Martin and Smith, 1996).
Studies have shown that patients with dementia have a
longer length of stay in hospitals, more readmissions and
greater use of medical services compared to those without,
even after controlling illness severity and functional impair-
ment (Holmes and House, 2000; Saravay et al., 2004; King
et al., 2006). Patients with dementia in the United Kingdom
typically stay for about 11 days in hospitals, 5–7 days longer
than those without dementia (Alzheimer’s Society, 2009).
This conceals considerable variability: 25% are discharged
within 5 days, but 10% stay longer than 30 days (Goldberg
et al., 2013).
Potential reasons for increased length of stay include
greater functional impairment, slow or uncertain recov-
ery, non-compliance with tests, treatment and therapy and
carer strain. The need for explicit decision-making process
for those lacking mental capacity, concern about taking risk
on behalf of vulnerable adults, funding problems and the
availability of suitably skilled community services and care
homes can further delay discharge.
Patients with dementia have a greater risk of readmis-
sion (Daiello et al., 2014). A United States retrospective
cohort study found that patients with dementia had greater
odds ratio of readmission (1.8) compared to patients with-
out dementia. Higher readmission rates were further asso-
ciated with antipsychotic use and discharge from nursing
homes. Potential reasons why patients with dementia may
have greater readmission rates include factors such as they
are less likely to benefit from discharge education, adhere
to instructions and report symptoms (Becker et al., 2010).
Furthermore, patients with dementia are more likely to be
admitted with ambulatory care conditions than those with-
out dementia (Phelan et al., 2012) and hence, readmission
rates are greater.
However, it is not just patient factors that increase vul-
nerability to discharge and failed transitions of care. A
study into the practice gaps (difference between desired and
actual practice) of hospital staff found that discharge was
identified as a technical gap, however dependent on and
178 Dementia
preceded by attitudes of staff towards patients with demen-
tia and ownership of this complex group (Teodorczuk et al.,
2013). Hence, the socio-cultural ward environment and
degree to which staff are able to effectively own and manage
patients with dementia within the ward environment are an
important determinant of discharge success (Teodorczuk
et al., 2015).
However, a recent well conducted trial of routine geri-
atric care versus joint mental health medical care failed to
show an improvement on the length of stay or readmission,
though, those patients on the specialist units had greater
satisfaction (Goldberg et al., 2013). Various reasons might
support this finding, including the fact that frailty among
dementia patients might be the driving factor behind the
length of stay and readmission rate. Arguably, there is
a need to look beyond these ‘harder’ outcomes towards
more relevant outcomes of patient and carer experience.
Alternatively, it could have been the socio-cultural environ-
ment in the standard care unit that may have been optimal
and therefore, less appropriate as a comparator. Either way,
what is clear is that, in terms of understanding discharge
factors for patients with dementia it is a multifactorial com-
plex construct and there is a need for further work studying
socio-cultural environments and exploring factors other
than such traditional measures as length of stay, as markers
of good quality care.
16.10 IMPLICATIONS FOR CLINICAL
PRACTICE
Four general principles can guide, though not guarantee a
successful discharge and help address key factors important
to effectiveness of safe discharge processes. They are listed
as follows
1. Considering discharge as a process and not an end point
Planning for discharge should begin at the begin-
ning of hospitalization. The process can be broken
down into pre-discharge interventions (e.g. medica-
tion reviews and discharge planning reviews), bridging
interventions and post-discharge interventions such
as, a post-discharge phone call. Successful approaches
for patients with dementia such as those piloted
through the Royal Free My Discharge project in the
United Kingdom include allocating a care profes-
sional (e.g. an occupational therapist) with a specific
remit to facilitate discharge (Royal Free London NHS
Foundation Trust, 2014). Furthermore, bridging
partnerships with other organizations in the voluntary
sector and with community services are essential to
help plan a supported discharge.
2. Personalize the discharge plan
Arguably, the focus of hospital processes can be
on treating diseases rather than the patient. However,
more so for patients with dementia, discharge plans
must be personal taking account of individual factors
including time of discharge and decision-making
capacity. Educating patients and carers and sharing
information such as, a fact sheet on dementia, can help
further understanding the patient such as the Age UK
Factsheet (Age UK, 2013).
Personalizing a discharge plan involves ‘joining up’
knowledge about the patient to promote and harness
collaborative practice. Key professionals involved in
the planning process include the pharmacist (concor-
dance and dispensing in the community), occupa-
tional therapy (to assess safety of home environment
risks and functionality), medical and nursing staff (to
coordinate, follow up and proceed with treatment),
physiotherapy (mobility needs and fall risks) and
social workers (to address funding issues, instigate
carer support and reduce risks where present [e.g. door
alarms if risk of wandering]). At all points carers must
be part of the process.
3. Assessing capacity at the right time
Identifying whether a patient has capacity to
decide on residence destination has been shown to
be a critical event. This is especially pertinent for
patients with cognitive impairment who may lack
capacity, though, this is not always clear-cut. In
particular, it is essential to ensure that it is under-
taken at the right time, by the right person assessing
the right decision. Furthermore, staff undertaking
capacity assessment should have the right skills to do
it. In an ethnographic study (Poole et al., 2014) out of
13 people deemed to have capacity nine went home
whereas, out of 16 deemed not to have capacity, only
one went home.
It is also important to ensure that, where
patients have borderline capacity the right deci-
sion is made and the patient has the best chance of
demonstrating capacity, if transfer to a step down
unit may be necessary. In some settings, if there is
provision, a cognitive rehabilitation unit staff can
be helpful, both physical and mental health staff can
be effective.
4. Ensuring a realistic contingency plan
Where the risk of a failed discharge is high, a clear
and realistic contingency plan that both family and
staff are aware of is crucial. If a patient is discharged
to the community this should include identification
of risks common to patients with dementia such as
wandering, driving, operating gas cookers and medi-
cation management included within the discharge
plan. Conversely, if a patient is discharged to a care
home, education of staff to understand behaviours
and enhance communication is essential. A formu-
lation including antecedents and consequences of
behaviour as well as understanding behaviours in the
context of a patient’s background and medical ill-
ness may help facilitate this process and increase the
probability of a safe discharge.

16.11 CHALLENGES AND SOLUTIONS
The acute hospital is challenging for a person with demen-
tia and disruptive to familiarity and routine that people
with dementia rely upon. Hospitals are busy, noisy, active
places. This can be over-stimulating and overwhelming for
those who are disorientated or with impaired reasoning or
processing ability. The assessment model, in all disciplines,
is based on repeated and intensive questioning, by many
different people. Locations change rapidly (emergency
department, admissions unit, ward, X-ray department,
physiotherapy gym), staff are busy and often stressed and
nights can be very disturbing for both staff and patients.
In the United Kingdom, the majority (but not all) of
people with dementia in hospitals are looked after by spe-
cialist geriatric medical services. Consultant geriatricians
have a broad training in medical sub-specialties and should
be expert in clinical therapeutics, rehabilitation and pal-
liative care. The central role of multidisciplinary working,
family engagement and consideration of mental health and
social factors and the importance of links with commu-
nity rehabilitation, care homes and old age psychiatry are
acknowledged. Physiotherapists, occupational, speech and
language therapists and nurses specializing in older peo-
ple bring eclectic approaches to addressing functional and
practical problems. Outreach and liaison services may exist,
especially for orthogeriatrics and admission units. Recently,
in the United Kingdom, there has been a great expansion
in older people’s liaison mental health services. This has
been driven by evaluation of ‘RAID’ (Rapid, Assessment,
Interface and Discharge) models of care, where properly
commissioned and funded psychiatric teams work in gen-
eral hospitals. These services decrease costs and length of
stay in the hospital and improve patient satisfaction with
care (Tadros et al., 2013). These teams work alongside gen-
eral hospital staff to provide assessment, advice, discuss
with families, plan and follow up, also establishes links
between inpatient and community mental health services
and staff coaching or training.
16.12 LEARNING NEEDS OF HOSPITAL
STAFF IN RELATION TO
DEMENTIA CARE
The importance of educating staff has been alluded to
throughout the chapter. It is clear that patients with demen-
tia present significant challenges to staff. To overcome these
challenges, training is essential, though not sufficient as a
stand alone. In terms of the content of the training process,
the important areas to cover have been identified in an in
depth grounded theory study of staff practice gaps in rela-
tion to managing the confused older patients (Teodorczuk
et al., 2013). These include (1) ownership of the confused
patient, (2) addressing negative attitude, (3) developing an
Managing people with dementia in the general hospital 179
understanding of how frightened the patient is in hospi-
tal, (4) promoting carer partnerships, (5) fostering person-
centred care, (6) understanding how to communicate with
patients suffering from dementia, (7) recognition of cogni-
tive impairment and (8) specific clinical needs (e.g. capacity
assessments and discharge planning).
As demonstrated in Figure 16.1 these practice gaps or
learning needs are hierarchically organized at a theoreti-
cal level, addressing the core level learning needs (e.g. of
attitudes and ownership) is essential in order to succeed
with the more technical learning needs such as, discharge
of patients. Furthermore, it is possible that the core level
learning needs may be related by means of a vicious circle.
Staff may fail to gain confidence of a patient on the ward
and therefore, develop negative attitudes that can lead to a
patient feeling frightened and behaving in a manner that
is ‘challenging’, thereby further reducing the ownership of
such a patient in the ward.
Evidence suggests that, if educational programmes are
designed specifically to target these learning needs, with a
clear focus on the core level needs and breaking the vicious
circle, practice can be influenced effectively (Teodorczuk
et al., 2014). To train staff successfully an interprofessional
approach focussed on both formal and informal learning is
advocated and involving patients and carers in the teaching
processes can address issues like negative attitudes. In addi-
tion to this, it is clear that organizational processes should
be adapted to help the systems learn about the patient and
staff to implement good dementia care practices. Successful
organizational approaches underpinned by contempo-
rary educational theory have been reported in a study by
Teodorczuk et al. (2015). Approaches typically focus on
encouraging learning about the patient not only at an indi-
vidual level but equally at team and system levels. These
Ide d sp
bli
nti ots
n
fie
d
Specific
clinical needs
Par
tne
rsh
Common clinical needs
ip
con
Recognition, communication
cep
and person-centred care
t
Pat
ien
Core non-clinical needs
t’s
fea
Ownership and negative attitudes
r
Figure 16.1 Hierarchy of practice caps including hid-
den element. (From Teodorczuk, A. et al., International
Psychogeriatrics, 25, 645–655, 2013.)
180 Dementia
include relaxing carer visiting times, reducing ward moves
and targeting senior managers to learn about hospital expe-
riences of dementia and delirium. Ultimately, if systems are
adapted around the new epidemiology and demography of
hospital inpatients, then it becomes easier for staff to oper-
ate, own and manage patients with dementia.
16.13 CONCLUSIONS
As the population ages a period of epidemiological tran-
sition follows. Morbidity of old age, mental and physical
comorbidity of chronic diseases are now a norm in the
general hospitals. The systems and structures are inevita-
bly challenged as a result, increasingly burdening hospi-
tal staff managing a different demography and ultimately
having a negative impact on patients and carers. In this
context, this chapter aims to upskill and draw aware-
ness towards these challenges in relation to the patient
admitted with dementia. Important areas such as pain
and physical illness in patients suffering from dementia
as well as key educational messages for staff, are out-
lined. However, teaching and inculcating staff knowl-
edge alone will fail unless followed by practice behaviour
training. Perhaps the challenge for professionals working
with dementia patients is to move beyond the traditional
­physical-mental health divide and adopt a holistic collab-
orative approach towards practice that is relevant to man-
aging the increasing complexity of dementia patients in
the general hospitals.
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The role of nursing in the management of
dementia
MAREE MASTWYK AND BEVERLEY WILLIAMS
Dementia care is not the care of the dying: it is about meaningful life for the living.
17.1 INTRODUCTION
The nurse’s role in the management of dementia patients
encompasses many areas including, but not limited to,
assessment and education in memory clinics, provision of
support services in the home and direct care in hospitals
and care facilities. This chapter will focus on the direct
care provided to the person with dementia (PWD) who is
cognitively impaired, is surrounded by strangers and may
be driven by emotions, particularly, fear. The fundamental
tenet of nursing is to provide a safe, secure environment, so
we need to ameliorate that fear.
Dementia care is a nursing speciality. It is important
that the nurse has an interest in or, better still, has a pas-
sion in this area and recognizes that the journey through
dementia is unique for each individual. In simple words,
it is of crucial importance to make the journey as comfort-
able as possible. A nursing assessment is key to achieving
this and should include consultation with the PWD and
their family; learning their history, background, abilities
and shortfalls, likes and dislikes. Keep in mind the basic
human needs: nutrition, hydration, exercise, sleep, hygiene,
safety and comfort and be aware that if these needs are not
being met, the PWD may exhibit ‘challenging’ behaviours
in order to be heard (Box 17.1).
17
—Wylie (2003, p. 35)
BOX 17.1: The nurse needs
●● Understanding, patience, resilience, sense of
humour
●● Interest/passion in caring for the person with
dementia
●● Education, guidance and support in the role
17.2 PATIENT AUTONOMY – ANY
STAGE OF THE ILLNESS IN
ANY SETTING
The emphasis today is on person-centred care (Kitwood,
1993) to maintain autonomy and dignity. This can only
be accomplished if the opinions of the PWD are sought
and respected (Pringle-Specht et al., 2009). The PWD
needs a partner to compensate for cognitive losses and
promote more efficient use of remaining functional abili-
ties (Pringle-Specht et al., 2009), not one who takes con-
trol. Nurses need to foster the PWD’s independence for
as long as possible. Not only cognitive/functional deficits
need to be considered when drafting a care plan, but the
PWD’s abilities, interests and culture are important too.
183
184 Dementia
Self-esteem has an impact on the way we feel about our-
selves, interact with other people, handle problems and it
determines our level of relaxation and safety (ReachOut
Australia, 2009). It should be understood that the same
does for the PWD as well.
PWD can share their knowledge, experience and needs
and are now included in focus groups with other stake-
holders, e.g. driving cessation (Perkinson et al., 2005).
Alzheimer’s Association fact sheets include suggestions
from PWD (Alzheimer’s Australia, 2012b). Pringle-Specht
and Bossen consulted Taylor, a person with probable
Alzheimer’s disease (AD) for their paper Partnering for
Care: The Evidence and The Expert, in March 2009. PWD
are able to guide us in designing strategies for care for them
and others suffering like them.
In later stages, the family can be a valuable resource of
information about the PWD. However, until unable to com-
municate, he or she can be consulted directly about future
plans, needs and wants. Alzheimer’s Australia (2012a) rec-
ommends planning with the PWD soon after diagnosis to
enable them to express their desires, wants and needs for
consideration at the time when they are no longer able to
express themselves, including medical, financial and legal
concerns. This planning should also include end-of-life
decisions (see Chapters 33 through 35).
Planning by the family on behalf of the PWD can be dis-
tressing for the family. If important decisions are made in
consultation with the PWD early, this can remove a poten-
tial source of stress from the family as the PWD’s life nears
its end.
Person-centred care requires person-centred staff and
management to promote and provide a supportive envi-
ronment. Residents in a nursing home will still have some
self-awareness and some ability to participate in decisions.
Allowing them to make small simple choices for themselves
can help maintain their self-esteem (Box 17.2).
17.3 HOSPITAL NURSING CARE
Caring for a PWD in a hospital setting requires patience
and a calm approach. Most PWDs will recall aspects of
a hospital admission, despite their dementia. Even if the
patient has severe dementia, unpleasant feelings and emo-
tions from previous admissions may still be remembered,
so nurses need to approach the patient in a friendly, non-
threatening manner. Remember, the PWD is in a strange,
noisy environment and surrounded by strangers.
17.3.1 CARE OF A PWD IN A GENERAL
WARD
●● Provide a single room if possible to minimize noise and
confusion; preferably one with an en suite so that the
toilet can be found easily.
●● Greet the PWD by name.
BOX 17.2: Role of nursing
●● Promote independence
●● Provide a safe, secure environment for patients
and staff
●● Advocate on the patient’s behalf, when needed
●● Educate patient, family, other nurses and staff with
regard to patient’s behaviour
●● Promote health, prevent illness/injury
●● INTRODUCE yourself, ask if the PWD remembers you
when you go into the room on later occasions and intro-
duce yourself again if necessary.
●● EXPLAIN every procedure, even if it happens every
day during the admission, and even if you are only
in the room to replace a filled urine bottle. You may
need to remind the PWD frequently why they are in
hospital. This may be frustrating for you but is more
frustrating and confusing for the PWD if there is no
understanding.
●● Focus the PWD’s attention. If two nurses are required
for a procedure, only one should instruct the PWD if
their cooperation is required to complete a task.
●● If you need a distraction, chat about the PWD’s past
life – job, family, hobbies. Remember that these early
memories will be the last to fade away.
●● Ask permission before helping yourself to the locker or
wardrobe. We see these cupboards as an extension of
our working environment – the PWD may misinterpret
your movements as theft.
●● The PWD may not be able to report pain – look for non-
verbal cues: grimacing, restlessness, agitation.
●● Use caution when giving pro re nata (prn) medication
for agitation – pain may be the cause.
●● Extend visiting hours for next of kin, other family
members and friends – hospitals are extremely noisy
environments and some noises can be frightening for
the patient. If a trusted visitor is present, they can help
explain what is going on and keep the PWD calm.
●● Place an orientation board in the line of sight of the
PWD with the day, date, location and why the PWD is
in the hospital.
●● Facilitate watching favourite programmes on television
for the PWD.
●● Ask the family to bring familiar objects and photos into
the room and to play the PWD’s favourite music.
17.3.2 EMERGENCY DEPARTMENT (ED)
Finding a quiet corner for the PWD in an ED is going to be
difficult. It is important to have family close and attempt
to minimize the stimulus from hospital equipment/hustle
and bustle as much as possible. Every time you approach
the PWD, introduce yourself. Increased stress and pain can

BOX 17.3: Key points to caring for people
with dementia
Key points when caring for a person with dementia in
any environment are:
●● Remember: the patient is in a strange environ-
ment, surrounded by strangers
●● INTRODUCE yourself and the task to be carried
out to prevent fear in the patient
●● Allow autonomy, enhance self-esteem (allow
choices, maintain abilities)
●● One stimulus/voice at a time to focus the patient’s
attention
●● Treat patient with dignity
●● Maintain routine
●● Do not ‘infantilize’ the patient
●● The patient will remember EMOTION
cause changes in behaviour – ‘exiting behaviour’ in particu-
lar, trying to ‘walk away’ from the cause of pain or change
in facial expressions (James and Hodnett, 2009) are com-
mon. Hospital volunteers can be of benefit to the PWD,
staff and carers by remaining with the PWD and explaining
procedures where appropriate (James and Hodnett, 2009).
Providing training in dementia care for staff will improve
outcomes by reducing stress for both PWD and staff (James
and Hodnett, 2009) (Box 17.3).
17.4 PAIN AND MEDICATION
Experiencing pain is different for everybody. People have
different pain thresholds which may further be lowered by
fatigue and depression. For those who are cognitively intact,
the presence of pain is easily articulated. Thus preferred,
effective medications and other methods of pain relief are
immediately provided.
Cognitive impairment is a substantial barrier to the
assessment and management of pain. It is common for
older PWDs to experience pain associated with arthritis,
spinal canal stenosis, diabetic neuropathy, painful legs, etc.
A PWD may be incapable of reporting pain verbally. The
nurse needs to know the PWD’s past record and current
medical history, both, to identify possible causes of pain and
to facilitate appropriate management.
If the PWD is unable to communicate adequately, our
observations and knowledge of the PWD need to be relied
upon. Gait, facial expressions (frown, grimace), skin colour,
behaviour, placing cold or hot things on a body part – can
all be observable indicators of pain. Vital signs (heart rate,
blood pressure, temperature) can provide important infor-
mation, especially in the assessment of non-verbal, elderly
dementia patients. Observe, gather information from all
team members, consult with the doctor, commence an
The role of nursing in the management of dementia 185
analgesic regimen and continue to observe, evaluate and
document patient behaviour.
Medications, when used well, can assist pain manage-
ment. However, the fact that older people have an increased
sensitivity to some drugs, especially opiates, must be con-
sidered. If an increased sedative effect is present, this may
lead to falls and fractures, loss of muscle strength, immobil-
ity and decreased cognition (see Chapter 16).
Depending on the cause of pain, regular paracetamol is a
safer option than anti-inflammatories, which may have gas-
trointestinal or other side effects.
An effective approach to pain relief is to combine
­medication with a non-drug approach: massage, heat, exer-
cise – all to increase circulation – or distraction. As tired-
ness can increase pain, take into account the PWD’s sleep
pattern too.
Regular medication reviews are required to avoid unnec-
essary polypharmacy. Medications prescribed earlier in
life may now be unnecessary or causing side-effects. Used
wisely, medications can help with symptoms of pain, agita-
tion and anxiety. Medication can improve sleep at night and
increase daytime participation in activities.
17.5 RESIDENTIAL CARE
17.5.1 ASSESSMENT
Dementia care today is based on person-centred care,
founded on a holistic model designed and developed by
the late Tom Kitwood and Kathleen Bredin during the late
1980s (Kitwood, 1993). The basic tenets of this work are the
following:
●● Uniqueness – Everyone is different.
●● Complexity – We all see things differently and are
influenced by the changes and events that occur during
our lifetime.
Most facilities will have their own PWD assessment tool.
Whichever tool is used, the assessment needs to be person-
centred and keep to the PWD’s at home routine as much
as possible. For example, if they showered in the evening
at home, can this be maintained? Information gathering
should involve the PWD, include the family and close
friends, list abilities, needs and details of the person’s life
story so that new staff can quickly gain an insight into the
person they may be caring for on a particular day. Of course,
assessment of fall risks, compliance with special diets, etc.,
also need to be included, but the emphasis needs to be on
the PWD – their life, culture, things they love, things they
hate, usual routine. Moving into a care facility will cause con-
fusion and the PWD will need support. Talking to the PWD
helps them feel welcome and use of knowledge obtained
about PWD will assist in maintaining their self-esteem and
safety, thus reducing anxiety and contributing to a settled
186 Dementia
environment for all. A brief, dot-point biography of the
PWD in front of the notes documented would be helpful.
Once the assessment and a comprehensive care plan are
complete, it is important to establish a routine in the daily care
of the PWD. If they are capable of dressing with supervision
it would be an insult to dignity, autonomy and self-esteem to
dress them yourself for expediency. It is important to work at
the pace of the PWD. Information gathered during the assess-
ment can also be used to distract the PWD at times of potential
distress/anxiety during the provision of care and can also be
used in reminiscence and validation therapy (see Chapter 23).
The care plan needs to be reviewed and amended regularly as
needs of PWD change over time. Two PWDs with the same
diagnosis may be very different in their daily functioning.
17.5.2 A NOTE ON CULTURE
Some residential facilities are culture specific and have car-
ers from the same cultural background. The PWD’s culture
needs to be considered if this is not the case. Despite cog-
nitive deficits, participating in religious practices can still
bring comfort to the patient. Family or friends can help
provide this. PWDs of non-English speaking backgrounds
may have spoken the local language fluently prior to diag-
nosis, but with the progression of dementia, may revert back
to their native tongue. PWDs approached with dignity and
respect are more likely to respond positively. Non-verbal
communication – facial expression, tone of voice, gentle
directing – can be powerful.
17.6 ENVIRONMENT – PHYSICAL
PWDs with dementia may have perceptual difficulties. Even
in the absence of cognitive difficulties, an older person may
have impaired sight, hearing or a gait disturbance. Older
people need a simple, uncluttered, well lit environment
that is safe to navigate. Family can assist by personalizing
the PWD’s living space to make it identifiable to the PWD.
Colour and material choices are also important. Even in an
old building appropriate change can be made during build-
ing maintenance. An ideal environment for the PWD needs:
●● To be calm and welcoming and not too busy. Advise all
staff to avoid unnecessary noise (e.g. not to drop a large
bundle of cutlery into a sink).
●● Contrasting colours between walls, floors and doors.
Toilet doors particularly, need to be of a different colour
to differentiate them from other doors, so that the PWD
can identify and find the toilet when needed. In bath-
rooms, if the walls, floor, tiles, toilet, basin are all white, a
PWD with visuospatial difficulties may be unable to find
the toilet and may become agitated, incontinent or use
the black-lined rubbish bin instead. Coloured toilet role
holders, towel dispensers and taps make them easier to
locate.
●● To avoid surfaces/paints that reflect light. Sun glare may
give the appearance of spills on the floor.
●● Floor coverings that are easy to clean, not slippery
and absorb noise. The floor surface should be level.
Particular care needs to be taken if bedroom areas are
carpeted and day rooms are surfaced with linoleum.
Surface changes may contribute to falls.
●● Hand rails on all walls.
●● Adequate lighting. No dark corners or shadows which
may distort shapes to produce something frightening.
●● Appropriate signage – at eye level, perhaps use the
accepted universal symbols for the toilet as well as the
word toilet; pictorial dinner plate with knife and fork on
either side for the dining room, etc.
●● An outside area to walk in, sit for awhile or, perhaps,
participate in gardening activities.
●● Background music – PWD choice, or relaxing,
­non-stimulating music.
●● To provide a PWD’s individual bedroom area –
­personalized with familiar furniture and recognizable
belongings, family photograph on the door, pictures/
photographs of relatives on the walls. Asking the family
to help with this arrangement will help them feel they
are still contributing towards caring for the PWD.
17.7 ENVIRONMENT – SOCIAL
Everyone requires daily mental stimulation. A PWD who
cannot walk, talk or participate actively in group activities
can still be a passive observer. Previous leisure activities can
still be enjoyed with a little creative modification. Most peo-
ple enjoy dancing. PWDs who cannot dance will still benefit
from being present in the room while others dance – they
can enjoy the movement, music and rhythm. Sports fans
can still enjoy watching sports on television. Appropriate
diversion therapies can be provided by occupational or
diversional therapists (see Chapter 19).
Multi-sensory stimulation can be provided with a
Snoezelen room, a Dutch initiative, which may be useful in
calming agitated PWDs. As its objective is to stimulate the
PWD’s senses – sight, sound, smell, touch and taste – the
room may require: comfortable seating, a solar projector,
bubble column, a revolving mirror ball, soft gentle music
(i.e. sounds of nature, aromatherapy oils/candles and many
other innovative ideas that assist to soothe the PWD). Such
rooms promote relaxation through sensory stimulation and
can be calming for agitated PWDs, though monitoring is
needed because everyone’s experience is different and some
PWDs may become distressed or more agitated by these
arrangements (Wylie, 2003).
Any sensory stimulus can be therapeutic. This might
include sitting in the fresh air, enjoying the warmth of the
sun, the sounds of leaves in the breeze and birds chirping,
or smelling the aroma of cooking when one is unable to
cook.

Family and friends can contribute to the This Is Your Life
book (see Section 17.9.1.2) continually and can see who has
visited when and it can be used to provide conversation/
reminiscence prompts.
Music can be an entertainment, used as a therapy to
promote memories, stimulate sensation and conversation
(Baird and Samson, 2015), or to calm agitated PWDs (see
Chapter 29). The choice of music should be the PWDs, not
what the staff or family chooses. It is the PWD’s home,
everybody else is a guest there.
17.8 TIME, PLACE, PERSON
17.8.1 ORIENTATION
The PWD’s peace of mind is more important than their
knowledge of time and place. If a 93-year-old woman thinks
that her aunt still lives down the certain street ‘near here’,
there is no point in causing distress by telling her that she is
93, the year is 2016 and that her aunt could not possibly still
be alive. It would be better to comment on the fond memo-
ries she must have of her aunt and encourage her to talk
about those.
When orientation of the PWD is important, such as meal
or shower times, the PWD should be greeted appropriately
in a non-threatening way, to alleviate any fear felt at being
approached by a stranger and to gain cooperation. A little
thought is required to provide the information needed for
this task without putting the PWD under pressure. For
example, ‘Hello Therese, I’m Ann, one of the nursing staff.
It’s 12 o’clock and lunch will be served very soon. Let me
walk with you to the dining room’. In this context, orienta-
tion to person, time of the day and purpose of the activity
has been explained and the PWD does not need to make a
decision.
When PWDs do not recognize family members, it is
often distressing to the family but not necessarily to the
PWD. The PWD may still remember the emotion associated
with that family member and smile or say ‘hello’ when they
enter the room. It is important to point out to the family
that even though the PWD cannot recall their name, they
are still happy to see them.
17.8.2 PERCEPTION
Other factors to consider are disturbances of perception
and misinterpretation of stimuli. The PWD’s reality is dif-
ferent from ours. They may tell their family that they want
to go home. If the family takes the PWD home for a visit,
the PWD may say that he or she still wants to go home.
Perhaps ‘home’ means a calm and safe place where they
feel comfortable and at peace. Whilst in a state of anxiety, a
PWD may become agitated and become a challenge for staff
attempting to provide care.
The role of nursing in the management of dementia 187
17.8.2.1 Perceptual impairment
Due to confusion, the PWD could find themselves living in
a state of fright perpetually. A black jumper on furniture
may look like an animal; a PWD with Balint’s syndrome
(difficulties with visual perception) may not be able to see
what is directly in front of them causing feelings of insecu-
rity, making them prone to falls and unable to see food on
the plate right in front of them. Dementia may affect visuo-
spatial awareness: glaring light on pale floors may look like
water and the PWD may try to step over it risking a fall.
The nurse needs to be alert to the PWD’s sensory impair-
ments in order to provide assistance when required. This may
include helping with meals, moving clothes from one place to
another or directing the PWD away from potentially danger-
ous or anxiety provoking situations. This may be as simple
as using coloured crockery for distinguishing food items
or standing in a patch of light on the floor to avoid visual
misperception.
17.9 COMMUNICATION THERAPIES
Deficits in the ability to communicate are often an early
symptom of dementia: word finding difficulties, partial
comprehension of conversation, problems with reading and
writing. Communication is made up of three parts: 55%
body language (facial expression, posture, gestures); 38%
tone and pitch of the voice; only 7% is speech (Alzheimer’s
Australia, 2012b). It is dependent on the listener listening
and patiently giving the speaker time to speak. Give the
PWD the respect of waiting for their response rather than
second guessing for them or speaking on their behalf.
17.9.1 THERAPIES FOR MODERATE TO
SEVERE DEMENTIA
17.9.1.1 Reminiscence therapy (RT)
RT involves discussion of past events and can be a posi-
tive activity even if the PWD cannot participate actively
(Alzheimer’s Australia, 2012c). Photographs, pictures, music,
TV shows, books, can be used to trigger memories. It is
important to know your PWD before involving them in RT,
as some memories may be distressing. RT does not always
need to be conducted as structured group therapy. It can also
be used as a device for distraction at any time – in the ED or
anywhere when the PWD is becoming agitated.
17.9.1.2 Validation therapy (VT)
The PWD’s reality is different from ours. By entering their
reality, we can establish feelings of trust and security in
the PWD and alleviate distress and anxiety (Alzheimer’s
Australia, 2012b). VT consists of exploring an issue raised
188 Dementia
by the PWD, even if it obviously may have no bearing on
the present. It is useful when the PWD’s short-term memory
has deteriorated to the point that understanding of the pres-
ent is cognitively beyond them and they have reverted to
memories from their past to survive (Alzheimer’s Australia,
2012c). The person attending the PWD can promote discus-
sion about their memories and the emotions they felt in the
past. It does not matter if the details do not correlate with
reality. The PWD’s peace of mind is the goal to be achieved.
VT can be used to engage the PWD in conversation and
promote mental stimulation or to distract or redirect them
from doing something inappropriate without causing them
distress.
A This Is Your Life book compiled by a family member or
friend can be an excellent communication tool. Such a book
can include photographs, letters, personal details, such as:
immediate family tree, details of birth, anecdotes from fam-
ily folklore, qualification certificates. Keep one idea to each
page in the book to avoid overwhelming the PWD and place
labels on photos rather than testing the PWD’s memory
(Alzheimer’s Australia, 2012b).
17.10 EXERCISE/ACTIVITIES
‘Enjoyment doesn’t require memory’ (Alzheimer’s
Australia, 2012d). Exercise has a beneficial effect on both
physical and mental health. In a literature review, Leone
et al. (2008) found that exercise, particularly, can have a
positive effect on depressive symptoms, chronic diseases
and on the behavioural and psychological symptoms of
dementia (BPSD). Exercise can stimulate cognition and
the performance of activities of daily living in PWD. The
risk of falls can be reduced through balance and strength
training.
Benefits of exercise include:
●● Improved general well-being
●● Improved blood circulation
●● Strengthened immune and hormone systems
●● Increased lean muscle mass
●● Increased metabolism
●● Improved balance and coordination
●● Positive effect on BPSD
●● Enjoyment
Types of exercises that are beneficial:
●● Aerobic (walking, dancing, any exercise which requires
movement)
●● Progressive strength training (resistance and weight
bearing)
●● Flexibility and balance training (tai chi, bending/
stretching)
All activities need to be tailored according to the needs
and capabilities of the individual (Alzheimer’s Australia,
2012d).
17.11 THE NEED FOR SLEEP
Sleep hygiene must be considered. Lack of sleep has a
negative impact on the PWD’s behaviour and ability to
participate/function in activities in a meaningful way. An
appropriate sleeping environment must be provided and
other basic needs met: absence of pain, hunger, empty
bowel/bladder. Staff should be mindful of daytime rest
periods – catnaps are acceptable, a lengthy period of sleep
is not. PWDs need to be involved in daytime activities/exer-
cise both indoors and outdoors in order to feel tired enough
to sleep at night. The sleep/wake cycle can be reversed in
dementia and daytime activities can assist normal diurnal
awareness. Night sedation should be the last resort after all
other strategies have been attempted and have failed.
17.12 NUTRITION
Nutrition for PWD can be assisted by the environment in
which food is served. A noisy environment can be distracting
and frightening. A lack of sensory cues (smell, sight, touch,
taste and sound) will not encourage a person with dementia
to eat (Marshall, 2003). PWDs who have come from a small
home unit into a multi-bed facility may find meal times
confusing and overwhelming. A calm environment, back-
ground music and the opportunity to help with cooking and
serving may stimulate appetite (Marshall, 2003).
Food should be presented attractively. Smaller, more fre-
quent meals or nutritious finger foods may benefit small eat-
ers. Fluids should be offered frequently and in small quantities
to be taken easily. Some PWDs may require assistance to eat
because of a perceptual difficulty or severe dementia. Some
may need a trigger (coloured crockery or cutlery handles) or
cue, such as a guiding hand over theirs, to remind them of the
action of eating. A staff member eating with the PWDs may
benefit. Adequate time to eat must be provided and plates not
removed hastily because kitchen staff needs to go for lunch.
Care is provided to benefit the PWD and not the staff.
17.13 BEHAVIOURAL AND PSYCHIATRIC
SYMPTOMS OF DEMENTIA (BPSD)
Not all PWDs exhibit BPSD. Nursing education requires
knowledge of the different types of dementia, associated
symptoms and expected progression of each disease. Basic

understanding of the functional parts of the brain must
underpin any understanding of the behaviours exhibited.
Two people with the same diagnosis and same degree of
atrophy may not necessarily display the same problem in
their behaviours. Symptoms and responses to treatment
change during the course of the illness.
Challenging behaviours are not deliberate and staff
should not take such behaviours personally. It is a waste of
time arguing with a PWD who does not have the capacity
to reason. A PWD may not be able to process your words,
however, if delivered with a smile, warmth, a soft tone and
gentle touch, the person may respond in a more appropri-
ate manner. Communication is both verbal and non-verbal.
The message conveyed in a non-verbal manner may be more
powerful than spoken words (Box 17.4).
When are these behaviours most likely to occur?
●● Attending personal care/bathing
●● Dressing
●● Meal times
●● Late afternoon (sundowner syndrome occurs due to
fading light)
●● Night-time
●● Anytime
Those behaviours that are disruptive to others need to
be addressed. However, some behavioural patterns, such
as pacing and repetitive acts, need not necessarily disrupt
anyone. PWDs can rummage through a box or drawer pro-
vided a purpose, or wander around if it is safe in the ward
area. Sundowner syndrome may be alleviated by turning on
lights, closing curtains and not allowing shadows to be cast
in the room. Any behaviour only requires intervention if it
is distressing to the PWD or others. The nursing aim is to
minimize the occurrence of any negative behaviour.
Bathing often triggers BPSD. This is perhaps due to fear,
embarrassment and/or physical discomfort. Previously,
this PWD has bathed in private. An alternative to routine
showering or bathing, such as a traditional bed/sponge bath
using warm cloth steeped in non-rinse cleanser may help
(O’Connor et al., 2009).
Multi-sensory activities and exercise can help minimize
BPSD. Mental stimulation and exercise are basic human
needs and unmet needs can create problems.
Other stimulating strategies to moderate or prevent
BPSD are addressed in Chapters 23 and 24. Most require
human contact, so the personal interaction between the
PWD and person providing care may be the key to prevent
BPSD (O’Connor et al., 2009).
Sudden behavioural changes may be due to delirium
caused by an infection (commonly urinary tract infection
[UTI]), dehydration, electrolyte imbalance, constipation
or nutritional deficiency. These are all treatable, reversible
conditions.
The role of nursing in the management of dementia 189
BOX 17.4: Behavioural and psychological
symptoms of dementia
Depression, lowered mood, apathy, aggression,
agitation, resistance to personal care, wandering,
intrusiveness, pacing, sleep disturbance, verbal
outbursts or obscene abusive language, stealing,
hiding, h
­ oarding, inappropriate toileting, inappropri-
ate sexual behaviour, repetitive acts, suspicion and
accusations, anxiety, delusions, hallucinations
17.13.1 DISTRACTIONS – ‘QUICK-FIX’
SOLUTIONS
Another technique to deal with BPSDs is to recognize
the precipitant and redirect or distract the PWD to try
to prevent such behaviour. The fundamental require-
ment for a quick fix solution is to know your PWD. If the
PWD is becoming anxious, agitated or frustrated, greet-
ing them warmly, addressing by name with and an open,
outstretched hand may be all that is needed to calm them
down. Engage the PWD in a meaningful conversation – life
pre-retirement, their pastimes – anything to distract them
and focus their attention on something else.
There are many reasons why a PWD may exhibit problem
behaviour, most probably precipitated by an unmet need.
The solution does not always need to be pharmacological.
In managing a challenging behaviour, a holistic problem-
solving approach can be adopted to formulate strategies to
modify/eliminate/better manage their behaviour.
A simple problem solving model consists of:
Gathering information: What is the behaviour of concern?
When does it happen? What are the triggers? How
long does it persist? Who/what is it directed towards?
Is it due to boredom? Is it stimulated by a past mem-
ory? Can the family shed any light into the matter? Is
there an organic basis: urinary tract infection, pain,
sensory loss, constipation?
Assessment: By team – pooling of information from all
sources.
Planning: All members of the team contribute to develop-
ing a strategy to change the behaviour of the con-
cerned PWD. A review date is set.
Implementation: ALL members of the team follow the
plan on a daily basis; no saboteurs.
Evaluation: By team members regarding success or failure
of the strategy. Accurate documentation and commu-
nication between team members is imperative.
Reiteration: Modification of management strategies based
on the known successes/failures of those strategies
already tried.
190 Dementia
17.14 CARE OF THE FAMILY
…loved ones are not lost to us because they
have dementia.
—Young-Mason (2009, p. 43)
Family members grieve and fear for the PWD from the
moment of diagnosis. At different times they will feel lost,
angry and frustrated. There are carer support s­ervices
­available to which the nurse can refer carers while provid-
ing care at home and during the ­transition from home care
to a residential facility. Alzheimer’s Associations conduct
sessions for carers to learn ­effective ways of ­dealing with
problem behaviours (see Chapters 15 and 36).
The issues faced by carers after institutionalization of
the PWD are under-researched. Some carers visit rarely
whilst others stay on for most days. Some carers feel
redundant, guilty or isolated. All carers will require sup-
port from the nurse as well, especially when the PWD
is newly admitted. It helps the family to involve them-
selves with the PWD’s care – with the assessment, deco-
rating the PWD’s room, providing stimulation through
reminiscence, taking the PWD for walks, etc. They will
require explanations if the PWD’s behaviour is problem-
atic or if health is compromised. A family member with
enduring power of attorney may need guidance regarding
choice of appropriate treatment at times, if an advanced
care plan is not in place. This issue should be referred
appropriately.
17.15 CARE OF THE CARE PROVIDERS
Qualified nurses working exclusively with PWDs will
largely be working in administration, management or in
the community. Most of the care in dementia specific nurs-
ing homes is provided by personal care attendants (PCAs),
supervised by a registered nurse. It is incumbent on the
nurse manager to educate, support, mentor and lead by
example in the workplace.
17.15.1 STAFF EDUCATION
In any medical facility there are a host of different workers
who come in contact with PWDs – from medical staff to
cleaners. All staff in a facility that regularly caters to PWDs
requires some degree of training. In a facility in Suffolk,
England, nonclinical staff doubted the necessity of demen-
tia training given to them, but post-training reviews dem-
onstrated that training was valuable to all departments,
including the laundry staff (Moden, 2009).
Training needs to be relevant and meaningful. A recent
Australian paper found out that staff were aware of the need
for education and training but ‘were critical of the content
relevancy to direct care practices’ (Jones et al., 2013, p. 52).
Staff turnover in nursing homes varies greatly. Recent
research indicates that effective leadership, education and
support contribute to staff retention in nursing homes
(Chenoweth et al., 2010). The provision of education
and clinical supervision alleviates stress and positively
affects job satisfaction (Brodaty et al., 2003). It needs to be
acknowledged that the work can be unpleasant and seem-
ingly unrewarding but education and support can mitigate
the negativity.
The people providing the care need to have a voice.
Supportive facility managers acknowledge the need for reg-
ular staff forums and provide a budget for them. Strategies
to provide a forum for nurses to receive education and sup-
port in the workplace do not need to be expensive. They
could include:
1. Regular support sessions
2. Regular education sessions
3. Debriefing sessions or extraordinary meetings to
discuss specific issues that occur between regular
meetings, such as the death of a long-term resident,
a challenging PWD behaviour or a difficult family
member
4. Remunerate night staff for attendance and keep a
register to ensure that every staff member has the
opportunity to attend regularly
Perhaps, by providing a structured, safe environment for
the PWDs and a supportive environment for the nursing
staff, an effective milieu for both can be created.
17.16 CONCLUSIONS
This chapter is written from a practical perspective. When
all else fails, it is important to remember that common
sense is a great tool when dealing with the complexity and
diversity we face with people. PWDs, in some cases, amplify
the requirement that enables us to think clearly about and
make well-judged and informed decisions. The victims of
dementia are not limited to PWD alone. This chapter aims
to provide ideas to stimulate discussion that result in better
support for the care of the unfortunate people who endure
these degenerative and devastating illnesses.
People are whole people until the moment of
their death.
—Pringel-Specht et al. (2009, p.16)

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Social work and care/case management
in dementia
DAVID CHALLIS, JANE HUGHES AND CAROLINE SUTCLIFFE
18.1 INTRODUCTION
Social work, like any professional or occupational group, is
inseparable from the organizational and legislative context
in which it takes place since this defines the parameters of
practice. Prior to the introduction of care/case management,
descriptions of social work in services for adults, including
older people, tended to focus on profession specific activi-
ties, to the neglect of outputs such as the function of link-
ing the individual to networks of care. Moreover, social
work with older people, including those with dementia, was
typically a short term intervention (Hunter et al., 1990).
Assessments were often undertaken in a relatively narrow
and service-oriented fashion, followed by an allocation of
service prior to closure (Challis, 2003). Continuing manage-
ment of long-term problems for people living in the com-
munity was neglected. The advent of care/case management
required a useful redefinition of social work in relation to
long-term care of older people. It can be most simply defined
as a strategy for organizing and coordinating care services
at the level of the individual. Care/case management, there-
fore, involves mobilizing and influencing various agencies
and services to achieve clearly formulated goals, rather than
each provider pursuing separate and perhaps diverse goals
(Challis, 1993; Schultz and McDonald, 2014). It is helpfully
understood in terms of six criteria: the performance of core
tasks, effective coordination, explicit goals, a specific target
population, a long-term care focus and an impact on service
development as well as individual cases. This is summarized
in Box 18.1. Various terms are used to describe this process
including case management, care management and care
coordination (Challis and Hughes, 2012).
Specialist care/case management for older people with
dementia is an area of practice in which there is much
scope for innovation and development (Challis et al., 2009).
192
18
Moreover, there is evidence of its effectiveness within this
group provided that it is appropriately targeted. In many
developed countries, care/case management services have,
it has long been argued, been intended for those people
at risk of admission to long-term care reflecting a policy
of ‘downward substitution’ by the provision of more cost-
effective community-based alternatives (Challis, 2003).
Two examples demonstrate the international applicability
of care/case management as a means to provide effective
community-based care for older people with dementia.
Early research in the United States revealed that this target
group experienced a greater reduction in their use of health
care and had lower costs within an approach where care/
case managers had small caseloads; undertook frequent
home visits; with appropriate use and knowledge of local
resources (Eggert et al., 1990). In England, an exemplar
care/case management site also demonstrated its capacity
to support those with dementia in their own homes. Key
characteristics of the service were the following: trained
and experienced staff; small caseloads targeted on the
most vulnerable older people; long-term support; finan-
cial management arrangements in which care costs were
explicit, care packages costed and, within limits, bud-
gets devolved to front-line staff; and systematic records
for assessment and monitoring (Challis et al., 2002a). A
recent Cochrane review of case management and dementia
indicated reduced admissions to nursing and residential
homes and lower healthcare costs from case management.
However this was dependent upon key factors: targeting
the intervention on the correct population; a clear and
explicit specification of the form and content of the case
management intervention and related to this, model fidel-
ity (Reilly et al., 2015). Other work indicates the impor-
tance of the degree of influence over resources which case
managers possess, where more control is associated with
better outcomes (Challis, 2003).

BOX 18.1: Key characteristics of care
management
●● Core tasks: case finding and screening; assess-
ment; care planning; monitoring and review
●● Functions: coordination and linkage of care
services
●● Goals: providing continuity and integrated care;
increased opportunity for home-based care; make
better use of resources; promote well-being of
older person
●● Target population: long-term care needs; multiple
service requirements; risk of institutional placement
●● Differentiating features of long-term care: inten-
sity of involvement; breadth of services spanned;
lengthy duration of involvement with older person
●● Multi-level response: linking practice-level activities
with broader resource and agency level activities
18.2 PATTERNS OF PRACTICE
Increasingly countries are developing strategies for the care
of people with dementia which include enhanced care at
home, thereby demonstrating the important contribution
of social work and care/case management to such service
development. This is detailed in international strategies and
plans in, for example, France, Holland, Ireland and Japan for
people with dementia, with care/case management identified
as the means to coordinate the necessarily multiple service
inputs as an alternative to care home admission (Ministry
of Health Welfare and Sports, 2009; Arai et al., 2010; Cahill,
2010; Guisset-Martinez, 2012). The four countries within the
United Kingdom have their own dementia strategies which
have either adopted a care management/care coordination
approach (Department of Health, 2009, 2013; Department of
Health, Social Services and Public Safety, 2011; The Scottish
Government, 2013), or have proposed better integration of
Assessment
Referral
(i) Short-term interventions
Case finding
Assessment
and screening
(ii) Long-term care
Figure 18.1 A model of care.
Social work and care/case management in dementia 193
services (Welsh Assembly Government, 2011). In Australia,
the strategic vision for the development of services suggests
a not dissimilar role for social workers, that of helping peo-
ple with dementia and their families ‘navigate’ the commu-
nity care system with provision located within mainstream
services (AHMC, 2006; Brodaty and Cumming, 2010). By
contrast, the Norwegian strategy for people with dementia
emphasizes care planning, the implementation of home care
services and day care programmes and the development of
a competent workforce (Norwegian Ministry of Health and
Care Services, 2007; Engedal, 2010).
The core tasks of long-term care embodied in care/case
management, detailed in Figure 18.1, offer an approach suit-
able for the community-based care of vulnerable people with
long-term conditions. Since older people with dementia typi-
cally have complex health and social care needs, it is impor-
tant that agencies have in place procedures and protocols
within care/case management arrangements which facilitate
an appropriate level of response, a feature more likely to be
associated with a differentiated approach to care/case man-
agement. This requires a distinction to be made between
older people with complex needs requiring a multiservice
response and those with less complex needs which are met
by a single service response provided by one agency (Hughes
et al., 2005); however, it is not always available. In England,
for example, little progress was made in the development of
a differentiated approach to care/case management follow-
ing the community care reforms of the 1990s. Intensive care/
case management, an important component of a differenti-
ated approach, was not widespread within older people’s ser-
vices (Sutcliffe et al., 2008; Chester et al., 2015). The purpose
of intensive care/case management is to permit more flexible
responses through improved coordination and appropriate-
ness of care by use of a designated care manager, and is a
prerequisite for the provision of complex packages of care to
enable older people with dementia to continue living in their
own homes (Applebaum and Austin, 1990; Challis, 2003;
Department of Health, 2009; NICE, 2013).
A review of case management operation and process has
indicated that clarity of definition about the form, content
Re-referral
Brief
Closure
intervention
Care Monitoring Closure
planning and review
194 Dementia

and quantity was essential (Reilly et al., 2010). A model of Table 18.1 Lewisham Case Management Scheme: setting
care/case management that can successfully support older and role
people with dementia at home has been proposed using
Shorter-term care
eight standards of good practice that include intensive
care/case management. Four of these were related to the Community mental health team for older people
framework within which care/case management is under- Doctors, nurses, psychologist
taken: provision by specialist multidisciplinary teams; Occupational therapists, social workers
integrated arrangements for commissioning domiciliary
and respite services; joint financial arrangements facilitat- Key workers
ing health and social care provision; and organizational Longer-term care
arrangements promoting a differentiated approach to
ensure an appropriate level of response. The remaining Case managers
four were associated with the process of care/case manage- Social workers with budget
ment: a continuing targeting process to ensure a level of Service to patients with dementia
response suitable to a person’s needs; a multidisciplinary
Care management
assessment process appropriate in terms of content and
Source: Challis, D. et al., Supporting People with
timing; care planning, which supports and enhances qual-
Dementia at Home Challenges and Opportunities
ity of life; and sufficient monitoring and review to ensure
for the 21st Century, Ashgate, UK: Aldershot,
adjustments to care plans occur when required (Hughes
2009. With permission.
et al., 2005). These features remain important (Abell et al.,
2010; Challis et al., 2011, 2014a; Clarkson et al., 2011a,
2011b, 2012; Sutcliffe et al., 2010).
BOX 18.2: Practice interventions and
strategies
18.3 INTENSIVE CARE/CASE Case finding and screening
MANAGEMENT
●● Targeting of appropriate cases

The Lewisham Case Management Scheme offered a practi- Assessment

cal demonstration of care management providing commu-
nity support to older people with dementia living at home
(Challis et al., 2009) and an illustration of the role of social
work within this. It was cited in the government’s National
Dementia Strategy as an examplar of intensive care/case
management preventing inappropriate care home admis-
sions and was one of a family of similar studies (Challis
and Davies, 1986; Challis et al., 1995, 2002a; Department of
Health, 2009). Specifically, it was established within a mul-
tidisciplinary setting for a target population of individuals
with a diagnosis of dementia, identified as having unmet
needs and at the risk of entry to institutional care, despite
input from statutory services. Its aim was to provide effective
integrated community-based long-term care spanning the
health and social service interface. The service was provided
by social services care/case managers based in a commu-
nity mental health team for older people. Most importantly,
care/case managers were able to purchase care in response
to identified need within defined parameters. This enabled
the development of a specialist paid helper service which was
available to those receiving care/case management input.
The service setting and roles are summarized in Table 18.1.
Box 18.2 details the process of assessment and care/case
management within the scheme. With regard to implement-
ing the care plan, the goals of intervention in care/case man-
agement were identified by retrospective analysis of 80 care
plans. These were analyzed under seven categories: support-
ive, therapeutic, practical, preventive, social, destinational
●● Structured approach
●● Severity of need assessed
Implementing the care plan
●● Goal defined
●● Strategies of intervention and resources
identified
Monitoring, review and case closure
●● Achievement of goals reassessed
●● Problems reviewed
●● Outcome by domain of assessed need
evaluated
and organizational. The most frequently reported were
supportive (68%), therapeutic (66%) and practical (56%).
Supportive goals were almost exclusively intended for the
benefit of informal carers, the most frequently reported cat-
egories were to relieve carer burden, provide respite and assist
carers. Therapeutic interventions were most often directed
at devising strategies to reduce problem behaviours associ-
ated with the individual’s deteriorating state. Practical goals
were most frequently focused on assistance with personal
care, healthcare and domestic care of the older person. These
demonstrated that the prime objectives of the scheme were to
support, sustain and enhance the quality of life of the older
person in his/her own home, and thereby to assist the carers.

In the second year of the Lewisham Case Management
Scheme, its effects began to show in a lower rate of admission
to care homes for older people with dementia receiving care/
case management than for those receiving standard care. At 6
months, older people receiving case management were more
satisfied with their lifestyle at home, and there was evidence
of a reduction in their needs associated with activities of daily
living. At 12 months, there was a significant reduction in the
amount of care input and distress experienced by carers of
the older people in receipt of case management.
Social care provider costs were higher for those receiving
care/case management, since care/case manager visits and the
paid helper service were not available to those receiving stan-
dard services. On the other hand, there was a positive gain for
the carers of those in receipt of care/case management, since
financial and other costs were lower for this group compared
to the carers of those receiving standard services. Moreover,
when all costs to society were accounted for, including infor-
mal care, the weekly cost of supporting older people with
dementia and their carers was not significantly higher for
those receiving intensive care/case management, although
that of the main component, statutory services, was greater.
As demonstrated above, this specialist scheme, located in
a multidisciplinary team which integrated health and social
care services, was successful in providing care to older
people with dementia to enable them to remain at home
rather than enter long-term care and provided effective sup-
port to their carers. This approach is consistent with other
UK and international evidence relating to the provision
of specialist care for this group of older people (Chu et al.,
2000; Eloniemi-Sulkava et al., 2001; Minkman et al., 2009).
Moriarty and Webb (2000) noted factors that could opti-
mize care for people with dementia and their carers. These
included responsive care management systems, effective
monitoring systems, and home care and day care services
sensitive to changes in an individual’s care needs and which
provide practical support to carers. The latter is particularly
important since the centrality of support for carers remains
a constant theme (Moriarty, 1999; Brodaty et al., 2005;
Gaugler et al., 2005; Sutcliffe et al., 2013). National and inter-
national policy has endorsed this approach (AHMC, 2006;
Department of Health, 2009; Republique Francaise, 2011a,
b) although a recent report has suggested that care/case
management could substantially reduce health and social
care costs but increase the costs of unpaid care (Knapp et al.,
2014).
18.4 SOCIAL WORK IN INTEGRATED
CARE SETTINGS
Within multidiscplinary teams, arrangements need to be in
place to facilitate the multidisciplinary assessment of people
with dementia and particularly to ensure that specialist cli-
nicians contribute to this process. A number of UK s­ tudies
have suggested potential gains from greater integration of
Social work and care/case management in dementia 195
secondary health care with the decisions made in the con-
text of care/case management (Brocklehurst et al., 1978;
Peet et al., 1994; Sharma et al., 1994; Challis et al., 2004).
Research conducted within a specialist mental health team
for older people has found that the process of assessment can
be undertaken by any of the members within it (Lindesay
et al., 1996), and more generally, growing role substitution is
emerging in community mental health teams for older peo-
ple (Challis et al., 2014a). More recent work has suggested
other gains arising from closer integration between social
care and old age mental health services (Sutcliffe et al., 2008;
Clarkson et al., 2011a, 2011b; Challis and Hughes, 2012).
The experience of Australia, which has the community care
reforms most analogous to those in England, gives credence
to this type of arrangement (Challis et al., 1995; Howe and
Kung, 2003; Government of South Australia, 2009).
Other work in relation to social work and social care
integrated with health provision would seem to concur
with this. Multidisciplinary assessments in the commu-
nity, involving social workers and secondary healthcare
professionals, have increased over time and are associ-
ated with better care outcomes for people with cognitive
impairment (Clarkson et al., 2011a, 2011b; Sutcliffe et al.,
2010). Furthermore, the use of more standardized assess-
ment processes in social work and social care improves
identification of people with dementia in the commu-
nity, and potentially earlier diagnosis and access to ser-
vices (Clarkson et al., 2012). It has also been suggested
that delayed discharges of older people with cognitive
impairment may be reduced by the adoption of a case
management approach (Challis et al., 2014b). However,
a cautionary note remains in that the case management
alone is not a panacea. Effective case management cannot
be delivered in isolation but depends upon access to and
influence over the allocation of services (Challis, 2003;
Challis et al., 2011; Reilly et al., 2010). It is anticipated that
the effective care of people with dementia will benefit from
these new service configurations and arrangements which
pay less attention to traditional boundaries whether pro-
fessional or organizational than hitherto.
18.5 CONCLUSIONS
The emergence of dementia specific services may lead to
further interprofessional role blurring which, if managed
correctly, could be the basis of improved care for people
with dementia and their carers. Within this, social work
and care/case management have a distinct role in rela-
tion to the provision of long-term community-based care.
Developments in England over the last 25 years provide evi-
dence of a change in the role, focus and setting for social
workers and other professions working with people with
dementia with an increasing emphasis on care/case man-
agement as a means of coordinating complex packages of
care as an alternative to care home placement (SSI/SWSG,
196 Dementia
1991; Department of Health, 2001; 2009). Care coordination
features strongly in official guidance with service commis-
sioners advised to work with local dementia partnerships to
agree and implement a robust service model for care coor-
dination (NICE, 2013).
While a changed role for social workers has emerged with
the introduction of personal budgets for social care services
(cash-for-care), permitting older people and their carers to
organize and manage their own care (Department of Health,
2008; Department of Health (Australia), 2012), social work-
ers will still be required to undertake care coordination for
the most frail elders. Indeed, there is evidence that greater
flexibilities and personalized care can be provided by care/
case managers with budgets (Challis and Davies, 1986;
Challis et al., 1995, 2002a; Sutcliffe et al., 2012). Concurrently
there has been an increase in both community-based multi-
disciplinary teams for older people with mental health prob-
lems and those with social workers as core members (Challis
et al., 2002b, 2014a; Tucker et al., 2009).
For social work, there are two challenges consequent on
these changes which have an international resonance. First,
the profession-specific contribution to the care of older peo-
ple with dementia and their carers has changed primarily to
that of responsibility for the care for people living at home
and, by virtue of changes to long-term care funding, gate-
keepers for admission to residential or nursing home care.
Second, and in antithesis to this clarity, the social work role
in respect of the care of people with dementia has become
less profession specific. Within multidisciplinary teams,
there are more opportunities for the sharing of tasks offer-
ing informal small-scale opportunities for service substi-
tution. There is thus a tendency for less specificity of role
for staff as services become more community based. This
leads unsurprisingly to a degree of insecurity among pro-
fessional groups, because each derives their unique qual-
ity from a training and occupational function. Roles come
to be negotiated rather than simply professionally defined
within groups to a greater extent in community-based ser-
vices and therefore may be seen as less clearly delineated by
professional origin. This process may well occur to a greater
extent as the process of closer integration between health
and social care develops.
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Occupational therapy in dementia care
ALISSA WESTPHAL
19.1 INTRODUCTION
Occupational therapy (OT) is concerned with maximiz-
ing a person’s engagement in meaningful and required
occupations and roles. The profession is built on the phil-
osophical foundation that engaging in meaningful and
purposeful occupations and roles is essential for main-
taining health and well-being (American Occupational
Therapy Association [AOTA], 2008). The OT clinical
model of practice recognizes occupational function-
ing as arising from a systemic and dynamic relationship
between the person, the physical, social and cultural
environment and the occupation (Law et al., 1996). This
relationship between the person, environment and occu-
pation is often disrupted by physical and psychiatric con-
ditions. Occupational therapists (OTs) use rehabilitative
and adaptive approaches to address these occupational
performance issues and maximize functioning (Fisher,
2006a; Hopkins and Smith, 1993).
Dementia causes skill loss, resulting in deteriorations
in occupational functioning. The disease trajectory, whilst
progressive, differs for each person and is frequently
accompanied by additional functional difficulties caused
by age-related physical conditions and behavioural and
psychological symptoms of dementia (BPSD) (see Chapters
8, 9 and 16). Those with dementia are commonly supported
by caregivers who themselves experience difficulty dur-
ing the progression of the disease. The OT clinical model
provides a biopsychosocial–occupational–­environmental
framework, offering OTs a significant and unique role in
holistic response to the complex and progressive occu-
pational dysfunction, which is unique to the experience
of each person with dementia and their caregivers (Letts
et al., 2003).
19
19.2 OCCUPATIONAL THERAPY ROLE
The role of OT in caring for people with dementia has
received growing research interest over the past decade as
part of the shift to provide evidence based practice. The
OT’s role varies according to the level of experience and
training of the OT (McGrath and O’Callaghan, 2014), the
specific care setting, presenting issues, severity of the per-
son’s dementia and the cultural context (Letts et al., 2011).
Roles of OT can include
●● Contributing to diagnostic formulation, including early
identification of cognitive impairment and disease
progression.
●● Facilitating recovery and/or maintenance of skills,
e.g. physical functioning, developing compensatory
memory strategies.
●● Maximizing the person’s independence in everyday
activities through modifications of the activity, environ-
ment, communication and approach and use of adaptive
equipment where required.
●● Maintaining the person’s sense of self-worth and support-
ing their identity through facilitating their engagement in
meaningful, necessary and interesting activities and roles.
●● Recommending supports which allow the person to
remain in their preferred care environment or alternate
accommodation, when required.
●● Minimizing risk and maximizing safety of the person’s
occupational performance within their environment,
e.g. driving capacity.
●● Addressing BPSD using non-pharmacological approaches.
●● Developing and reviewing activity programmes and
environments which support the needs of people with
dementia in a group or residential setting.
199
200 Dementia
●● Supporting and building the capacities of caregivers and
services to effectively care for people with dementia.
●● Developing evidence to inform and advance clinical
practice.
●● Contributing to the development of policy in areas of
health and ageing.
The OT process involves assessment, treatment plan-
ning, implementation and evaluation. Best practice advo-
cates the engagement of both the person with dementia and
their caregiver(s) throughout this process (Strong, 2003).
19.3 ASSESSMENT
19.3.1 PURPOSE AND PROCESS OF THE
OT ASSESSMENT
The goal of OT assessment is to gain a comprehensive
understanding of the abilities, strengths and deficits of the
patient and their caregivers and the available resources to
do so (Letts et al., 2003). Completion of OT assessments can
provide specific information in the following areas:
1. The person
a. Cognitive function: Memory acquisition, storage
and retrieval, learning, orientation, judgement,
insight, decision making, planning, concentration,
task shifting, reasoning, problem solving, mental
flexibility, emotional and behaviour regulation
b. Perceptual and sensory function: Visual, auditory,
proprioceptive sensation, stereognosis, praxis,
agnosia, illusions and misidentification
c. Physical functioning: Movement, balance, mobil-
ity and transfers, hand function, coordination and
impact of illness on the patient
d. Communication skills: Comprehension, verbal and
non-verbal social skills, receptive and expressive
dysphasia and adaptive communication
e. Psychological state: Mood, anxiety, past trauma and
motivation
f. Past and current occupational preferences: Interests,
roles, habits, routines and meaningful activities
2. The environment
a. Physical, social, temporal, cultural and spiritual
characteristics: Contrasts, temperature, accessibil-
ity, level of sensory stimulation, lighting, design,
furnishings, cues, personalization, language use,
values, expectations, supports, knowledge, toler-
ance and flexibility
3. Occupational functioning
a. Personal, domestic and community activities of daily
living (Personal Activities of Daily Living [PADLs],
Domestic Activities of Daily Living [DADLs] and
Community Activities of Daily Living [CADLs]):
Eating, dressing, grooming, bathing, toileting,
medication management, home and money
management, leisure, telephone use, driving and
transport, work and technology use
b. Other activities: Work, sleep and rest, social engage-
ment and leisure
c. Task issues: Demands, complexity, sequencing,
environmental context, cues and familiarity
d. Risk issues: Risks to the person with dementia,
caregiver and others associated with occupational
dysfunction
4. The caregiver
a. Knowledge: Understanding of the person they are
caring for and dementia related changes
b. Caring role: Relationship, difficulties, burden,
changes, motivation, concerns and readiness to
engage and adopt interventions
c. Communication and approach
5. Behaviour and occupational performance
a. The person with dementia: Occupational engage-
ment and BPSD (incidence, triggers and responses)
b. The caregiver: Role engagement
OT assessment facilitates include identification of the
person and caregivers’ needs and intervention priorities.
Whilst, overlapping at times, the information gathered
complements that obtained by other professional disciplines
providing a unique picture of the impact of dementia on the
person’s activities of daily living (ADL) and occupational
performance (Fossey, 2001).
The focus of assessment changes with disease progres-
sion, reflecting the changing needs of the person and care-
giver (Zgola, 1999). In the early stages of dementia, the
OT’s role is focussed on maintenance of ADL performance
within the home. With disease progression, the focus
typically shifts to maximizing and providing meaningful
engagement and facilitating appropriate care and support.
OT assessment information is collected through inter-
views, observation and standardized assessments. No sin-
gle assessment measures all areas of interest. Instead, the
OT chooses the most appropriate tool. Understanding the
present issues and the person’s background, including their
level of education, premorbid functioning and roles and
cultural history is necessary to facilitate informed selection
and interpretation of assessment tools. Finally, developing a
trusting and supportive relationship, adapting communica-
tion and approach, focussing on abilities and engaging the
caregiver, all assist with the assessment process and maxi-
mize the accuracy of the results.
19.3.1.1 Interview
Interviews provide a foundation for identification of
areas requiring assessment, allowing the OT to gain an
understanding of the life story of the person with demen-
tia. Interviews may be conducted with the person suffer-
ing from dementia, their caregivers, family members and
other relevant persons. Caregivers and family members are

frequently interviewed in order to obtain a collateral history
and understand their views on the person’s functioning.
Building rapport, basic counselling skills, use of interpret-
ers, adapting communication and language use in response
to the caregiver’s level of education and communication
deficits are common approaches used during interviews to
assist in developing therapeutic relationships and obtaining
information. Interviews may be used instead of observation
or standardized assessments when time or funding prohibit
more comprehensive assessment.
19.3.1.2 Observations
The functioning of a person suffering from dementia may
be observed when participating in work, daily living and
leisure activities that are relevant to them. Observational
assessments provide a flexible approach to identifying
functional performance issues (Alexander, 1994) and may
be completed at the pace and manner in which the person
is capable or accustomed. Where possible, observations of
functional performance are completed within the environ-
mental contexts familiar to the person, often during home
visits. This aims to minimize the patient’s anxiety, their
need to learn new skills and maximize their orientation.
19.3.1.3 Standardized tests
Assessment tools are often used by occupational therapists
in addition to the aforementioned methods to
●● Gain an objective and measurable picture of a person’s
performance in particular areas, including BPSD.
●● Assess the severity of cognitive or occupational dys-
function compared to a normative group.
●● Establish a baseline measure of functioning against
which subsequent assessments may be compared,
e.g. quantifying change or efficacy of interventions.
A wide range of tools exists for use of practitioners for
people who have dementia. They can be divided into cogni-
tive, functional performance, environmental, risk, quality
of life, caregiver and behavioural assessments. A selection of
assessments commonly reported in the occupational ther-
apy literature includes the following:
●● Cognitive and perceptual skill assessments: Mini-mental
state examination (Folstein et al., 1975); hierarchical
dementia scale (Cole and Dastoor, 1996); Lowenstein
occupational therapy cognitive assessment for geri-
atric population (Elazer et al., 1996); Allen cogni-
tive level screen (Allen et al., 2007); Allen diagnostic
module placemat (Earhart, 2006); revised memory and
behaviour problems checklist (Teri et al., 1992); execu-
tive function performance test (Baum et al., 2008);
Middlesex elderly assessment of mental state (Golding
and Cognitie, 1989) and Addenbrooke’s cognitive
examination – revised (Mioshi et al., 2006).
Occupational therapy in dementia care 201
●● ADL and leisure functioning: Assessment of motor and
process skills (Fisher, 2006b); perceive, recall, plan and
perform system of task analysis (Chapparo and Ranka,
2006); interview for deterioration in daily activities in
dementia (Teunisse and Derix, 1997); Barthel index
(Mahoney and Barthel, 1965); functional assessment
measure (Hall, 1997); functional independence mea-
sure (Guide from the Uniform Data Set for Medical
Rehabilitation, 1993); structured assessment of indepen-
dent living skills (Mahurin et al., 1991); activities of daily
living questionnaire (Johnson et al., 2004); daily activities
questionnaire (Oakley et al., 1991); kitchen task assess-
ment (Baum and Edwards, 1993); Lawton instrumental
activities of daily living scale (Lawton and Brody, 1969);
Bristol activities of daily living scale (Bucks et al., 1996);
functional activities questionnaire (Pfeffer et al., 1992);
Canadian occupational performance measure (Law et al.,
1991); Cleveland scale of ADLs (Patterson et al., 1992);
pool activity level instrument (Pool, 2008) and assess-
ment of living skills and resources (Williams et al., 1991).
●● Environmental and quality of care assessments: Safety
assessment scale (de Poulin et al., 2006); dementia care
mapping (Bradford Dementia Group, 1997); home envi-
ronment protocol assessment (Gitlin et al., 2002); safety
assessment of function and environment for rehabili-
tation (Oliver et al., 1993) and in-home occupational
performance evaluation (Stark et al., 2010).
●● Engagement: Expanded group activity form
(Thorgrimsen et al., 2002: expanded from Bender et al.,
1987); pool activity level instrument (Pool, 2008); activ-
ity in time and context (Wood et al., 2005) and positive
response schedule for severe dementia (Perrin, 1997).
●● Carer assessments: Zarit carer burden interview (Zarit
et al., 1980); perceived change index (Gitlin et al., 2006);
task management strategy index (Gitlin et al., 2002);
readiness to change (Gitlin and Corcoran, 2005) and
caregiver assessment of management problems (Gitlin
and Corcoran, 2005).
19.4 INTERVENTION
OT interventions focus on maximizing functioning, pri-
marily using adaptive or compensatory rather than rehabil-
itative approaches. Interventions are individually tailored,
reflecting the differences in the presenting issues and goals,
the stage of the person’s dementia, the need and abilities of
the caregiver and the results of the completed assessment
(Graff et al., 2006). Ongoing review of OT interventions is
required to ensure they best address the issues being expe-
rienced by patients and needs of the person with dementia
and their caregivers. Evidence supporting OT interven-
tions with the person and their caregivers is growing, with
many practices still guided by good clinical care principles
(Jensen and Padilla, 2011; Letts et al., 2011; Padilla, 2011a,
2011b; Thinnes and Padilla, 2011).
202 Dementia
19.4.1 THE USE OF ACTIVITIES
Activity interventions aim to preserve the person’s dignity
and self-esteem by successfully engaging them in meaning-
ful, required and purposeful activity that is congruent with
their occupational history, interests, roles and motivations.
Knowledge about the person, including their retained abili-
ties, allows the OT to modify and provide activities that best
fit their skills, throughout the disease trajectory. General
principles for activity interventions include the following:
●● Familiar and novel activities (Perrin et al., 2008):
Familiar activities provide continuity and familiarity
for the person with dementia, allowing them to partic-
ipate using well-learned skills. Activities can be used
to provide role continuity and reinforce identity in the
person, for example, a doll or child representational
therapy, pet therapy, domestic chores and men’s sheds
are helpful. Role-based activities become increasingly
important, as many roles are removed with the pro-
gression of dementia in the patient. On the other hand,
novel activities have fewer preconceived expectations
of performance potentially providing failure free
experiences. Robotic technologies (e.g. Paro) are an
example of novel activities that can increase interac-
tion, interest, pleasure and quality of life (Roger et al.,
2012; Klein et al., 2013; Moyle et al., 2013; Robinson
et al., 2013).
●● Simplifying activity demands and structure (Hellen,
1998; Padilla, 2011b): OT’s grade activities according
to the skills and abilities of the person. Reducing the
number of steps in an activity, providing assistance only
where needed and limiting choices to match the per-
son’s abilities, all reduce the task demand and support
successful occupational performance. Simplification
of tasks by caregivers has demonstrated improvements
in the person’s functioning and BPSD, decreasing the
number of upset and burdened caregivers, as well as
improved effect on patients (Gitlin et al., 2003, 2005).
Where OT skill is unavailable, Montessori activities
which offer a graded activity approach may be used to
increase engagement and reduce some BPSD (Camp,
2006; Lin et al., 2009; van der Ploeg et al., 2013). Care
should be taken to ensure the activity remains mean-
ingful for the person and not simply utilized to exercise
cognitive, perceptual and motor skills and to occupy
time.
●● Temporal adjustments (Pool, 2008): Allow the person
to set the pace and provide activities within a familiar
routine. When this is not possible, due to time limita-
tions, priority should be given to those which are most
important to the person.
●● Engage multiple senses (Pool, 2008): Activities that
engage the senses become increasingly important with
disease progression, affording opportunities for engage-
ment to those with severely impaired cognitive and
communication skills.
●● Experience and variety (Hellen, 1998; Truscott, 2004):
Activities provide opportunities for sharing experi-
ences, reminiscing, building friendship, giving pleasure,
allow emotional expression and creativity. The focus of
activities shifts from the product or outcome to the pro-
cess of doing. Variety of activity opportunities remains
important.
●● Physical activity (Thuné-Boyle et al., 2012): Access to
indoor and outdoor opportunities for physical activity
can assist in maintaining physical and mental function-
ing, along with managing BPSD.
●● Individualized (Padilla, 2011a; Robert Dooley and
Hinojosa, 2004): Caregivers can be engaged in providing
activities congruent with the person’s life story and tai-
lored to their interests, needs and abilities. Individualizing
activities can be cost effective, pleasurable for the person
and assist in reducing BPSD and in addition, benefit
the caregiver by reducing the time providing care and
improving their sense of confidence in their role (Graff
et al., 2006; Gitlin et al., 2008, 2009, 2010).
19.4.2 ENVIRONMENT ADAPTATIONS
Environmental adaptations involve changes to the physi-
cal, social and organizational/institutional environments
of the person with dementia and their carers. Modifying
environments can maximize the person’s occupational per-
formance by providing accessible opportunities for engage-
ment, compensating for skill deficits, utilizing strengths of
the patient, minimizing risk and managing BPSD (Cooper
and Day, 2003; Brawley, 2006; Padilla, 2011b).
Greater evidence exists for environmental interventions
in long-term care settings (Fleming and Purandare, 2010).
Despite this, many of the principles of environmental inter-
ventions are applicable across other care settings, including the
homes and throughout the disease trajectory. Environmental
intervention principles include the following:
●● Promoting comfort (Calkins, 2005): Preferred tempera-
ture, familiar furnishings and objects, appropriate
pressure care, preferred size of objects and familiar
caregivers provide comfort.
●● Optimal sensory stimulation (Calkins, 2004, 2005):
Sensory stimulation can be altered to meet the needs of
the person by changing the location or level of sensory
stimulation, e.g. reducing noise in the environment.
●● Contrasts and lighting (Brawley, 2006): Maximizing
contrast between items can optimize orientation to
and awareness of objects. Conversely, minimizing
contrasts can be used to camouflage or reduce cueing.
Glare, shadows, poor lighting levels and sudden lighting
changes should be addressed.
●● Cueing, shaping and compensating for occupational
performance issues (Cooper and Day, 2003; Brawley,
2006; Marcy-Edwards et al., 2005; Padilla, 2011b):
OTs prescribe and recommend adaptive equipment
to optimize the person’s functioning, address safety

concerns and reduce caregiver burden (Gitlin and Chee,
2006; Graff et al., 2006). These include shower stools,
grab rails, non-slip mats, hand held showers, com-
mode chairs, contrasting toilet seats, modified clothing,
large calendars, talking clocks, modified telephones
(with large photo buttons), contrasting crockery and
napery, modified cutlery, specialized seating, medica-
tion dispensing packs, personal alert alarms, isolation
switches for ovens and stoves, stove dial covers, smoke
and gas detectors, signs and labels. Structured routines,
development of activity specific areas, task-related items
placed in the task environment, furniture placement,
placement of photos and objects personally familiar to
the person may be used to cue and support the person’s
engagement. Objects may be removed or disguised to
be as unobtrusive as possible. This can reduce cueing or
allow use of objects where engagement is not desired or
is unsafe. Finally, environments should make sense, be
visually accessible, contain familiar aspects and provide
clear cues for what is expected of the person (Fleming
and Purandare, 2010).
●● Simplification (Calkins, 2004): Reducing clutter and dis-
tractions can minimize the complexity of the environ-
ment, reducing the demands placed on the person.
●● Privacy (Brawley, 2006): Provision of privacy during
PADLs and other activities remains crucial to caring for
the person with dementia.
19.4.3 WORKING WITH FAMILIES
AND CARERS
Caregivers have a crucial role in facilitating the person’s
occupational performance. This role changes with disease
progression in the patient. Interventions with caregivers
aim to improve their confidence and role performance and
reduce burden by
●● Building on the caregiver style of caring and increas-
ing their willingness to utilize interventions (Corcoran,
2011; Gitlin and Corcoran, 2005).
●● Building caregiver capacities to understand, care for
and support continued engagement of the person with
dementia in meaningful activities.
●● Supporting caregiver to attend to their occupational
roles and needs.
Elements of the OT intervention process with caregivers
include flexibility, affording choice, making small changes
gradually, providing education and information that is rel-
evant and timely, encouraging caregiver breaks, drawing on
their experiences as an expert on the person with dementia,
validating their experience, readjusting interventions based
on the caregiver’s feedback and both written and multi-­
sensory learning to communicate the recommended inter-
ventions (Josephsson et al., 2000; Graff et al., 2003; Gitlin
and Corcoran, 2005; Egan et al., 2006; Letts et al., 2011;
Occupational therapy in dementia care 203
Thinnes and Padilla, 2011). This process minimizes excess
disability for the person by assisting caregivers often through
role play or modelling, to learn skills and generate strategies
effectively matching their communication, approach and
assistance to the person’s abilities. Finally, OTs assist in min-
imizing disruption to the caregiver’s occupational identity
by encouraging use of support services and engagement in
meaningful activities (Hasselkus and Murray, 2007).
19.4.4 MANAGING BPSD
The emergent paradigms for understanding and treating
BPSD view these symptoms as arising from unmet needs,
difficulties coping with stress, reinforced learning and
changes in pathology (O’Connor et al., 2009; see Chapters 8
and 9). The OT model of practice provides scope for under-
standing the multifactorial and changing aetiology of BPSD
and intervening in a patient’s care in a caregiver-centred
manner. Through this model, OTs view BPSD as arising
from poor fit or mismatch between the environment and/or
occupation and skills and attributes to the person, many of
which are listed in Section 19.3.1. Short-term OT interven-
tions modifying the aspects of the activity and environment
and building caregiver capacities have demonstrated ben-
efits for the person and caregivers (Gitlin et al., 2001, 2003,
2005, 2008, 2009, 2010; Graff et al., 2003, 2006, 2007). But,
OTs require training in this area to maximize intervention
outcomes (Voigt-Radloff et al., 2009, 2011). OT interven-
tions focus on identifying triggers and optimizing fit and
use many of the principles and approaches outlined earlier.
Additional principles include the following:
●● Utilization of the BPSD: Some behavioural symptoms
can be effectively utilized. Pacing may be provided with a
purpose through engaging the person in physical activi-
ties such as sweeping, going for a walk outside or cleaning
windows. An apron customized to include multi-sensory
occupational opportunities may be used to reduce cloth-
ing removal due to ‘fiddling’ with shirt buttons where
discomfort is not the triggering issue. Finally, where the
BPSD can be understood in the context of the person’s
previous occupational identity, jobs may be provided that
addresses this need. For example, tactile floor tiles may
be laid out for the person who previously was a tiler and
now crawls around feeling the floor surface.
●● Refocussing attention: Providing a person with an
alternate purposeful activity that is not reliant on
cognitive processing, or placing them in an alternate
environment, can assist in distracting and shifting their
behaviour from the BPSD.
●● Environmental placement: Environments influence and
often engender particular behaviours (Law et al., 1996).
For example, libraries, churches and playschools are
areas associated with quieter activity. Environments can
be manipulated to promote or cue alternate behaviours.
In some cases, positioning in the environment can cue
BPSD. For example, for a person who has difficulty
204 Dementia
sitting long enough to consume their meal, distracting
them away from changes in visual stimuli (people walk-
ing by) can assist in reducing cues that encourage them
to get up and walk away.
Thorough assessment is always required when faced with
BPSD. Reversible causes should always be treated and inter-
ventions should be individualized, risk addressed and the
caregiver supported in understanding, responding and cop-
ing with the BPSD. Finally, OTs should regularly review
interventions to ensure the current trends and address the
issues of concern.
19.5 CONCLUSION
Whilst the specific role of the OT differs across settings
and is based on the severity of the person’s dementia and
surrounding issues, occupational dysfunction remains a
common theme. OTs are skilled in assessing and provid-
ing unique individualized and responsive interventions that
address performance issues and BPSD experienced by the
person suffering from dementia. Addressing these issues
assists in optimizing functioning and maximizing the qual-
ity of life of the patient and their caregiver.
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Speech and language therapy in dementia
assessment and management
BRONWYN MOORHOUSE AND CAROLINE A. FISHER
20.1 INTRODUCTION
Communication is integral to successful living (Lubinski,
1991); however, in dementia its breakdown is well docu-
mented. People with dementia (PWD) live for up to 20 years
after diagnosis and require help with communication to
optimize quality of life (Bourgeois, 2002), circumvent com-
munication related behaviour problems and reduce care-
giver burden (Savundranayagam et al., 2005). This chapter
outlines cognitive-linguistic deficits seen in dementia and
the assessments used by Speech and Language Therapists
(SLTs) to examine them. It explores how SLTs can help PWD
and their carers to optimize interactions, and discusses safe
eating and swallowing. This chapter highlights, and further
advocates for, the ongoing need for SLT services in dementia
diagnosis and care.
20.2 COGNITIVE-LINGUISTIC AND
OROMOTOR CHANGES IN
DEMENTIA
Subtle changes in language functioning occur as part of
normal ageing. Word-finding difficulties and reductions
in confrontation naming, verbal fluency and spelling
have been observed in a number of studies from the sixth
decade of life onwards (Au et al., 1995; Stuart-Hamilton
and Rabbitt, 1997; Machulda et al., 2013). Grammar sim-
plification and reductions in the understanding of complex
(written) language begin from the middle of the eighth
decade (Bayles and Tomoeda, 2007). Beyond normal age-
ing, more pronounced language changes are observed
208
20
across many of the cortical dementia syndromes, and are
often diagnostically important for differentiating between
underlying dementia pathologies. The following sections
outline these changes.
20.2.1 MILD COGNITIVE IMPAIRMENT
Mild cognitive impairment (MCI) captures the juncture
between normal ageing and dementia. MCI is diagnosed
in individuals who experience subjective cognitive difficul-
ties, as well as mild cognitive reductions on neuropsycho-
logical assessment, but experience no significant difficulties
with activities of daily living (Gauthier et al., 2006). MCI
includes amnestic, non-amnestic and multi-domain sub-
types (Petersen and Negash, 2008) and having MCI places
individuals at up to 50% risk of developing dementia, within
5 years (Gauthier et al., 2006).
Over the last decade, research into early language
changes in MCI has increased significantly. Semantic
category fluency performances often differentiate those
with MCI from normal controls (see Taler and Phillips,
2008, for a review). However, deficits in letter fluency
performances also occur frequently, with some studies
showing differences according to MCI subtypes (Brandt
and Manning, 2009; Carter et al., 2012; Weakley et al.,
2013). Deficits in naming in MCI often contribute to a diag-
nosis of non-amnestic and multi-domain MCIs. A number
of studies have reported poorer naming in people with
MCI than controls (Taler and Phillips, 2008; Carter et al.,
2012). Naming deficits may predict higher likelihood of
future dementia, although outcomes differ depending on
MCI subtype and dementia syndrome (Testa et al., 2004;
Belleville et al., 2014). In conversation, reductions in the
use of thematic information (Harris et al., 2008) and the
 Speech and language therapy in dementia assessment and management 209
quality of complex discourse production (Fleming, 2014)
have also been observed. Further, subtle input processing
deficits have been observed in auditory, reading and oral
spelling comprehension (Tsantali et al., 2013).
20.2.2 ALZHEIMER’S DISEASE
Alzheimer’s disease (AD) is the most common neurode-
generative syndrome. There are significant primary deficits
in memory functioning and secondary difficulties in other
cognitive domains, including language, which restrict daily
functioning (Dubois et al., 2010). From a language perspec-
tive, word-finding difficulties in early AD are common.
Conversation is often vague and semantically empty (Bayles
and Tomoeda, 2007). Communication is usually successful
for brief periods, but breaks down during lengthy interac-
tions (Haak, 2002). Basic language comprehension is often
intact (Bayles et al.,1992) but may show some decline for
longer grammatically complex sentences (Clark, 1995), or
material requiring inference (Fried-Oken et al., 2000) or
abstraction (Haak, 2002). Poor memory and executive func-
tioning in AD increase conversational repetition, and reduce
topic maintenance and adherence to turn-taking conven-
tions (Watson et al., 1999). Oral reading, reading compre-
hension, spelling and writing are often relatively spared, but
written passage generation is poor (Bayles et al., 1992; Haak,
2002). On standard language tests, individuals with early AD
exhibit similar but more pronounced difficulties than those
with MCI, especially in the areas of verbal fluency, naming,
comprehension (auditory, reading and oral spelling) and
narrative output (Carter et al., 2012; Tsantali et al., 2013).
As AD advances, communicative intent and general
message frameworks are still evident in the moderate
stages; however, utterances are depleted of content words
(Haak, 2002) and are less concise with reference errors
abounding (Bayles and Tomoeda, 2007). Due to pervasive
lexical retrieval difficulty, generic labels (e.g. ‘thing’) often
replace content words (Bourgeois, 2002) and the person
may withdraw or speak excessively (Clark, 1995). Automatic
and social phrases may be retained, but people often forget
what they wish to say (Haak, 2002) or repeatedly ask the
same questions (Byrne and Orange, 2005). Paraphasias,
confabulations and non-words appear and discourse break-
down increases with poor propositional topic development,
difficulty changing topic and maintaining discourse flow
(Mentis et al., 1995; Fried-Oken et al., 2000; Bayles and
Tomoeda, 2007). In the very later stages, language output
may breakdown altogether, with people eventually becom-
ing mute (Bourgeois, 2002). Language input processing is
also affected as AD advances. Comprehension of complex
grammar deteriorates and abstract interpretation is lost,
although the understanding of one- (Haak, 2002) and
sometimes two-stage (Fried-Oken et al., 2000) commands
can remain preserved until very later stages. In these stages,
reading comprehension and writing are often limited to
single words (Haak, 2002) and accuracy is reduced (Bayles
et al., 1992).
20.2.3 HIPPOCAMPAL SCLEROSIS (HS) –
AGEING SUBTYPE
In later old age, there is a second neurodegenerative disease
that is characterized by significant memory problems. The
primary features of HS, ageing subtype, are hippocampal
atrophy and significant memory problems in the absence of
seizure activity (cf. HS due to temporal lobe epilepsy). HS
is difficult to distinguish from AD and increases in preva-
lence from the age of 85 years (Nelson et al., 2011). On cog-
nitive evaluation, HS bears a number of similarities to AD
with significant deficits in new learning and memory, and
reductions in language measures, including confrontation
picture naming and verbal fluency (Corey-Bloom et al.,
1997; Nelson et al., 2011). Two studies have indicated that
verbal fluency performances may be less affected in HS than
AD (Zabar et al., 1998; Nelson et al., 2011). However, this
finding is not consistent across studies, with confrontation
naming (Zabar et al., 1998) and short-term auditory atten-
tion, also being identified as distinguishing cognitive fac-
tors between HS and AD.
20.2.4 VASCULAR DEMENTIA (VAD)
Rates of cerebrovascular pathology increase with age. In
some individuals the degree of pathology is significant and
causes notable cognitive impairment. When these changes
are progressive, resulting in cognitive impairments that
significantly affect functioning, VaD may be diagnosed.
Autopsy series have indicated, however, that VaD as a ­solitary
pathology is less common, and usually occurs comorbidly
with other neurodegenerative conditions, particularly AD
(Barker et al., 2002). In VaD, individual deficit profiles vary,
depending on infarct locations, and are less uniform across
language areas than with AD (Hopper and Bayles, 2001).
Nonetheless, Vuorinen et al. (2000) found little difference in
moderate AD and VaD group averages for deficits in com-
prehension, naming and description tasks. While, Powell
et al. (1988) reported greater motoric speech involvement in
VaD (e.g. dysarthria and intonation changes).
20.2.5 DEMENTIA WITH LEWY BODIES
(DLB)
The primary clinical features of DLB are progressive c­ ognitive
decline, fluctuating attention and alertness, recurrent visual
hallucinations and parkinsonian motor features (McKeith
et al., 1996). DLB also has a high level of co-mor­bidity with
AD (McKeith et al., 1995). Impaired language output in
DLB is common, but the rates and nature of impairment in
‘pure’ DLB compared to ‘pure’ AD differ across studies. It
is generally ­associated with poor verbal fluency (letter and
semantic ­category), due to difficulties with attention and set
maintenance, variable naming performances and difficulties
on semantically based activities (Hamilton et al., 2008). Often,
mild extrapyramidal features (e.g. dysarthria and dysphagia)
are also observed (Tomoeda, 2001).
210 Dementia

20.2.6 FRONTOTEMPORAL DEMENTIA
(FTD)
FTD is an umbrella term for neurodegenerative condi-
tions causing language and/or behavioural decline, with
the underlying neurodegenerative changes localized to the
frontal and temporal lobes (Grossman, 2002; Rohrer and
Rosen, 2013). There are four well-described subtypes of this
condition. These are behavioural variant FTD (bvFTD) and
the three primary progressive aphasia (PPA) syndromes –
nonfluent PPA (nfPPA), logopenic PPA (lPPA) and semantic
PPA (sPPA).
Behaviour changes are the most prominent feature
of bvFTD. They include marked alterations in personal-
ity, impulsivity, disinhibition, inappropriate or offensive
remarks, hyperorality and changes in dietary preferences
(Pressman and Miller, 2014). The degree and nature of the
cognitive dysfunction in bvFTD is variable. Many cases
show little cognitive impairment in the early stages; how-
ever, impairments in memory, executive function and lan-
guage domains are seen at times, particularly as the disease
progresses (Piguet et al., 2011). Specific language difficulties,
when present, have been found to occur with verb naming
in the early and later stages, on tasks requiring seman-
tic processing similar to sPPA, and are described below
(Harciarek and Cosentino, 2013).
The remaining three FTD syndromes are characterized
by language decline, with the nature and severity of the
aphasia progressing over time. The language features of each
syndrome are described below, and the main distinguishing
features are summarized in Table 20.1 (where information
has been collated from Gorno-Tempini et al. (2004, 2011)
and Harciarek and Cosentino [2013]). Non-fluent PPA is
characterized by halting, non-fluent speech and articula-
tion difficulties. Speech fluency is reduced and problems
with sentence construction and syntax also become appar-
ent. Although not always observed, sentence level auditory
comprehension deficits have been documented with com-
plex sequential commands and syntactic constructions
(Grossman et al., 1996; Hodges and Patterson, 1996; Blair
et al., 2007; cf. Gorno-Tempini et al., 2004). Despite initial
divergent presentations, evidence suggests that nfPPA pro-
gresses towards eventual mutism at a more rapid pace than
in AD (Kertesz et al., 2003).

Table 20.1 Language features of the primary progressive aphasias by subtype

Subtype
Areas of Deficit nfPPA sPPA lPPA
Apraxia of speech ✓ – –
Agrammatism in ✓ – –
spontaneous speech
Speech fluency ✓ – ✓
Sentence construction ✓ – –
Syntax ✓ – –
Pragmatics of language – ✓ –
Phonologic paraphasias – – ✓
Repetition of single/short ✓ – –
words
Repetition of sentences ✓ – ✓
Letter fluency ✓ ✓ ✓
Semantic fluency ✓ ✓ ✓
Confrontation naming ✓ ✓ ✓
Object knowledge – ✓ –
Semantic matching – ✓ –
Auditory word recognition – ✓ –
Sequential commands ✓ – ✓
Syntactic comprehension ✓ – ✓
Single-word comprehension – ✓ –
Surface dyslexia – ✓ –
Surface dysgraphia – ✓ –
Sources: Gorno-Tempini, M.L. et al., Neurology, 76, 2011; Harciarek, M. and Cosentino, S. International Review of Psychiatry, 25, 2013;
Gorno-Tempini, M.L. et al, Annals of Neurology, 55, 2004.
Abbreviations: lppa, logopenic primary progressive aphasia; nfPPA, nonfluent primary progressive aphasia; sPPA, semantic primary progres-
sive aphasia.
✓ Represents commonly found areas of deficit (mild, moderate or severe).

✓ An area of difficulty that is a defining feature of the disorder.

– An area where deficits are not generally observed.

 Speech and language therapy in dementia assessment and management 211
sPPA is characterized by impaired functioning on all
activities that are dependent on semantic knowledge (see
Table 20.1). Confrontation picture naming and semantic
category verbal fluency performances are both impaired
at a more severe level than in nfPPA, lPPA and AD. Poor
matching of picture-based semantic associations is seen on
tasks such as the Pyramids and Palm Trees Test (Howard
and Patterson, 1992). Repetition is generally well preserved
along with speech fluency in conversation and articulation,
while single-word comprehension is reduced. However, as
the disease progresses, difficulty with pragmatics, including
turn-taking, thematic perseveration and interruptions may
develop (Kertesz et al., 2010).
lPPA is characterized by word retrieval deficits in spon-
taneous speech, moderately impaired confrontation nam-
ing abilities and marked difficulty with sentence repetition,
but relatively spared single-word repetition (see Table 20.1).
Fluency of spontaneous speech in lPPA is affected, due to
frequent word-finding difficulties, but agrammatism is not
observed. Phonological paraphasias are also frequently
noted.
20.3 COGNITIVE-LINGUISTIC
ASSESSMENTS USED IN
DEMENTIA
In diagnosing the presence and type of dementia, individ-
ual profiles of cognitive-linguistic functioning ideally form
a part of a memory clinic evaluation (Ames et al., 1992).
Accurate early dementia diagnosis is crucial in identifying
strengths and weaknesses for optimal informational coun-
selling, some interventions and effective care plan devel-
opment. It also allows for establishment of baselines for
intervention effects or decline over time (Tomoeda, 2001).
Appropriate cognitive-linguistic normative data help to
distinguish those with early dementia from the ‘worried
well’ (Bryan et al., 2001). Normative data are essential for
determining whether difficulties represent actual deficits,
or are within the performance distribution seen in nor-
mal ageing. An individual’s academic and occupational
history should also be taken into account, along with esti-
mated premorbid intelligence quotient (IQ) (if known from
neuropsychological assessment). Premorbid IQ can affect
performance on a variety of language activities, includ-
ing confrontation naming, verbal fluency and token tasks
(Steinberg et al., 2005), while education level can affect the
diagnostic utility of verbal fluency tasks in differentiating
normals and those with MCI or early dementia (Radanovic
et al., 2009).
The best known cognitive-linguistic assessment designed
specifically for dementia assessment is the Arizona Battery
for Communication Disorders of Dementia (ABCD)
(Bayles and Tomoeda, 1993). It assesses mild-to-moderate
dementia across five constructs: linguistic comprehension,
linguistic expression, verbal memory, visuospatial skills
and mental status. Although developed in the United States,
ABCD norms have also been found appropriate with UK
(Armstrong et al., 1996) and Australian (Moorhouse et al.,
1999) samples. The Barnes Language Assessment (BLA)
(Bryan et al., 2001) assesses mild, moderate and sometimes,
severe dementia. It examines expression, comprehension,
reading and writing, memory and executive functions
using items adapted from existing tests. A third tool, the
Progressive Aphasia Severity Scale (PASS) (Sapolsky et al.,
2014), quantifies impairments across 13 speech, language,
pragmatic and functional communication domains. It
is particularly useful for distinguishing PPA subtypes
and determining deterioration in language over time and
requires skilled clinical judgements of language function-
ing, based on domain specific language test performances
(discussed below).
In addition to general language batteries, SLTs can also
utilize individual speech and language tests to compre-
hensively examine a language skill in more detail often
using normative data most appropriate to the population
being assessed. Examples include the Boston Naming Test
(BNT) (Kaplan et al., 2001), the Controlled Oral Word
Association Test (COWAT) (Strauss et al., 2006), the
Sentence Production Test (SPT) (Wilshire et al., 2014), the
Putney Auditory Comprehension Screening Test (PACST)
(Beaumont, 2002), the Psycholinguistic Assessments of
Language Processing in Aphasia (PALPA) (Kay et al., 2009)
the Pyramid and Palm Trees Test (PPT) (Howard and
Patterson, 1992) and the Cambridge Semantic Memory
Test Battery (Adlam et al., 2010). Tests of functional and
pragmatic language skills may also be useful, particu-
larly for shaping therapeutic intervention, examples of
these include the Functional Linguistic Communication
Inventory (FLCI; Bayles and Tomoeda, 1994), the
Communication Outcome Measure of Functional
Independence (COMFI) (Santo Pietro and Boczko, 1997)
and the Latrobe Communication Questionnaire (LCQ)
(Douglas et al., 2000).
20.4 OPTIMIZING COMMUNICATION
IN DEMENTIA
It is useful to conceptualize communication interventions
in dementia in terms of the International Classification of
Functioning, Disability and Health (ICF) (World Health
Organization [WHO], 2001) (Byrne and Orange, 2005).
Interventions are described below with reference to this
framework. Irrespective of intervention level and the chal-
lenges involved, every effort should be made to involve
those with PPA (Croot et al., 2011), PWD and/or their regu-
lar communication partners in collaborative goal setting
(see Volkmer, 2013 for detailed discussion).
212 Dementia
20.4.1 ICF, DISABILITY AND HEALTH
IMPAIRMENT-DIRECTED
INTERVENTIONS
Impairment-directed approaches to restore communica-
tion often involve relearning or maintenance of the abil-
ity to name specific word groups or learn key information
in PWD. Spaced retrieval training (SRT) (using recall at
g radually increasing intervals) (Abrahams and Camp,
­
1993; Brush and Camp, 1998), or coaching on picture
description and word category assignments (Arkin and
Mahendra, 2001) facilitated performance on specific tasks
with some­maintenance over several weeks (Abrahams and
Camp, 1993). More recently, Hopper et al. (2010) exam-
ined SRT in learning face-name associations primarily in
AD. Some participants could learn and relearn semantic
information, however, associations faded within 6 weeks.
Limited recent studies examining specific impairment-
directed therapy may reflect an emphasis shift of commu-
nication interventions for more global dementias to other
ICF levels, where carry over is more likely to be enduring
(discussed below).
Conversely in PPA, recent impairment-directed studies
have proliferated; however, due to rarity of this disorder,
participant numbers in individual studies remain small
and findings somewhat anecdotal. As for more common
dementias, therapeutic efficacy may be gauged by stabil-
ity or slowed deterioration as well as improvement (Croot
et al., 2011). Acquisition and retention patterns may also
vary according to PPA type (Newhart et al., 2009). Jokel
and Anderson (2012) found that errorless word relearning
precipitated better performance and maintenance in sPPA.
Reviews of PPA naming therapy studies also revealed
promising immediate and maintenance results; however,
potential for generalizability requires further research
(Carthery-Goulart et al., 2013; Jokel et al., 2014). Savage
et al. (2014) reported generalization of relearned names
on a specific description task in sPPA; however, circum-
stances leading to conversational generalization remain
uncertain. In an individual with nfPPA, Henry et al.
(2013) found that after simplification and repetition inter-
ventions for speech sound and syllabic errors, oral read-
ing and picture description inaccuracies remained below
pretreatment levels for 6 months or longer. Beeson et al.
(2011) used graded semantic feature analysis followed by
generative naming tasks – an intervention designed to tax
lexical retrieval on demanding tasks to facilitate retrieval
in more functional contexts in an individual with lPPA.
They found significantly improved naming post-treatment
and at 6-month follow-up indicative of both maintenance
and some generalization. Interestingly comparison of
functional magnetic resonance imaging (fMRI) before
and after treatment showed marked activation in the left
dorsolateral prefrontal region (consistent with strategic
planning and monitoring of l­ exical retrieval), not engaged
during pretreatment scanning. Graham (2014) reviewed
the promising but limited findings regarding spelling treat-
ments in lPPA and discussed need for additional research
to elucidate appropriate dysgraphia therapies across PPA
types. Tsapkini et al. (2014) found that phoneme-to-
grapheme conversion training augmented by non-invasive
transcranial direct current stimulation in nfPPA or lPPA
improved spelling on untrained items, which was mostly
maintained at 2-month follow-up.
20.4.2 ICF, DISABILITY AND HEALTH
ACTIVITY AND PARTICIPATION-
DIRECTED INTERVENTIONS
These interventions aim primarily to optimize the func-
tional communication of PWD. Clark and Witte (1991)
advocated adaptive strategy training in early AD – e.g.
saying ‘Please repeat exactly what you just said’ or ‘Give
me a little time. I’m having trouble finding the exact
words’ or ‘I forgot what we were discussing’. They also
suggested self-cueing strategies (e.g. using circumlo-
cution or semantically related words) and teaching of a
script strategy for simple storytelling (e.g. theme, char-
acters, setting and events) to improve cohesion and topic
maintenance in AD (Clark, 1988 – cited in Clark and
Witte, 1991). Carers reported maintained or increased
functional communication and aphasia test scores that
were stable for 6 months.
Group programmes using residual communication
strengths with tangible stimuli may also be beneficial.
Santo Pietro and Boczko (2001) used procedural memories
to facilitate communication in residents with AD. During
‘breakfast clubs’ members used greetings, discussed and
chose food, helped one another prepare ingredients, set
the table, made general conversation, cleaned up and said
goodbye. SLTs provided visual and semantic cues, paired
choices and trigger phrases to facilitate choice making.
Participants improved significantly on the ABCD and also
had more self-initiated on topic comments per session, more
cross-conversation exchanges and increased procedural ini-
tiation. Matched controls in a conversation group, showed
either no gains or slight declines.
Several studies have examined activity/participation-
directed therapies in PPA. Cartwright and Elliot (2009)
facilitated comprehension of a half-hour TV documentary
in four people with PPA using techniques including initial
topic priming, pausing to allow clinician-facilitated updat-
ing of a whiteboard plot summary and a clinician-supported
feature analysis guide sheet. Between pre- and post-test (on
different episodes with opportunity to independently use
the guide sheet), participants retold significantly more infor-
mation units, approaching performance of controls. Kindell
et al. (2013) analysed spontaneous adaptive facial, spatial
and tone-of-voice–based enactment in one individual with
sPPA. They concluded that examining adaptive strategies
that facilitate conversational repair may be a fruitful place
to begin therapy. Wong et al. (2009) had previously initiated
 Speech and language therapy in dementia assessment and management 213
this type of work and argued, given ultimate progression,
that it makes sense to focus on conversational effective-
ness because such strategies remain useful in later stages of
sPPA. They targeted use of residual (automatic) verbal and
non-verbal abilities along with props in a discourse-based
intervention with an individual with sPPA. The communi-
cation partner was educated to interpret underlying non-
verbal messages and facilitate multimodal message delivery
to both herself and other conversation partners. This indi-
vidual continued to participate in conversation despite dis-
ease progression.
20.4.3 ENVIRONMENTAL SUPPORTS TO
COMMUNICATION
Conversation is collaborative. Where one partner has
AD, the other can use strategies to optimize interaction
(Muller and Wilson, 2008). People with mild AD should
be ­encouraged to speak (even when having word-finding
­difficulties) and urged to use spared communicative abilities
to reinforce self-worth – e.g. reading to a grandchild (Haak,
2002). When optimizing comprehension, the partner should
match language complexity to individuals (Haak, 2002) –
initially, using slightly slower speech and reduced informa-
tion (Bourgeois, 2002) and with progression, conversing
about tangible things, ­simplifying vocabulary, using non-
verbal cues and restating messages when they are not under-
stood (Bayles and Tomoeda, 2007) or forgotten (Enderby,
2002). Before s­tarting, it helps to orient the PWD to topic
and then maintain and extend (Kessler et al., 2001). In later
dementia, ­questions with alternatives (e.g. ‘do you want fish
or chicken?’), short ­utterances and names (rather than pro-
nouns) are useful (Haak, 2002). Demonstration to aid com-
prehension, ­avoiding sarcasm and innuendo, use of native
language and familiar wording (e.g. respectful title or maiden
name) also promote ­conversation. When confusion occurs,
carers should r­eintroduce themselves (Haak, 2002). Use of
­questionnaires (e.g. LCQ; Douglas et al., 2000) r­egarding
communicative behaviours are useful not only in under-
standing PWD, but also in ­giving SLTs insights into ­effective
interventions for individual c­ ommunication ­partners. These
types of ­interventions bear many similarities with ‘Supported
Conversation’ now widely used in n ­ on-progressive aphasia
(Kagan et al., 2001) and also being introduced for PWD
(see Volkmer, 2013 for detailed discussion). Carers are likely
to benefit from such training protocols along with more
dementia-specific programmes described below.
Santo Pietro (2002) highlighted SLTs’ role in training
trainers or care staff to use effective communication in a
‘teaching by modelling’ paradigm, which identifies envi-
ronmental supports and barriers to effective communica-
tion. The FOCUSED programme for carers, uses role-play
to emphasize strategies based on an interactive discourse
model – F: face-to-face, O: orient to conversation topic, C:
continue the topic, U: unstick communication blocks, S:
structure questions, E: exchange conversation and D: direct
short sentences (Ripich and Wykle, 1996). Ripich et al.
(2000) found that 6 months post-training, when planning
a menu together, FOCUSED trained carers asked signifi-
cantly more yes/no and choice questions (associated with
successful communication outcomes) than did controls.
A DVD-based carer training programme titled RECAPS
and MESSAGE (acronyms to prompt memory and com-
munication strategies) was developed by Smith et al. (2011).
It provides information on memory and communication
necessary in everyday life and commonly preserved and
affected abilities across dementia stages. It includes acted
vignettes demonstrating strategies and scenarios to prompt
strategy use. Evaluation of efficacy among professional car-
ers revealed significant increases in knowledge about sup-
port strategies and some increases in carer satisfaction
(Broughton et al., 2011).
Bourgeois (1992) evaluated use of personalized memory
wallets to enhance communication in AD. Wallets con-
tained individualized simple written information, draw-
ings and photographs. After role-playing, carers used
wallets to facilitate discussion about ‘day’, ‘family’ and
‘yourself’. During training and maintenance, participants
made novel on-topic statements and fewer ambiguous utter-
ances. Most participants used their wallets spontaneously
to initiate conversations. Haight et al. (2006) evaluated out-
comes when care staff used similar ‘Life Story Books’ with
15 PWD. Intervention resulted in significantly improved
scores compared with controls on depression, mood, mental
status and communication scales. Bourgeois (2013) further
outlines evolution of memory books and their usefulness
in enhancing conversation, communicating basic needs
and reducing challenging behaviours. Because senses of
smell and taste may be relatively preserved in later demen-
tia, stimulation via spice jars, scratch and sniff books, or
ethnic foods (Lubinski, 1991; Bourgeois, 2002) or having a
pet or a toy present (Hopper et al., 1998) may also facilitate
communication.
Fried-Oken et al. (2012) outlined three treatment goals
for Augmentative and Alternative Communication (AAC)
use in PPA – compensating for progressive language loss
(rather than skill recovery), starting early while learning is
still possible and including key communication partners in
training. Initially, SLTs may support usage of appropriate
electronic communication devices or develop individually
tailored communication books with specific information,
questions and text or gestures to reduce communication
breakdown. As PPA progresses, SLTs should work with
individuals and partners to develop AAC devices such as
talking photo albums or tablets with AAC applications to
express choices, needs and feelings. In later stages, with
minimal functional language, partners can support par-
ticipation by carrying conversation content and presenting
limited choices.
Talking Mats are an innovative, accessible and inex-
pensive system supporting people with limited communi-
cation in giving information, making decisions or setting
goals. Structured topics are presented to support compre-
hension and expression. Three sets of pictorial symbols
214 Dementia
(topic, options and visual scale) are used. The person places
relevant options under the visual scale (e.g. happy, unsure,
not happy), which is photographed for further reference.
Murphy et al. (2005) found Talking Mats assisted seven
PWD and minimal speech express to views on activ-
ity themes by supporting communication and reducing
memory load. Use of talking mats to discuss problems with
daily living (‘managing’, ‘needing assistance’, ‘not manag-
ing’ scale) was also more effective than usual communica-
tion modes (Murphy and Oliver, 2013). SLTs have a crucial
role to play in supporting PWD (particularly those with
disproportionate language decline in PPA) to participate
in capacity and decision making assessments. This support
usually involves tailored use of AAC (see Volkmer, 2013 for
detailed discussion).
In late dementia, when many individuals become
non-intentional communicators (see Bloomberg et al.,
2009), SLTs can work with carers to make ‘personal
­communication ­dictionaries’ (PCDs) (Siegel and Whetherby,
2000). Compilation of PCDs requires careful observation
and ­documentation of consistent non-verbal behaviours –
‘What the person does’ (e.g. takes your hand and pulls it
towards his mouth), ‘What it might mean’ (e.g. ‘I’m hungry
or thirsty’), ‘What you should do’ (e.g. give food or drink if
­appropriate). PCDs are especially useful when staff do not
know the ­person, but may also help familiar carers ­structure
observations to best meet individual needs and reduce
­ 2011). If there is no medical living will, guardians should
­problem behaviours. PCDs should be easily accessible for
reference and amendment.
20.4.4 PERSONAL AND ENVIRONMENTAL
BARRIERS TO COMMUNICATION
Rejecting optimal communication strategies can cre-
ate unnecessary barriers (Byrne and Orange, 2005).
Furthermore, for PWD, Palmer et al. (1999) reported signif-
icantly reduced problem behaviours after hearing aid fitting
while Lemke (2011) outlined strategies to reduce audiologi-
cal assessment challenges. Vision should also be corrected,
background noise limited, lighting optimized (Enderby,
2002) and dignity and cultural sensitivity maintained
(Lydall-Smith et al., 1996). Poor management of medical
conditions and drug regimens can also hinder communi-
cation (Clark, 1995). Although physical space is often lim-
ited and opportunities for solitude or intimacy are rare,
socialization can also be minimal (Lubinski, 1991). Some
attitudes should also be challenged, e.g. ignoring those with
severe communication issues (Lubinski, 1991).
20.5 EATING IN DEMENTIA
Mid-to-late dementia individuals often develop malnutri-
tion, weight loss and/or dehydration. Bourgeois and Hickey
(2009) stress that SLTs must consider dysphagia along with
other precipitating factors, e.g. distractibility, reduced
initiation, poor eating environment and limited mealtime-
assistance. Recently, the issue of bland institutional food has
been addressed by some organizations (e.g. Morgan-Jones
et al., 2014), but remains a widespread problem. SLTs also
have a role in ensuring optimal oral hygiene particularly
when PWD have significant risk of aspiration pneumonia
and especially when they drink free (unthickened) water
under controlled circumstances (Karagiannis et al., 2011).
SLTs assess oropharyngeal function to reduce choking and
aspiration risk (e.g. by modifying consistencies or position-
ing) (Gillick and Mitchell, 2002). Although SLTs may use
instrumental examinations to investigate dysphagia, PWD
often cannot cooperate with such procedures (Gillick and
Mitchell, 2002). A percutaneous endoscopic gastrostomy
(PEG) tube is sometimes inserted to administer nutrition
directly into the stomach when PWD can no longer swallow
safely or reject food or drink (Gillick and Mitchell, 2002).
Although many consider withholding food cruel, people
appear to experience little thirst or hunger at life’s end
(Bourgeois and Hickey, 2009). PEG limitations include diar-
rhoea and nausea in 10% of people, tubes frequently being
pulled out (Gillick and Mitchell, 2002) and insufficient evi-
dence of increased survival rates (Sampson et al., 2009).
Some individuals with an ‘unsafe swallow’ can still tolerate
oral intake if optimal assistance and positioning are main-
tained and consistencies are carefully monitored (Cullen,
decide based on what they believe the PWD would have
chosen for themselves. As part of a team, SLTs should pro-
vide family with clear information regarding PEGs versus
other options (e.g. mouth swabs), so they can make the best
decision for their relative (Gillick and Mitchell, 2002).
20.6 CONCLUSIONS
In recent years, knowledge about SLTs’ role in assessing and
managing dementia has increased. There is greater under-
standing of PPA and of AAC to facilitate interactions and
better use of the ICF framework to promote communica-
tive participation. There is also greater awareness of issues
around eating in dementia. However, there is an ongoing
need to broaden the evidence base for SLT interventions
in PWD. Single case investigations require collection of
lengthy baseline as well as intervention data, while group
studies require strict selection criteria and well-matched
control groups (Lum, 2001).
The upcoming demographic explosion of PWD is well
recognized. Consequently SLTs have developed policy posi-
tion papers, submissions to governmental enquiries and
detailed examinations of service provision (e.g. Taylor et al.,
2009; Speech Pathology Australia [SPA], 2012; Torresi et al.,
2012; Royal College of Speech and Language Therapists
[RCSLT], 2014). These publications reflect increasing
acknowledgement of the specialist role SLTs have to play in
direct service provision and workforce training. Recently,
 Speech and language therapy in dementia assessment and management 215
such services have improved in the United Kingdom; how-
ever, issues regarding equity of access persist (RCSLT, 2014).
In Australia, denial of optimal communication intervention
for many older Australians living in care facilities remains
an issue (SPA, 2014). As such, there is an ongoing need for
professional associations to use research findings to further
advocate for equity of access to SLT services for those living
with dementia in all its forms.
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Role of the physiotherapist in the management
of dementia
SUE LORD AND LYNN ROCHESTER
21.1 INTRODUCTION
Physiotherapy (and exercise) plays a key role in preserva-
tion of movement in people with cognitive impairment and
dementia, with evidence to suggest that exercise may also
be protective of future decline in memory. Over the past
decade, understanding of the role of cognition in motor
control has increased with consequences for independent
and safe mobility and this knowledge provides a strong
rationale for physiotherapy intervention. Recognition of the
trajectory of cognitive impairment assists in understanding
the role of physiotherapy across the continuum, which is
adapted to suit personal factors such as age, ethnicity, pre-
existing comorbidities and environment – all of which may
act as barriers or facilitators for the patient.
This chapter outlines physiotherapy treatment for people
with cognitive impairment and dementia and provides a
model to guide implementation of the same. First, we pro-
vide an overview of physiotherapy in dementia manage-
ment and then outline specific physiotherapy interventions.
A clinical framework for physiotherapy is presented and a
problem-oriented approach to key impairments is discussed.
The term ‘physiotherapy’ is extended to include ‘exercise’
and ‘activity’ and the term ‘dementia’ is used throughout
to denote Alzheimer’s disease (AD), Parkinson’s disease
with dementia (PDD), Lewy body dementia, frontotem-
poral dementia and vascular dementia. General principles
of physiotherapy are broadly applicable to all dementias,
however, we also highlight specific techniques. We consider
cognitive impairment along with a continuum of severity,
from mild cognitive impairment to dementia and whilst it is
beyond the scope of this chapter to systematically examine
220
21
the evidence for physiotherapy in dementia, we have referred
to current literature where appropriate.
21.2 ROLE OF THE PHYSIOTHERAPIST
Physiotherapy has its roots in movement science and views
movement as central to health and well-being. The role of
the physiotherapist is to maximize independence and par-
ticipation in work, family and society activities through
preservation of motor and cognitive functions. What is
becoming clear increasingly is that physiotherapists should
be involved in the management of people with cognitive
impairment right at the very outset of signs, rather than
restrict input to the later stages of the disease, which has
been the traditional approach. Often, the role of physiother-
apy is one of consultation with reference to external service-­
providers and education is a key focus. Identification of
services and personnel in the early stages is likely to include
gym referrals, personal trainers and community classes.
Over time, these will be supplanted by physiotherapy assis-
tants, dementia ‘buddies’, carers and support workers. In
the early stages there is less need for ‘hands-on’ physiother-
apy but this changes as expert handling and facilitation is
required to ensure optimal positioning, safe transfers and
mobility and comfort. Behavioural changes, altered mood,
loss of motivation and poor compliance impact on the
receptivity of physiotherapy as disease progresses and its
utility is questioned. Priorities of management will lie else-
where. Throughout the disease, physiotherapy must be rel-
evant and suited to an individual’s context and needs, skill
and experience is required to optimize input. Figure 21.1

MCI/Mild
Maintain physical Continue with MCI/mild
capacity aims and add
Strength Reduce carer
Balance burden
Endurance Reduce falls risk
Flexibility Manage
Maintain cognitive behavioural change
capacity
Maintain mobility
Maintain independent
ADL
Maintain leisure
activity
Figure 21.1 Broad aims of physiotherapy across the stages of dementia.
outlines the broad aims of physiotherapy across the spec-
trum of cognitive decline and Figure 21.2 projects how these
aims might be achieved.
21.3 INTERVENTION APPROACHES
FOR DEMENTIA
21.3.1 EXERCISE
The mainstay of physiotherapy management is exercise,
delivered in a variety of modes and combinations to suit the
personal preference of the individual, the stages of demen-
tia and the context. The aims of exercise are to maintain
physical capacity, particularly, strength and balance, which
are integral to effective locomotion. The benefits of exer-
cise are threefold. First, exercise helps to maintain physi-
cal and cognitive capacity to maintain/optimize physical
performance in activities of daily living (ADL), and thereby,
promote independence and quality of life. Second, exercise
helps avoid the secondary consequences of decondition-
ing associated with reduced mobility and a sedentary life-
style. Third, an emerging body of evidence suggests that in
the initial stages of dementia (mild cognitive impairment
[MCI] and mild dementia) exercise may have an important
role to play to maintain cognitive function or capacity. Each
of these features is considered and outlined in detail in the
following.
21.3.1.1 Exercise: maintenance of motor
performance
Almost undisputedly, exercise improves physical and
cognitive performance in older adults. Most exercise pro-
grammes, whether of low or high intensity, general or spe-
cific, are able to show a positive physiological response. For
people with cognitive impairment or dementia, improved
Role of the physiotherapist in the management of dementia 221
Moderate Severe
Reduce carer burden
Reduce falls risk
Delay
institutionalisation
Reduce secondary
risks of immobility
Train carer/staff in
effective moving and
handling
outcomes have been reported for a range of gait outcomes
and mobility, strength and power, balance and activities
of daily living (for reviews see Pitkala et al., 2003; Forbes
et al., 2013). However, the translation from improvement in
impairment to gains in function and levels of activity is not
automatic (Chin et al., 2008) and physiotherapists need to
be aware of personal, contextual and environmental factors
that impede translation of gains to daily functions. Early
intervention is likely to yield greater benefits before demen-
tia is established because the potential for motor learning
is greater and compensation more effective. Targeting gait
dysfunction and falls risk in mild cognitive impairment and
treating this aspect as a prodromal stage for dementia may
ultimately yield to greatest benefits.
21.3.1.2 Exercise: prevention of secondary
deconditioning and secondary
age-related risk factors
The protective effect of sustained physical activity over
the life span is well recognized, even in older adults who
participate in physical activity at a later stage in life.
­
Guidelines advocate that people living with chronic dis-
eases remain active to mitigate multi-system deconditioning
brought about by increased sedentary behavior (Thompson
et al., 2003), which is an independent risk factor for poor
health outcomes. The definition of ‘activity’ in the guidelines
is broad and includes walking, dancing, exercise classes,
circuit training etc. Counter-intuitively, sedentary behav-
iour and activity yield quite different cellular and molecular
responses. One is not the inverse of the other and the impact
of sedentary lifestyle on vascular integrity, cardiovascular
health and diabetes has been reported often (Manns, 2012).
Implications from this body of research are that preservation
of activity is critical for as long as possible. Beyond subtle
physiological responses, increased sedentary behaviour also
impacts on muscle tissue and loss of joint integrity. Over
time, there is an inability to carry out previously rehearsed
222 Dementia
Disease stage Possible interventions
Activities Exercise
MCI • Dancing • Strength
• Endurance
• Balance and coordination
• Flexibility
• Complex motor/cognitive
training
Mild • Computer games • As above
– with family
Moderate • Walking groups • As above with adaptations
and supervision (e.g. seated
exercise for postural
instability)
Severe • Gym or NA
community
exercise groups
Figure 21.2 Examples of possible interventions to address physiotherapy aims with respect to the stages of dementia.
Abbreviation: MCI, mild cognitive impairment.
sequences of movement simply because the action is not
repeated often enough.
Several questions remain unanswered with respect to
exercise, most notably the dosage, intensity and timing of
it. Provision of a standardized exercise protocol is almost
impossible given the range of variables that impact the out-
come of their implementation on the patient. As a guide,
exercise three times a week for 30 minutes, over 6–8 weeks
should yield benefits and if improvement is not evident after
this, then it is unlikely to be worth extending the interven-
tion. Securing a behavioural change is the ultimate goal of
any exercise intervention, but this is ultimately challenging
for people with cognitive impairment who may also have
associated mood disorders and reduced motivation. The
potential to ensure carry over from exercise to daily, func-
tional tasks must be recognized and encouraged, so that
regular practise ensues. Intensity must be sufficient to chal-
lenge motor performance. For example, although exercise
is overall protective for first fall in dementia (Allan et al.,
2009), Sherrington (Sherrington et al., 2008) reported that
it was not effective in reducing falls in people with demen-
tia who were living in care homes, possibly because the
exercises were mostly in sitting position, which has limited
effect on postural mechanisms. With respect to timing, the
earlier the intervention, the greater the gains, which in turn
are more likely to be sustained in future. Physiotherapy is
often administered too late, when deconditioning and attri-
tion of habitual motor patterns impair function.
21.3.1.3 Exercise: protection of
cognitive function
Guidelines for healthy ageing emphatically include exer-
cise as a protective agent for cognitive decline, which has
been extended to include people with cognitive impairment
and dementia. Longitudinal studies suggest a causal link
Functional training Compensatory strategies
• Transfers • Cueing
• Complex sequences • Prompting
• Diary reminders
• As above • As above
• Training carers to cue and
prompt the patient
• Training care staff needed • Training care staff needed in
in moving and handling moving and handling the
the patient patient
between higher levels of physical activity and reduced risk
of cognitive decline and dementia, with a recent meta-anal-
ysis reporting an 18% reduction in risk of cognitive decline
and dementia due to physical activity (Blondell et al., 2014).
There is evidence to suggest cognitive retraining alone has
a positive impact on selected features of cognition in cog-
nitively impaired older adults (Forbes et al., 2013) and a
review of 15 studies reported a benefit of cognitive train-
ing for people with dementia over and above any medica-
tion effect (Woods et al., 2012). More recently, arguments
have been put forward for combining motor and cognitive
retraining strategies (see the following). Given the close
relationship between cognition and gait and the compen-
satory role of cognition in maintaining gait performance
improved benefits seem plausible, however, further studies
are required to evaluate single component versus multicom-
ponent interventions.
21.3.2 COMPENSATORY STRATEGIES
Compensatory strategies develop in response to motor
impairment and reflect versatility of the motor system to
adapt effectively (Shumway-Cook and Woollacott, 2007).
Use of compensatory strategies to bypass deficits in motor
control is a feature of this versatility. However, timing of
introduction of compensatory strategies is critical because
once the new motor pattern is established it will become the
default pattern and this expediency does not always produce
the most efficient movement. Movement patterns become
ingrained often prior to retraining or relearning has been
attempted. A simple illustration is the use of hand support to
attain sit to stand/stand to sit, which becomes increasingly
difficult with age but is amenable to ­retraining. The goal is
achieved at the expense of decreased concentric and e­ ccentric
muscle work, abnormal postural control ­strategies, reduced
preparedness for safe walking. People with ­dementia show
 Role of the physiotherapist in the management of dementia 223
retained capacity for implicit motor learning ­(van Halteren-
van Tilborg et al., 2007) and also through explicit ­learning
techniques, via observational learning and ­learning through
guidance (van Tilborg et al., 2011). Cognition is used to
enhance use of ­compensatory strategies and is used to good
effect via attentional ­mechanisms or via use of overt cues or
prompts. Evidence supports the use of visual and auditory
cues to enhance gait in Parkinson’s disease (PD) (Nieuwboer
et al., 2007) and has the potential to be ­effective even as
­cognitive i­mpairment advances – especially if ­cueing skills
are embedded and taught earlier. Identifying the thresh-
old of cognitive impairment from which learning can be
achieved is difficult and compounded by associated features
such as reduced motivation, anxiety, depression and reduced
self-efficacy (Burn et al., 2006).
21.3.3 NOVEL INTERVENTIONS
Current interventions reflect the contemporary view
­outlined in the following that motor control (especially
gait and balance) is underpinned by neural substrates,
which are partly shared by cognitive networks (Thom
and Clare, 2011). Approaches vary from specific dual task
retraining programmes to general activities, with a recent
­systematic review reporting benefit of a combined approach
(Lee et al., 2015). Schwenk reported greater improve-
ment in gait p ­ erformance from cognitive and gait tasks
(dual-task t­raining) compared to a programme of exer-
cises only (Schwenk et al., 2010). Dance is gaining momen-
tum as an intervention (Kattenstroth et al., 2013) and
although, ­evidence of efficacy for both dance and music
as therapy in dementia is lacking (Vink et al., 2004) there
is some ­support for a positive impact on behaviour and
­socialization (Guzman-Garcia et al., 2013). Technology is
used to good effect. In a recent review of physical and cog-
nitive ­interventions in ageing, Bamidis et al. (2014) argued
for the use of exergaming (computer games that require
intense physical activity), which may be appropriate in the
very early stages of cognitive decline.
21.4 A CLINICAL FRAMEWORK FOR
PHYSIOTHERAPY: INTERPLAY
BETWEEN COGNITIVE AND
MOTOR SYSTEMS
Recent evidence in the field of motor control provides a
strong rationale for physiotherapy intervention. Neural
systems that underpin cognitive function are also impli-
cated in the control of movement, thus, strengthening the
link between cognition, gait and falls in dementia. This ‘top
down’ control is evident even in cognitively healthy older
adults (Lord et al., 2014). Gait is not an automatic motor
task, independent of cognition, as previously believed. Use
of a dual task research paradigm (e.g. walking whilst reciting
numbers) reveals the extent to which cognition (primarily
attention) is used (Verlinden et al., 2014). A seminal study
by Lundin-Olsson (1997) showed an increased risk of falls
for older, cognitively impaired adults who stopped walk-
ing whilst talking compared with those people who could
successfully carry out both tasks simultaneously. Some
features of motor control are selectively associated with
cognitive impairment. There is, for example, a functional
relationship between the hippocampus, which degenerates
early in amnestic pathology (evidenced by loss of short-term
memory) and spatial disorientation via visual, vestibular
and proprioceptive loss, which leads to gait disturbance
(Scherder et al., 2007). Because of this close relationship,
gait has predictive value for future cognitive decline, as evi-
denced by large community cohort studies and a threshold
for pathological gait (gait speed below 1 m/s) has been iden-
tified from the predictive models (Studenski et al., 2011).
Recent evidence supports the sensitivity of a motoric risk
syndrome (combined motor and cognitive outcomes) to
predict future cognitive decline (Verghese et al., 2014). The
relative contribution of cognitive function to gait, balance
and falls in dementia is likely to be higher than contribu-
tion from other neural systems such as sensorimotor func-
tion, however, this has not been examined yet. Figure 21.3
contrasts traditional and current views of the association
between motor and cognitive function and its consequences
and provides a theoretical basis to development of novel
interventions that challenge motor and cognitive systems
simultaneously (see the following).
21.5 A PROBLEM-ORIENTED
APPROACH TO PHYSIOTHERAPY
We consider the main problems that physiotherapists
address: gait and postural control, falls, transfers and seat-
ing. We take an evidence-based approach to inform man-
agement of these problems and consider the underlying
mechanisms of motor impairment in cognitive decline.
We then complete this section by considering some of the
­complications that arise with dementia that are likely to
impact physiotherapy. For a summary of selected resources,
see Table 21.1.
21.6 GAIT AND POSTURAL CONTROL
Gait impairment is common in older adults, with 35% pre-
senting a clinically observable deficit (Studenski, 2012).
Global features of gait (such as gait speed) are sensitive to all
dementias and also sensitive to severity of cognitive impair-
ment. Goldman et al. (1999) reported a slower gait veloc-
ity for people with AD and moderate dementia (Clinical
Dementia Rating (CDR) Scale: CDR stage 1) compared with
mild dementia (CDR stage 0.5). The prevalence and sever-
ity of gait disorders is also dependent upon the dementia
224 Dementia

(a) Traditional view

Slow gait velocity

Instability Falls - fractures

MCI
Cognitive impairment Dementia

(b) Alternative, emerging view

Slow gait velocity

Instability Falls - fractures

Cognitive impairment MCI

Executive function–working memory
Dementia

Figure 21.3 Traditional and contemporary views of the decline in cognition and mobility and their consequences.
(a) Traditional view. (b) Alternative, emerging view. (From Montero-Odasso, M. et al.: Gait and cognition: A comple-
mentary approach to understanding brain function and the risk of falling. Journal of the American Geriatrics Society, 60,
2127–2136, 2012. Copyright Wiley-VCH Verlag GmbH & Co. KGaA. Reproduced with permission.)

Table 21.1 Resources for physiotherapists

Reviews Dementia and physical therapy (Blondell, et al., 2014)
Cognitive stimulation to improve cognitive functioning in people with dementia (Woods et al., 2012)
Exercise programmes for people with dementia (Forbes, et al., 2013)
Music therapy for people with dementia (Vink et al., 2004)
Effects of combined cognitive and exercise interventions on cognition in older adults with and without
cognitive impairment: A systematic review (Law et al., 2014)
Efficacy of physical exercise intervention on mobility and physical functioning in older people with
dementia: A systematic review (Pitkala et al., 2013)
Educational CSP Physiotherapy Works: Dementia Care
resources http://www.csp.org.uk/publications/physiotherapy-works-dementia-care
Living well with dementia: A national dementia strategy
https://www.gov.uk/government/publications/living-well-with-dementia-a-national-dementia-strategy

subtype (Allan et al., 2005) (see Table 21.2), with it being the
greatest in Lewy body dementia (LBD), especially, PDD and
the lowest in AD. Other features of gait are specific to under-
lying pathophysiology and can be used to discriminate state
of diseases. For example, reduced step length and start hesi-
tation is a sign of a frontally mediated ‘cautious’ gait (Nutt
et al., 1993), whereas increased step asymmetry and reduced
step length is an indicator of PD gait. However, the aetiol-
ogy of gait disorder in 15%–30% of older adults diagnosed
with gait impairment is unclear (Kafri et al., 2013) and
the broad classification ‘high-level gait disorder’ (HLGD),
which exemplifies a shared gait and cognitive pathology, is
most often applied. An added complication to dementia is
the presence of white matter lesions (WML) and cerebro-
vascular disease (CVD), both of which contribute further
to gait disturbance, balance and falls (Inzitari et al., 2013).
A systematic review found that in AD gait impairment was
associated with a higher burden of WML with changes
associated with frontal–subcortical lesions and atrophy
and hypometabolism of the hippocampus (Annweiler et al.,
2012). It is important to keep these features in mind when
assessing gait and using gait as a tool for differential diag-
nosis of different forms of dementia. Physiotherapists have a
key role to play in informing diagnosis and disease progres-
sion in this way.
Although physiotherapy has a positive effect on a
range of balance and gait deficits in dementia (Shaw et al.,
2003; Christofoletti et al., 2008), the preservation of ‘nor-
mal’ gait and amelioration of specific gait deficit is not a
primary focus for intervention even in the early stages.
Instead, a more global approach is required. The empha-
sis is on functional mobility such as encouraging out-
door walking or community exercise classes. As a result
of these interventions, improvement in at least some gait
characteristics is likely to occur without them being tar-
geted at, specifically.

Table 21.2 Annual prevalence and incidence of falls (falls/1000 persons) and prevalence of gait and balance disorders in
different dementia subtypes
Controls AD
Prevalence (%) 36 47
Incidence 1,023 2,486
(falls/1000
people)
Gait disorder, 3/42 (7) 10/40 (25)
N (%)
Source: Allan, L.M. et al., PloS One, 4, e5521, 2009; Allan, L.M. et al., Journal of the American Geriatrics Society, 53, 1681–1687, 2005.)
Gait and balance disturbances are important risk
factors for falls with a higher prevalence in demen-
tia compared with non-demented older adults (Tinetti
and Williams, 1998; Shaw, 2002; Allan et al., 2009).
Preservation of effective balance is critical but challeng-
ing. Use of tai chi and other balance-specific interven-
tions have been reported to improve postural control in
older adults (Logghe et al., 2010), although to our knowl-
edge this has not been replicated in people with cogni-
tive decline and dementia. Improvement in balance, gait
and functional mobility is likely to be a positive spin-off
from general exercise and activity and maximum gains
may be achieved by taking a broader approach. What is
evident is the added burden apparently placed by gait and
balance disorders on falls risk in dementia, highlighting
the complex relationship between gait, balance, cognition
and falls.
21.7 FALLS
The consequence of falls in older adults with dementia is
drastic and includes an increased risk of serious injury
(Kallin et al., 2005), institutionalization (Morris et al., 1987)
and mortality (Morrison et al., 2000). Remaining mobile
and free from falls is a therapeutic priority in older adults
and those with dementia and understanding falls in demen-
tia is of critical importance to mitigate the burden caused
not only to the patient, but also the carer (Lowery et al.,
2000). People with dementia are two to three times more
likely to fall than age-matched healthy counterparts, with
institutionalized adults also at a higher risk compared with
community living adults (Kropelin et al., 2013). Figures
vary, but overall suggests a prevalence of around 40% for
community dwelling adults (Allan et al., 2009) and 60%
for people living in residential care (Eriksson et al., 2008).
Falls risk is highly dependent upon the type of dementia,
with highest incidence and prevalence occurring in people
with dementia associated with Lewy body dementias (LBD
and PDD) (Table 21.2) (Allan et al., 2009). Fall-related inju-
ries are also greater in LBD while Lewy body disease and
Role of the physiotherapist in the management of dementia 225
VAD DLB PDD PD
47 77 90 61
3,135 9,087 19,000 4,617
31/39 (79) 43/46 (93) 24/32 (75) 20/46 (43)
Parkinson’s disease are identified as risk factors for falls in
patients with dementia. A second risk factor relates to medi-
cation with polypharmacy, identified as a risk factor for falls
in older adults (Neutel et al., 2002). Psychotropic medica-
tions increase somnolence, confusion and loss of awareness
of surroundings and antidepressants are also associated
with falls risk. Treatment of falls in dementia is challeng-
ing. There is no convincing evidence to mitigate falls risk
in dementia, however, current evidence points to the need
for targeted selection of participants and individualized
therapies. A recent pilot study reported 32.6% reduction in
falls and decreased agitation in people with dementia living
in a residential care home through the use of personalized
interventions based on behavioural and cognitive profiles
(Bharwani et al., 2012).
21.8 TRANSFERS AND POSITIONING
As disease progresses even simple functional tasks such as
sit to stand, bed mobility and transfers from bed to upright
standing position is challenging. Independent mobility
effectively ceases and supervision and assistance is required
to facilitate movement. Loss of movement is due to cognitive
rather than pure motor decline. Effective movement is more
likely to occur if complex sequences of movement are bro-
ken down into a series of sub-movements, which are carried
out in a consistent manner by all staff handling the patient,
with repetition critical to success. In the earlier stages, men-
tal preparation of movements prior to their execution may
also be helpful. Physiotherapy in the later stages is centred
on ensuring safe mobility and 24-hour comfort via optimal
positioning. Vital to successful physiotherapy at this stage
is input from multidisciplinary team members who provide
expertise and options for seating. Contoured chairs and
low beds may be useful and semi-recumbent positioning
in a wheelchair may promote better head control and pos-
ture. A sensitive approach is required to balance the need
for restraint with comfort and freedom, with evidence to
suggest a key role of education in appropriate application of
restraint in late-stage dementia (Testad et al., 2005).
226 Dementia
21.9 COMPLICATIONS IMPACTING ON
PHYSIOTHERAPY
Behavioural disturbances in the later stages are challenging
to work with. Aggression, frustration, diminished commu-
nication and mood disturbances (depression, anxiety) are
problematic to deal with and can result in futile encoun-
ters. In future, attention will be paid to how physiotherapy
is administered – choosing a suitable environment, use of
language, command and facilitation. Identifying sources
of discomfort and pain is also challenging and it is not
always apparent how much to encourage a movement when
it appears to cause distress. Use of a standardized assess-
ment of pain and discomfort (Kovach et al., 2001) may help
clarify the situation, but this remains an important feature
of dementia management.
21.10 MEASUREMENT
Because dementia is a progressive disorder, use of out-
come measures is not routine. It may be required at
discrete time points, for example, to monitor change in
performance over a predefined period of time for a spe-
cific reason, or to measure response to an intervention.
Estimation of ‘true change’ over and above measurement
error is difficult, given the natural course of the disease.
The repertoire of standardized, generic measures com-
monly used in physiotherapy can be applied to people
with dementia, such as gait and balance measures, func-
tional mobility outcomes, activities of daily living scales
etc. Measurement at the level of activity and participation
rather than impairment is advised. Measurement of carer
burden may be appropriate alongside quality of life mea-
sures. If the intervention focusses on improving cogni-
tive performance, measurement of cognitive function is
relevant.
21.11 SUMMARY
Emerging evidence supports physiotherapy in the man-
agement of dementia throughout the disease process with
research to support efficacy even in advanced stages of the
disease. Physiotherapy is adapted to suit the individual at all
stages of dementia with a strong focus on maintenance of
physical activity in the early stages where exercise is consid-
ered to have a neuroprotective effect. The role of the physio-
therapist throughout the disease is mostly consultative and
effective liaison with all personnel involved in the care of
the person with dementia is essential.
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Therapeutic effects of music in persons with
dementia
LINDA A. GERDNER AND RUTH REMINGTON
Awake, arise, listen to the song of life … At first all may seem confusion … but wait, strive to catch the deeper melody, for the
song its there.
22.1 BEHAVIOURAL AND
PSYCHOLOGICAL SYMPTOMS
OF DEMENTIA
The presence of agitation or behavioural and psychologi-
cal symptoms has been reported as high as 90% in persons
with Alzheimer’s disease or related dementias (ADRD)
(Fernández et al., 2010). Agitation interferes with care
delivery and social interaction, ultimately having a nega-
tive impact on the person’s quality of life (Léger et al., 2002;
Sloane et al., 2004; Samus et al., 2005). Management of these
behaviours has been identified as a major stressor to health-
care professionals (Brodaty et al., 2003). For this reason
much of the research that has evaluated the effects of music
in persons with dementia (PWD) has focused on agitation
as the primary outcome variable.
The presentation of music can be grouped into the fol-
lowing three categories: classical music or music believed
to be calming or relaxing, individualized or preferred
music, and music activities implemented by a certified
music therapist.
22
Albert J. Atkins
A Song of Life, 1905
22.2 CLASSICAL MUSIC OR MUSIC
BELIEVED TO BE CALMING/
RELAXING
Calming music (CM) has been shown to reduce agitation
in nursing home residents (Remington, 2002; Hicks-Moore,
2005). The response to calming or relaxing music is related
to the qualities of the musical sound that produce a cogni-
tive and physiological response in the participant, whereas
familiar music relies on the emotional response to the music
to achieve the effect (Remington, 2002). In research, music
chosen for its calming qualities has been referred to as an
experimenter-centred approach, minimizing response
bias in studies (Elliot et al., 2011). Characteristics of music
that have been shown to be relaxing include a slow tempo,
80–100 beats per minute (Elliot et al., 2011). It has also been
suggested that a tempo less than the resting heart rate is
more calming (Watkins, 1997), whereas a faster tempo
heightens arousal (Ziv and Dolev, 2013). A constant, subtle
rhythm with a regular beat played at a constant volume and
in a major key was found to be relaxing (Elliot et al., 2011).
229
230 Dementia
Piano and strings are more calming than percussion or
brass instrumentation. Vocals are more likely to induce
memories and arousal (Remington, 2002; Ziv and Dolev,
2013).
Goddaer and Abraham (1994) hypothesized that ‘relax-
ing’ music would buffer the ‘general noise level’ found in
dining rooms in long-term care facilities, thus exerting a
calming effect that would reduce the frequency of agitated
behaviours in 29 persons with severe cognitive impairment.
Baseline data were collected during week 1. Music was
played in the dining room daily during the noon meal in
week 2. Music was removed during week 3 and reintroduced
during week 4. A modified version of the Cohen-Mansfield
Agitation inventory (CMAI) was used to measure the
dependent variable. Significant reductions were observed
on the cumulative incidence of total agitated behaviours
(63.4%) as well as the cumulative incidence of physically
nonaggressive behaviours (56.3%) and verbally agitated
behaviours (74.5%).
The findings of this study were replicated using a smaller
sample of subjects (n = 10) residing in a special care unit
(Denny, 1997). Classical music was played from 11:45 am
to 1:15 pm daily during weeks 2 and 4 in the dining room
during the noon meal. A modified version of the CMAI was
used to measure the dependent variable.
Tabloski et al. (1995) used a quasi-experimental design
with a convenience sample of 20 cognitively impaired nurs-
ing home residents to measure the effects of Kobialka’s
recording of Pachelbel’s Canon in D on the frequency of
agitation. The dependent variable was measured using the
Agitated Behavior Scale (Corrigan, 1989). Agitation was
assessed 15 minutes prior to the intervention, during the
15-minute presentation of music and throughout the 15
minutes following the presentation of music. The inter-
vention and assessment process were repeated approxi-
mately 1 week later. Repeated measure analysis of variance
(R-ANOVA) revealed a statistically significant reduction in
agitated behaviours during (p < 0.01) and after the music
intervention (p < 0.05).
Remington (2002) conducted a randomized controlled
trial to compare the effects of hand massage (HM) and
CM on the frequency of agitation in PWD. Agitated nurs-
ing homes residents were randomly assigned to one of four
groups (n = 17 each): (1) HM, (2) CM, (3) simultaneous
implementation of CM and HM or (4) control. A new age
arrangement of Pachelbel’s Canon in D was selected for
its calming qualities, such as a slow tempo of 52 beats per
minute (instead of 88–108 beats per minute in the original
orchestral arrangement), soft dynamic levels and repetitive
themes. The music did not contain recognizable lyrics or
melodies that might evoke emotional responses. Each group
received 10 minutes of the identified intervention with the
control receiving no intervention. The number of occur-
rences (frequency) and types of agitated behaviours were
recorded for 10 minutes on four occasions using a modi-
fied version of the CMAI immediately before the interven-
tion, during the intervention, immediately following the
intervention and again 1 hour following the intervention.
Findings report a statistically significant reduction in agi-
tated behaviours across all three experimental groups when
compared with the controls.
Using a repeated measures design, Thompson et al.
(2005) compared the effect of music (Vivaldi’s Four Seasons,
Winter) on language fluency in healthy older adults (n = 16)
and older adults with dementia (n = 16). Subjects were asked
to name as many examples of items in a category as they
could within 1 minute. Each subject was tested both with
music playing and without. Both the healthy subjects and
the subjects with dementia demonstrated a similar small
but significant improvement in performance when music
was played.
A reduction in agitation during mealtime was reported
in a quasi-experimental study involving 33 residents with
dementia in a special care unit. Residents were observed for
the number of agitated behaviours exhibited during the eve-
ning meal for 4 weeks. During weeks 1 and 3 no music was
played and during weeks 2 and 4 CM was played. The inci-
dence of agitated behaviours was decreased in weeks when
music was played compared with weeks when no music was
played (Hicks-Moore, 2005).
In an experimental study of the effect of a group music
intervention on agitated behaviours, Lin et al. (2011) found
a significant decrease in total agitation in the treatment
group. One hundred and four residents with dementia par-
ticipated in the study. The treatment group participated in
a 30-minute group music intervention twice a week for 6
weeks while the control group continued their usual daily
activities. The decrease in agitation was seen in each of
the four categories of agitated behaviours; physically non-
aggressive, physically aggressive, verbally non-aggressive
and physically aggressive. The effect of the intervention was
sustained at 1 month after the intervention (Lin et al., 2011).
The CMAI or a modified CMAI was used to measure agi-
tated behaviours in most of the music intervention studies.
The instrument and modification have demonstrated reli-
ability and validity and enable comparison across studies.
22.3 INDIVIDUALIZED MUSIC
Individualized music is defined as music that has been
integrated into the person’s life and is based on personal
preference (Gerdner, 1992). Extensive clinical experience
in combination with research findings led to the develop-
ment of a mid-range theory of individualized music inter-
vention for agitation (IMIA) (Gerdner, 1997). Elements
of the mid-range theory include cognitive impairment,
progressively lowered stress threshold, agitation and
individualized music. Cognitive impairment results in a
decreased ability to receive and process stimuli, resulting
in a progressive decline in the person’s stress threshold
(Hall and Buckwalter, 1987). Dysfunctional behaviours
such as agitation occur when the stress threshold is

exceeded (Hall and Buckwalter, 1987). Music may be used
as a means of communicating with this population even
in the advanced stages of dementia when the person
has difficulty or an inability to understand verbal lan-
guage and has a decreased ability to interpret environ-
mental ­stimuli. It is theorized that the presentation of
­individualized music (carefully selected music, based on
personal preference) will provide an opportunity to stim-
ulate remote memory. This changes the focus of atten-
tion and provides an interpretable stimulus, overriding
stimuli in the environment that is meaningless or con-
fusing. The ­elicitation of memories associated with posi-
tive feelings will have a soothing effect on the person with
dementia, which in turn will prevent or alleviate agitation
(Gerdner, 1997).
Primary propositions of this theory were tested using
an experimental repeated measures pre-test–post-test
crossover design that compared the immediate and resid-
ual effects of individualized music to classical ‘relaxation’
music relative to baseline on the frequency of agitated
behaviours in PWD. Thirty-nine subjects were recruited
from six long-term care facilities (LTCFs). An interview
guide was used to obtain specific information on the sub-
ject’s musical preference and to identify the importance of
music in the subject’s life prior to the onset of dementia.
If cognitive impairment precluded the subject from com-
pleting the form, a family member provided the informa-
tion. Group A (n = 16) received individualized music for 6
weeks followed by a 2-week ‘washout’ period and 6 weeks
of classical relaxation music, Group B (n = 23) received
the same protocol but in reverse order. Music interven-
tions were presented for 30 minutes, two times per week.
A modified version of the CMAI was used to measure the
dependent variable. An R-ANOVA with Bonferroni post
hoc test showed a significant reduction in agitation dur-
ing and following the presentation of individualized music
compared with classical music (Gerdner, 2000).
This seminal work served as the impetus for an expand-
ing body of research that supports the use of individu-
alized music for the management of agitation in PWD
(Ragneskog et al., 2001; Janelli et al., 2002; Suzuki et al.,
2004; Sung et al., 2006, 2008, 2010; Park and Pringle-Specht,
2009; Gallagher, 2011).
Japanese researchers (Suzuki et al., 2004) expanded
these efforts by adding functional and biophysiological
measures as well as behavioural outcome measures. The
study included 10 subjects with dementia who received
individualized or preferred music twice per week for 8
weeks. During the corresponding time period, 13 sub-
jects participated in a comparison intervention (games,
drawing, pasting pictures). Analysis, comparing baseline
with 1-week post-intervention scores, found that subjects
in the experimental group had a statistically significant
improvement in the ‘language’ subscale of the Mini-
mental State Examination (MMSE) and a statistically
significant reduction in ‘irritability’ as measured by the
Multidimensional Observational Scale. In addition, there
Therapeutic effects of music in persons with dementia 231
was a significant reduction in stress index as measured
by a salivary chromogranin A (CgA) following session
16. The authors concluded, ‘the changes in CgA levels
supported Gerdner’s mid-range theory’. No significant
findings occurred in the control group across outcome
measures.
Given its efficacy when implemented by research staff,
it is important to evaluate the effectiveness of individual-
ized music when implemented by trained staff and family
members. As a beginning, Gerdner (2005) conducted a pilot
study by using a mixed methodology that included both
quantitative and qualitative measures. After appropriate
training, staff and family played individualized music for
eight PWD living in an LTCF. The intervention was imple-
mented over a 4-week period. Individualized music was
played daily for 30 minutes at a prescribed time (prior to the
estimated ‘peak level’ of agitation). The mean rate of compli-
ance was 86.3%. In addition, staff administered music on an
as needed basis (when the PWD first began exhibiting signs
of agitation). Agitation was measured using a modified ver-
sion of the CMAI. A statistically significant reduction in
agitation was found during the immediate presentation of
music, with an overall reduction in agitation found on day
shift during weeks 1–8 and on evening shift during weeks
5–8. Staff and family interviews provided convergent valid-
ity to quantitative findings. In addition, staff and family
reported that individualized music provided a catalyst for
meaningful interaction between the person with dementia
and others.
Researchers in Taiwan evaluated nursing staff (n = 17)
knowledge and adherence to the evidence-based guideline
for individualized music. Initial training included an inter-
active educational programme. Ongoing reminders, a local
opinion leader and an audit checklist were used to facili-
tate and monitor continued adherence to the intervention
protocol. Comparison of pre- and post-test scores found a
statistically significant improvement (p < 0.001) in knowl-
edge of the intervention following the training session with
a mean compliance of 72% (Sung et al., 2008). In addition,
this study evaluated residents’ responses to individualized
music as measured by the CMAI (Sung et al., 2006). An
experimental group (n = 32) received individualized music
for 30 minutes, twice per week over 6 weeks, while the con-
trol group (n = 25) received usual care with no music. The
experimental group had a statistically significant reduction
in overall agitation (t = −2.19, p < 0.05) and physically non-
aggressive behaviours (t = −3.75, p < 0.0001) compared to
the control group.
Park and Pringle-Specht (2009) trained 15 family mem-
bers, caring for an older adult with dementia in the home,
on the use of the evidence-based guideline for individual-
ized music (Gerdner 2007). Outcome measures included the
modified CMAI. A quasi-experimental design was used in
which individualized music was implemented twice a week
for 2 weeks. There was a significant reduction in agitation
during the intervention period (p < 0.05) compared with
baseline and post-intervention periods.
232 Dementia
22.4 EVIDENCE-BASED GUIDELINE
An evidence-based guideline for the implementation of
individualized music was originally developed in 1996, was
refined over time and is now in the fifth edition (Gerdner,
2013). An evidence grade schema accompanies this guide-
line. The schema is used to assign a specific grade based on
the strength and type of evidence for each recommendation
within the guideline. An abridged version of the protocol
was originally developed for consumers in 2001 and has
been revised to accompany the most recent version of the
evidence-based protocol (Gerdner, 2015a).
The guideline describes the assessment criteria for use of
pre-recorded music for the purpose of alleviating agitation in
PWD. The assessment addresses the importance of ethnicity
in the identification of musical preferences. The importance
of ethnicity is underscored in a published case example of
a Mexican-American man who preferred guitar music that
reflected his ethnic heritage (Gerdner, 2015b). The guideline
also includes a recommendation for assessing the temporal
patterning of agitation so that the timing of the intervention
can be tailored to maximize the effects and benefits of the
intervention.
Importantly, the Oslo Resource Center for Dementia
and Psychiatric Care of the Elderly, under the direction
of Dr. Audun Myskja, implemented a previous version of
the evidence-based protocol for individualized music in
three nursing homes in Oslo, Sweden, and has incorpo-
rated the intervention into a complementary therapy mod-
ule designed with academic credits for a master’s degree at
Buskerud University College (GERIA, n.d.).
22.5 MUSIC THERAPY
Although the music interventions described above can be
utilized by professional and lay caregivers, music therapy
(MT) is a discipline in its own right. A music therapist
receives advanced training in music, psychology, physiol-
ogy and MT techniques and completes a clinical intern-
ship in a college degree programme (Parker, 2009). Music
therapy is presented to individuals or groups. Social inter-
action becomes an important part of the music session. The
therapist interacts with group members through singing,
eye contact and conversation between songs. Participants
benefit from the social stimulation from others in the group.
Familiar group singing during the sundowning period,
late afternoon and early evening, improved mood and social
behaviour in four nursing home residents with moderate
dementia who exhibited sundowning syndrome (Lesta and
Pelocz, 2006). Subjects’ mood and social behaviour were
assessed before, during and after a 30-minute group singing
intervention, using a facility constructed behaviour assess-
ment chart and a mood and social behaviour tool devel-
oped by the investigators. The authors concluded that the
increased positive social interaction exhibited by the sub-
jects supports Kitwood’s (1997) theory of personhood.
A group MT intervention reduced agitation in nurs-
ing home residents with dementia. Twenty subjects were
assigned to receive either 50 minutes of MT three times per
week for 15 weeks, or no experimental intervention. The
experimental group demonstrated a significant reduction
in agitated behaviours (Choi et al., 2009).
In a randomized clinical trial, Guetin et al. (2009) inves-
tigated the effect of individualized MT sessions on anxiety
and depression in adults with mild to moderate dementia.
Subjects were randomly assigned to the treatment group
(n = 15) receiving weekly sessions of individualized MT or
the control group receiving weekly reading sessions for 16
weeks. The individualized MT sessions used music of a style
chosen by each subject. Subjects in the experimental group
were exposed to a 20-minute sequence with a progressive
reduction in rhythm, frequency and volume followed by a
‘re-enlivening’ phase. Subjects were assessed for measures
of anxiety (Hamilton Scale) and depression (Geriatric
Depression Scale) at weeks 1, 4, 16 and 24. Results indicated
that anxiety was significantly improved in the MT group at
week 4 (p = 0.002) and week 16 (p = <0.001). The effect was
sustained for 8 weeks after withdrawal of the intervention
(p = 0.0002). A non-significant difference in depression was
reported for weeks 4 and 8, however, a significant reduction
in depression from baseline was observed in the MT group
by week 24 (p = 0.03). Although the sample appeared small,
it was determined by power analysis to be adequate for a
level of significance of 0.05 and power of 0.9.
Ziv et al. (2007) examined the effect of background
music on both positive and negative behaviours in a sample
of 28 nursing home residents with dementia. Positive, nega-
tive and neutral behaviours were recorded on an investiga-
tor developed scoring sheet for two 17-minute periods, one
with music and one without music. The music interven-
tion consisted of popular music from 1964, assumed to be
familiar to the subjects. Results indicated that more positive
behaviours and fewer negative behaviours were exhibited
while music was played (p = 0.001). There was no difference
in the frequency of neutral behaviours.
In a pilot study, Brotons and Marti (2003) examined
the effect of MT in 11 patients with probable Alzheimer’s
disease and their caregiver. In a residential setting, sub-
jects (patients) received 10 MT sessions over 12 days, four
alone and seven with their caregiver. Caregivers perceived
improved social behaviours (50%), emotional state (67%)
and physical/motor activity (33%). Most caregivers (66.7%)
reported feeling more relaxed after MT sessions. Anecdotal
observations reported include improved expressive lan-
guage, improved short-term memory and spontaneous
social interaction following MT.
Ueda et al. (2013) conducted a systematic review and
meta-analysis on the effects of MT on behaviour and psy-
chological symptoms in dementia (BPSD). Twenty studies
were selected including randomized controlled trials, con-
trolled clinical trials, cohort studies and controlled trials

and conducted a meta-analysis using standardized mean
differences (SMD). Findings showed that MT had small
effects on BPSD (SMD, –0.49; 95% confidence interval,
–0.82 to –0.17, p = 0.02).
22.6 CONCLUSIONS
Most research evaluating the effects of music in PWD has
been conducted in LTCFs. There is an obvious need to
expand these research efforts to other healthcare environ-
ments. Outcome measures have focused on the observa-
tion of agitated behaviours. There is also need to expand
these efforts through biophysiological measures. With the
emphasis on a reduction in negative behaviours there is also
need to develop ways to quantify the positive behavioural
response that has been noted anecdotally. Finally, feasibil-
ity studies are required to evaluate the cost effectiveness of
implementing music in PWD.
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Psychological, behavioural and psychosocial
interventions for neuropsychiatric symptoms
in dementia: What works, what does not and
what needs more evidence?
GILL LIVINGSTON AND CLAUDIA COOPER
23.1 INTRODUCTION
The neuropsychiatric symptoms of dementia (see Chapters
7 and 8) include disturbed perception, thought, mood or
behaviour (Finkel et al., 1996). Effective treatment is a pri-
ority as clinically significant neuropsychiatric symptoms
are distressing to the person living with dementia and con-
tribute significantly to caregiver burden (Coen et al., 2002),
institutionalisation (O’Donnell et al., 2004) and care costs
(Ryu et al., 2005), occur frequently and are ­persistent. The
prevalence of clinically significant symptoms is around a
quarter of those with mild cognitive impairment (MCI)
(Lyketsos et al., 2002; Ryu et al., 2011) one-third of people
with mild dementia rising to two-thirds with more severe
dementia in the community (Lyketsos et al., 2002; Ryu et
al., 2005) and around 80% of people with dementia in care
homes (Selbaek et al., 2008; Bergh et al., 2011). The symp-
toms are persistent in each setting: around 75% of people
with MCI have persistent symptoms (Ryu et al., 2011) and
80% of those in the community have symptoms for at least
6 months (Ryu et al., 2005). In care homes, symptoms such
as delusions, agitation, irritability and apathy (Lawlor,
2000; Margallo-Lana et al., 2001) are particularly likely to
remain a problem with about 75% persistence for at least
a year (Selbaek et al., 2008), making the need for effective
treatment a high priority.
Neuropsychiatric symptoms occur in clusters and the
most commonly defined clusters are agitation, psychosis
and mood disorder (Ballard et al., 2008). They may have
23
different aetiologies (Bruen et al., 2008) and require dif-
ferent management. Neuropsychiatric symptoms are often
treated with psychotropic medications (see Chapter 25).
There are major concerns about their safety, particularly
antipsychotics (Schneider et al., 2005) and also citalopram
(Porsteinsson et al., 2014), and efficacy (antipsychotics,
memantine, carbamazepine and cholinesterase inhibitors)
(Trinh et al., 2003; Schneider et al., 2006; Howard et al.,
2007; Fox et al., 2012). Guidelines, therefore, recommend
non-pharmacologic strategies as the preferred first line
treatment approach (except where there is imminent dan-
ger or safety concerns) (National Institute for Clinical
Excellence [NICE], 2006; Kales, 2015).
The acronym DICE (Describe, Investigate, Create,
Evaluate) outlines an approach to non-pharmacological
management of behavioural problems in dementia. This
is a systematic way of describing the problems, investigat-
ing possible causes, creating a plan and evaluating how well
treatments are working and whether there is a need to mod-
ify the approach (Kales, 2015).
Several previous reviews, including our own (Livingston
et al., 2005), considered all neuropsychiatric symptoms’
management together. A strategy that is successful for
one symptom may, however, not be right for another. Two
systematic reviews, including our own, have specifically
considered non-pharmacological management of agita-
tion in dementia (Kong et al., 2009; Livingston et al., 2014)
and another for depression and anxiety (Orgeta et al.,
2014). This chapter examines the evidence for each therapy
and discusses what works, what does not and what needs
235
236 Dementia
more evidence. We draw on evidence from our system-
atic reviews that give more details of the papers reviewed
(Livingston et al., 2005, 2014).
23.2 BEHAVIOURAL MANAGEMENT
AND COGNITIVE THERAPIES
23.2.1 COGNITIVE OR BEHAVIOURAL
MANAGEMENT TECHNIQUES
(BMTs) WITH PATIENTS
Two randomized controlled trials (RCTs) employed behav-
ioural management techniques (BMTs). One used a complex
intervention (life review, sensory stimulation, single-word
commands and problem-oriented strategies) and was inef-
fective (Beck et al., 2002). The second used a token economy,
which was less effective than a milieu treatment (Mishara,
1978).
In one RCT, 44 participants with dementia received
manual guided treatment for the patient and caregiver and
43 received a problem-solving treatment only for the care-
giver (Teri et al., 1997). Both interventions were equally suc-
cessful in improving depressive symptoms immediately and
at 6-month follow-up (Teri et al., 1997). Three smaller RCTs
also had positive results (Suhr et al., 1999; Benedict et al.,
2000; Spector et al., 2015). In one intervention, participants
were taught progressive muscle relaxation and 2 months
later they had significantly fewer neuropsychiatric symp-
toms. In the second intervention, the behaviour of patients
with multiple sclerosis associated dementia improved with a
cognitive behaviour intervention. Finally, a pilot RCT, found
that up to 10 Cognitive Behaviour Therapy (CBT) sessions
for people with dementia, with family caregivers supporting
them, may reduce patient depression (Spector et al., 2015). A
systematic review of psychological therapies for depression
in dementia, including two CBT interventions, concluded
that they may help depression but not anxiety (Orgeta et al.,
2014). But the studies, while hopeful, were not high quality
enough to be definitive (Orgeta et al., 2015).
●● There is consistent evidence from the RCTs that psycho-
logical therapies are a promising intervention that may
reduce depressive symptoms and the effects lasted for
months but no definitive evidence.
23.2.2 TEACHING CAREGIVERS BMT
Several disparate studies trained family caregivers in BMT.
Two high-quality studies found (at 3 months, 6 months or
12 months) that training family caregivers in BMT was inef-
fective over 4 or 11 sessions for severe or symptomatic agita-
tion in people with dementia living at home (Teri et al., 2000;
Gormley et al., 2001). Similarly, two studies that trained staff
and family caregivers in CBT for people with severe agita-
tion found no improvement compared with controls (Wright
et al., 2001; Huang et al., 2003). Training caregivers in BMT
did not help to reduce psychotropic drug use or symptom
frequency at 1-year ­follow-up (Weiner et al., 2002).
Combined exercise and BMT led to significant improve-
ments in depression at 3 months but not at 2 years (Teri
et al., 2003). In a pilot RCT, caregivers were taught BMT
either through written materials or in a home training pro-
gramme with the objective to reduce response to identified
stressors (Huang et al., 2003). Care recipients in the second
group were less aggressive, but this finding should be inter-
preted cautiously, as the study was small and raters were not
blind to the intervention status.
An excellent, adequately powered RCT trained ‘com-
munity consultants’ (primary care health workers) to use
a structured manual-based intervention (the STAR or Staff
Training in Assisted Living Residences-C treatment) (Teri
et al., 2005). They had eight sessions with 95 individual
patient/caregiver dyads at home, teaching them to monitor
behavioural problems, understand behaviour management
and modify antecedents or consequences. They also con-
centrated on improving caregiver communication, increas-
ing pleasant events and enhancing caregiver support. There
were significant improvements, maintained at 6 months, in
caregiver mood and care recipient neuropsychiatric symp-
toms. In a small study to evaluate the STAR programme
in UK care homes, residents demonstrated significantly
reduced symptoms of depression and behavioural problems
(Goyder et al., 2012).
●● The evidence that the STAR-C treatment which trains
staff helps neuropsychiatric symptoms is strong.
●● Teaching BMT’s principles to family caregivers seems
inefficacious in managing neuropsychiatric symptoms.
23.2.3 TEACHING FAMILY CAREGIVERS
TO CHANGE THEIR BEHAVIOUR
Ten studies (including nine RCTs) taught family caregivers
to change their interactions with relatives with dementia. In
an RCT of an educational programme for family caregivers,
comprising supportive counselling, psychoeducation and
training in management strategies, patients’ institutional-
ization rates decreased (Eloniemi-Sulkava et al., 2001) for
3 months but not in 2 years. A smaller study of the same
intervention with individual families found significant
improvements at 6 months in mood and ideational distur-
bance (McCallion et al., 1999a). One RCT, with 144 people,
compared a group intervention to treatment as usual and
the difference in neuropsychiatric symptoms at 16 weeks
approached significance (Herbert et al., 2003). In a fur-
ther trial, primarily powered for caregiver’s mental health,
neuropsychiatric symptoms improved immediately after
12 weeks training in stress management, dementia educa-
tion and coping skills but not 3 months later (Marriott et al.,
2000). A pilot RCT, with limited power, involved psycho-
education, instruction to caregivers on how to change their
 Psychological, behavioural and psychosocial interventions for neuropsychiatric symptoms in dementia 237
interactions with the patient or both (Burgener et al., 1998).
The difference in patients’ behaviour at 6 months again
approached significance.
●● BMT providing psychoeducation to caregivers about
changing their own interactions with patients may help
reduce neuropsychiatric symptoms possibly limited
to ­affective symptoms (National Institute for Clinical
Excellence and Social Care Institute for Excellence
[NICE/SCIE], 2006 3/id).
23.3 DEMENTIA-SPECIFIC THERAPIES
23.3.1 REMINISCENCE THERAPY
Reminiscence therapy is a group intervention using m ­ aterial
from the past, such as photos or music, to s­ timulate memory
and help create identity and intimacy. There is no evidence
it benefits neuropsychiatric symptoms (Baines et al., 1987;
Baillon et al., 2004; Livingston et al., 2005).
23.3.2 VALIDATIOIN THERAPY
Validation therapy is about individual uniqueness in order
to help people with dementia resolve conflicts by validating
their feelings rather than concentrating on facts. There is
one reasonably sized RCT (n = 88) that compares validation
therapy to usual care or a social contact group (Toseland,
1997) for neuropsychiatric symptoms. There were no differ-
ences at 1-year follow-up in nursing time or in psychotropic
medication and restraint usage.
●● There is no good evidence of benefit and there is some of
lack of efficacy.
23.3.3 REALITY ORIENTATION THERAPY
This is based on the idea that impaired orientation handicaps
people with dementia so reminders can improve function-
ing. There are two RCTs using reality orientation consider-
ing neuropsychiatric symptoms and both do not show any
significant benefit (Hanley et al., 1981; Baines et al., 1987).
●● There is no good evidence of benefit and some of lack
of efficacy.
23.3.4 COGNITIVE STIMULATION
THERAPY
Cognitive stimulation therapy (CST), derived from reality
orientation, uses information processing though themed
activities to engage people with dementia while providing
a group’s social benefits. Its main purpose is cognitive but it
might benefit neuropsychiatric symptoms. Three CST RCTs
(Quayhagen et al., 1995; Romero and Wenz, 2001; Spector
et al., 2001) showed some positive results on non-cognitive
symptoms, although the studies used different follow-up
end points (immediately after to 9 months after therapy).
There were early behaviour improvements, but by 9 months
no significant difference was found. One study showed
reduced depression (Spector et al., 2001). The final study did
not report whether behavioural differences were significant
(Quayhagen et al., 2000).
●● There is inconsistent evidence that CST improves
some neuropsychiatric symptoms immediately and for
months afterwards.
23.4 EDUCATING STAFF TO CHANGE
THEIR PERSPECTIVE AND
COMMUNICATION
Person-centred care, communication skills training and
dementia care all seek to change staffs’ communication
with and thoughts about people with dementia, encour-
aging them to see and treat people as individuals rather
than being task focused. Five RCTs have evaluated whether
these strategies reduce agitation (McCallion et al., 1999a,
1999b; Sloane et al., 2004; Chenoweth et al., 2009; Deudon
et al., 2009). All included supervision during training and
implementation.
One high-quality study of person-centred care training
found that severe agitation significantly improved dur-
ing the intervention and 8 weeks later (Chenoweth et al.,
2009). Two studies of improving communication skills or
person-centred care, for participants with s­ymptomatic
agitation, found significant improvements compared to
the control group during (McCallion et al., 1999a, 1999b)
and up to 6 months after intervention (McCallion et al.,
1999a). A large study including participants without high
agitation levels found that agitation improved significantly
during 8 weeks person-centred care training and 20 weeks
later (Deudon et al., 2009). One small study, where par-
ticipant’s agitation levels were unspecified, showed imme-
diate improvement in agitation during bathing compared
to the control group (Sloane et al., 2004).
One large, high-quality care home study evaluated
dementia care mapping. They observed and assessed each
resident’s behaviour, factors improving well-being and
potential triggers; they explained the results to caregivers
and supported proposed change implementation. Severe
agitation decreased during the intervention and 4 months
afterwards (Chenoweth et al., 2009).
Teaching communication skills also reduced patients’
depression at 6 months (McCallion et al., 1999b). A pilot
study of a nursing assistant implementing behavioural
methods found improvements in non-affective behav-
ioural symptoms (Lichtenberg et al., 2005). Staff education
to implement dementia specific therapies was ineffective
(Schrijnemaekers et al., 2002).
238 Dementia
●● Training paid caregivers in communication skills or
person-centred care or dementia care mapping, with
supervision during implementation is significantly
effective in care homes for symptomatic and severe
agitation, immediately and up to 6 months.
●● These strategies may be effective in alleviating patient
mood disturbance, immediately and over months.
23.5 PSYCHOSOCIAL INTERVENTIONS
23.5.1 SENSORY ENHANCEMENT
23.5.1.1 Music/music therapy
Music can be an activity or part of other activities, such
as mealtimes or bath times. (see also Chapter 22) There
were seven small RCTs of music/music therapy inter-
ventions’ effect on neuropsychiatric symptoms in our
systematic review (Livingston et al., 2005). All found
improvements in apathy, agitation or disruptive behav-
iour during or immediately after the session with no
longer-term effects.
Three more recent RCTs, all in care homes, evaluated
music therapy by protocol’s effect on agitation, typically
involving warming up with a well-known song, listen-
ing to and then joining in with music (Cooke et al., 2010;
Lin et al., 2011; Sung et al., 2012). The largest study that
included participants of all agitation levels found that
music therapy, twice a week for 6 weeks, was effective com-
pared to usual care (Lin et al., 2011). A second found a sig-
nificant effect compared to a reading group (Cooke et al.,
2010) and the third a borderline significant effect (Sung
et al., 2012).
●● In care homes, music therapy by protocol significantly
reduces agitation including in those with symptomatic
agitation immediately and not longer term.
23.5.1.2 Snoezelen therapy and other
sensory stimulation
Snoezelen therapy/multisensory stimulation (MSS) com-
bines relaxation, lights and sounds in specially designed
rooms for 30–60 minutes. We found seven RCTs in our
earlier systematic review. The largest RCT recruited 136
patients with moderate to severe dementia randomized to
MSS or a control activity (Baker et al., 2003). There was
no group difference in behaviour or mood and commu-
nication/interaction either in the short-term or 1-month
post-intervention. This large trial followed two promis-
ing small trials, which found (as did other studies) that
disruptive or agitated behaviour briefly improved in or
outside the treatment setting but there was no effect after
the treatment had stopped (Livingston et al., 2005). Van
Weert et al. (2005) subsequently reported that Snoezelen
over 18 months reduced aggression immediately after
treatment. An RCT (n = 120) comparing relaxing mas-
sage therapy and ear acupressure interventions to a no
treatment control found that both active treatments led to
improvements in depression and anxiety symptoms dur-
ing treatment and for up to 1 month afterwards among
people with dementia living in care homes in Spain
(Rodriguez-Mansilla et al., 2015).
Studies evaluating touch as an intervention have
found a significant improvement in symptomatic and
clinically significant agitation compared to usual care
(Remington, 2002; van Weert et al., 2005; Lin et al., 2009).
Three studies investigated ‘therapeutic touch’, defined
as a healing-based touch intervention focusing on the
whole person (Woods et al., 2005; Hawranik et al., 2008;
Woods et al., 2009). Despite therapeutic touch being
efficacious before and after analyses, therapeutic touch
tended towards being less efficacious than ordinary mas-
sage or usual treatment between group analyses. An RCT
meta-analysis found that sensory interventions, defined
as aromatherapy, hand massage and a thermal bath, were
an effective intervention immediately for agitation (Kong
et al., 2009).
●● There is evidence for short-term benefits, but no sus-
tained effects, of sensory stimulation in agitation.
●● There are contradictory results about sensory stimula-
tion effect on depressive and anxiety symptoms.
23.5.1.3 Aromatherapy
Two RCTs of aromatherapy in care homes explored effec-
tiveness at reducing agitation (Ballard et al., 2002; Burns
et al., 2011). One large high-quality blinded study found
no immediate or long-term improvement compared to the
control group for participants with severe agitation (Burns
et al., 2011). The other, a non-blinded study, found signifi-
cant improvements compared to the control group (Ballard
et al., 2002). A Cochrane review of aromatherapy for all
neuropsychiatric symptoms concluded that more research
is needed (Forrester et al., 2014).
●● When assessors are blinded to the intervention, aroma-
therapy has not been shown to reduce agitation in care
homes.
23.5.1.4 Visually complex environments
Nine studies investigated complex or distracting visual pat-
terns positioned near or on the exit (Livingston et al., 2005)
were extremely small without a control group. There are no
RCTs that attempt to reduce wandering in either domes-
tic or ward environments (Hermans et al., 2007). There is
a consistent effect that a complex environment that makes
the exit less clear decreases attempts to leave.
 Psychological, behavioural and psychosocial interventions for neuropsychiatric symptoms in dementia 239
23.5.1.5 Light therapy
Light therapy is hypothesized to reduce agitation through
manipulating circadian rhythms, typically by 30–60 min-
utes daily bright light exposure. Three RCTs, all in care
homes (Ancoli-Israel et al., 2003; Dowling et al., 2007;
Burns et al., 2009), have investigated its effectiveness in
doing so. Light therapy either increased agitation or did
not improve it.
●● There is no evidence that light therapy reduces symp-
tomatic or severe agitation in care homes, and it may
worsen it.
23.5.2 STRUCTURED ACTIVITY
23.5.2.1 Therapeutic activity programs
Five reasonably sized RCTs have evaluated group activities
for agitation in care settings; RCTs with standard activi-
ties reduced mean agitation levels and decreased symp-
toms in care homes while they were in place (Buettner
et al., 1997; Lin et al., 2009). One very high-quality RCT
found no additional effect on agitation of individual-
izing activities according to functional level and inter-
est (Kolanowski et al., 2011), although two lower-quality
RCTs did (Kovach et al., 2003; Cohen-Mansfield and
Jensen, 2006). All s­ tudies were in care homes, except one,
where some participants attended a day centre and others
lived in a care home (Cohen-Mansfield et al., 2006). None
specified a significant degree of agitation for inclusion.
Only one study measured agitation after the intervention
was stopped and it did not show effects at 1- and 4-week
follow-up (Kolanowski et al., 2011).
In a recent cluster-randomized trial in 18 nursing homes
in Berlin, which included 10 months of brief activities, pro-
vided once a week, there were significant group differences
in apathy during the 10-month intervention period, which
reflected an increase in apathy in the control but not in the
intervention group. These differences did not persist after
the intervention stopped (Treusch et al., 2015).
●● Activities in care homes reduce levels of agitation sig-
nificantly while in place but there is no evidence regard-
ing longer-term effect. There is no evidence for activities
in severe agitation, or outside care homes.
●● Evidence for other neuropsychiatric symptoms is incon-
sistent and inconclusive.
23.5.2.2 Exercise
One large RCT evaluated an exercise regimen for people
with dementia and their family caregivers (individually
tailored walking regimen designed to become progres-
sively intensive and last between 20 and 30 minutes,
at least five times per week). There were no significant
differences between groups in neuropsychiatric symptoms
(Lowery et al., 2014), possibly because of low adherence to
the intervention. A second RCT found no effects on behav-
iour when one caregiver walked or walked and talked with
two residents (Cott et al., 2002). A Psychomotor Activation
Program RCT involved 134 residents in 11 ‘group care’
homes (Hopman-Rock et al., 1999) in sporting activities
such as ball playing and hockey sitting down. There was a
trend for the behaviour to improve, but the high dropout
due to illness considerably reduced power.
●● Exercise therapy does not appear to be effective at
improving neuropsychiatric symptoms of dementia,
although it requires to be designed and more evidence
as to how to increase adherence to a programme.
23.6 WHAT WORKS, WHAT DOES
NOT AND WHAT NEEDS MORE
EVIDENCE?
Summarizing the evidence, there are therapies for which
we have evidence of efficacy in alleviating neuropsychiatric
symptoms immediately and over the longer term.
23.6.1 IMMEDIATE AND LONGER-TERM
TREATMENT
Overall, there is excellent evidence that training staff in care
homes about dementia, respecting the person as an individ-
ual, communication and sometimes behavioural skills alle-
viate mood disturbance, agitation and aggression in people
living with dementia, immediately and over months. There
is also evidence that for people with dementia living in care
homes activities and music therapy by protocol decrease
overall agitation, and sensory intervention decreases clini-
cally significant agitation immediately but not over the lon-
ger term.
Teaching family caregivers how to react to neuropsy-
chiatric symptoms, coping strategies that ensure that they
have emotional support and the principles of BMT are
effective in managing some neuropsychiatric symptoms.
It is, however, unclear whether the whole package is essen-
tial. In contrast, teaching the principles of BMT to caregiv-
ers as a sole intervention is of doubtful efficacy. However,
professionals (as opposed to families) using principles of
BMT with people with dementia may decrease depressive
symptoms.
23.6.2 WHAT DOES NOT WORK
Aromatherapy, exercise and light therapy have not demon-
strated efficacy in adequately powered studies. There is no
evidence that reminiscence therapy, reality orientation and
validation therapy help neuropsychiatric symptoms and
some evidence that they do not.
240 Dementia
23.6.3 WHAT NEEDS MORE EVIDENCE
The most promising strategies need more evidence and are
about the effect of coping strategies, behaviour manage-
ment, including increasing pleasant events and cognitive
behaviour strategies for people with dementia, depressive
symptoms and depression.
23.7 CONCLUSIONS
Overall, we judge that effective tools are available to treat
neuropsychiatric symptoms in dementia but the systems are
not yet in place where they can be routinely available. Finding
ways in which management strategies can be effectively, effi-
ciently and consistently delivered is now a high priority.
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Treating problem behaviours in dementia
by understanding their biological, social and
psychological causes
IAN JAMES AND LOUISA JACKMAN
24.1 INTRODUCTION
Behavioural and psychological symptoms of dementia
(BPSD) is a term used to describe problematic behaviours
displayed by people with progressive cognitive decline.
Until recently, a medicalized perspective was often used for
BPSD and the treatments chiefly involved the use of psycho-
tropic medication. Empirical evidence suggests that such
treatments are frequently ineffective and highly problematic
(Banerjee, 2009; Barnes et al., 2012). This chapter takes a bio-
psychosocial view of BPSD, preferring the term ‘Behaviours
that Challenge’ (BC), illustrating that these behaviours are
products of a number of factors including individualistic,
social and organizational features. The emphasis is, there-
fore, on understanding and acting on causal factors rather
than symptom alleviation. Hence, it is logical that the treat-
ment of BC needs to reflect this aetiology (James, 2011).
A Stepped-Care model of treatment for BC is presented
(Brechin et al., 2013), which reflects this emphasis and
is intended to encourage the use of evidence-based non-
pharmacological strategies as alternatives to psychotropics
(Lawrence et al., 2012). Such strategies often emphasize the
importance of good communication and interaction skills
from carers, which enable them to improve well-being and
reduce the risk of confrontations with people with demen-
tia. Particular emphasis is placed on caregiver communica-
tion and interaction skills in this chapter because these are
the carer activities utilized on a daily basis to cope and deal
with any problem behaviours. Indeed, when a BC occurs
medical and psychological treatments may or may not be
employed, but in contrast there will always be some form of
interaction needing to take place between the person with
244
24
dementia and the caregivers, often to prevent harm or dis-
tress occurring to someone in the immediate vicinity. The
chapter is in two parts with a theoretical perspective being
followed by a more practical section.
24.2 TREATMENT APPROACHES
24.2.1 NATURE AND CAUSES OF BC
From the term BPSD, there was an implication that behav-
ioural problems were a symptom or defining feature of
dementia; however, this is not the case. Indeed, the vast
majority of people with dementia do not regularly engage
in problem behaviours even when they are required to
cope with situations, such as 24-hour care settings, which
most of us would find restrictive and challenging (Bird and
Moniz-Cook, 2008). In order to understand the nature of
the behaviour, let us first look at the types of behaviours pre-
senting a challenge to caregivers and then we shall discuss
treatment strategies. Table 24.1 is a truncated list of behav-
iours reported as challenging, taken from an audit of the
work of the Newcastle Challenging Behaviour Team, the
full list is provided in James (2011).
These behaviours are not unique to dementia as many of
us may have engaged in some of these activities in the past
under specific settings, conditions and triggers. If we had
been observed engaging in such actions and then asked to
justify ‘why?’, we would have probably attempted to explain
the extenuating circumstances that had led us to behave in
such a manner (illness, tiredness, alcohol, fear, distraction,
recent argument, etc.). There may even be more than one
 Treating problem behaviours in dementia by understanding their biological, social and psychological causes 245

Table 24.1 Audit of behaviours that challenge referrals Figure 24.2 illustrates the case example of Mr A, who was
referred to the psychiatric services due to physical aggres-
Aggressive Forms of
sion towards staff on an inpatient ward. On one occasion,
BCs Non-aggressive Forms of BCs
Mr A hid behind a door and attacked a male nurse as he
Hitting Apathy entered the room, using an armlock he had been taught in
Kicking Depression the army. Staff were very frightened of him, attended him
Grabbing Repetitive noise in pairs and rushed any personal care tasks with him in
Pushing Repetitive questions order to complete jobs in the shortest possible time. Mr A
Nipping Making strange noises was extremely sensitive to psychotropic medication owing
Scratching Constant requests for help to his diagnosis of Lewy body dementia (DLB) and thus psy-
Biting Eating/drinking excessively chological approaches were preferred. The psychiatric team
Spitting Overactivity used a conceptual model (i.e. the Newcastle model) similar
Choking Pacing to the Iceberg model to understand the problematic behav-
Hair pulling General agitation iour. When this information was put together with a richer
Tripping someone Following others/trailing description of the BC from information gleaned from the
Throwing objects Inappropriate exposure of parts use of behaviour charts, a clear pattern began to emerge.
Stick prodding of body The attacks seemed to mainly happen in the morning and
Stabbing Masturbating in public areas were chiefly directed at male carers. During the attacks
Swearing Urinating in inappropriate places Mr A would typically say ‘That’s the last time you f*ck with
Screaming Smearing me’; ‘Think you’re big now...eh’.
Shouting Handling things inappropriately The psychiatric team met with staff and collated the
Physical sexual assault Dismantling objects information, leading to a set of hypotheses about the causes
Verbal sexual Hoarding things of his behaviour. Psychologists refer to these tentative
advances Hiding items hypothetical cause–effect relationships as ‘formulations’.
Acts of self-harm Falling intentionally From their discussions the following explanation began to
Eating inappropriate substances emerge: Mr A’s DLB made him prone to falling and poor
Non-compliance mobility. Often when he got up at night to go to the toilet,
Misidentifying he would fall against the wall giving himself bruises. In the
Source: James, I.A., Understanding Behaviour in Dementia that morning, forgetting he had fallen, he would be looking for
Challenges, Jessica Kingsley, London, United Kingdom, 2011. an explanation for his bruises and pain. His assumptions
led him to the belief that he had been assaulted by someone
of these contributing factors influencing our actions. From during the night while he was vulnerable in bed. Further,
a dementia perspective, it, therefore, seems sensible to give as he perceived himself to be a ‘strong’ man, he assumed it
people with dementia the benefit of looking at the circum- must have been done by a male carer because he would have
stances in which their behaviour occurred, before providing been able to fight off any woman.
the blanket explanation that ‘it’s all due to their dementia!’ This case, illustrating the Newcastle model, illustrates
Figure 24.1 outlines some of the common causal features a number of important things a number of important
associated with BC. Thus, when someone is engaging in BC things. First, a person’s BC has a number of moderating
it is helpful to collect information regarding these features factors (personality, physical and mental health, percep-
to explain his/her problem actions. tual issues, etc.). It is important to collect this background
Figure 24.1 is referred to as the Iceberg model; the tri- information in order to examine the context of the BC.
angle represents an iceberg and below the surface are all Second, a detailed description of the behaviour is required
the things about the person we cannot see that influence to understand how the moderating factors actually lead
the behaviour (James, 2011; James and Hope, 2013). These to the BC. Such information is often collected via behav-
would be regarded as moderating (background) features ioural charts; this information provides the where, when,
with respect to the BC. Some of these are age-related prob- who features of the behaviour. Third, although there are
lems, including pain, sensory loss, mobility issues; others numerous moderating factors, the key mediating features
are related to personality traits and attitudes. Above the line for the problematic behaviours are the person’s beliefs
(the surface) is what we can observe, which is the behav- and the resultant emotions that these thoughts produce.
iour (i.e. what we see the person do) and emotional states. As mentioned above, these are the key features of the CBT
Humans are extremely good at identifying and differentiat- cycle (Figure 24.3).
ing between the seven key emotional states (anger, sadness, Figure 24.3 outlines two cycles, Mr A’s and a typical
anxiety, happiness, shame, disgust, surprise) (Ekman, 1973; caregiver response. The cycles highlight the dynamics of
James, 2011). The key aspect mediating between the ‘above the interaction. The nature of the interaction has become
and below’ surface features is the person’s cognition (i.e. dysfunctional leading Mr A to become more unsettled
thoughts and beliefs). To this extent, the Iceberg model is a and confused. In order to resolve this problem, the psychi-
cognitive behavioural therapy (CBT) framework. atric team needed to help the staff understand the causes
246 Dementia

The Observables:
Environmental these features can be
Setting: recorded on a
Structure and carer behavioural chart
interactions Behaviour and
Emotions
Surface

Beliefs: e.g. These f**king carers

are beating me up!

Drug-related issues: Drugs interactions,

side effects

Mental health status: Perceptual difficulties:

Anxiety, mood, psychosis Visual, auditory, tactile

Cognitive and neurological:

Nature of dementia, cognitive
functioning
Metabolic changes: Impacting on
appetite, energy, irritability
Physical difficulties:
Falls, pain
Premorbid personality: A ‘short-fuse’

Figure 24.1 Iceberg model.

Mental health Life story Social environment

Previous history of depression. Paranoid
thoughts about being attacked, but due
to memory errors rather than a psychosis.
Personality
Very independent and single minded.
Likes company. Private around self-
care activities—embarrassed easily.
Finds it difficult to relax—always
keeping busy. Loved learning new
things. Proud of the idea he can
‘stand-up’ for himself.
Loves animals; often watches nature
programmes.
Hobbies—walking dog, clothes
shopping. Coped with stress by going
out for a walk, usually alone with dog.
Dad died when he was four. Mum and big sister relied on
him. Mum depressed for many years, later she became
agoraphobic. Mr Smith looked after his mum—visiting her
every evening for 10 years. He worked hard throughout
life. Passed exams, but responsibilities prevented him
going to college. Married May in his 30s, worked on the
docks. One son (Mark). Problem in marriage when May
admitted to affair, but issues resolved. After this he
became more independent, more suspicious of others.
Triggers
Aggression—When getting up in the morning, he
shouts and lashes out. Usually triggered by
presence of men attending to his needs first thing
in the morning.
Moved into care when wife had a stroke, prior to
that lived with wife and son. Now on top floor of
Dementia nursing home with 40 residents.
Doors unmarked—difficult to find way around.
No access to garden outside.
Cognitive abilities
DLB—moderately severe. Most confused
in mornings, some variability during day.
Prone to falling, particularly in
evenings/night.
(Neurospsych assessment could not be
completed). Frontal lobe deficits. Some
expressive dysphasia—milder receptive
dysphasia.

Physical health The aggression less evident later in day. Although Medication
Arthritis; dermatitis. presentation often fluctuates. Mirtazapine; diazepam; paracetamol.
Recent weight gain; diabetes II Psychotropic medication needs to be
high cholesterol. Pain and monitored carefully due to DLB.
discomfort. Prone to falling,
particularly at night.

Situation—Getting out of bed and /or washed in the morning

Emotion: Angry and aggressive.

Behaviour: Lashes out and shouts. Vocal: I will get you ... You f**king
bast*rds

Thought/need: Male carers are coming into my room at night and

beating me up. Need to protect himself and revenge the assault.

Figure 24.2 Newcastle model for Mr A: information from above and below surface factors of iceberg model. (From James,
I.A., Understanding Behaviour in Dementia that Challenges, Jessica Kingsley, London, United Kingdom, 2011.)
 Treating problem behaviours in dementia by understanding their biological, social and psychological causes 247
Trigger: Mr Smith experiencing pain first thing in
the morning and seeing bruises
PWD
Thoughts/understanding of
situation: I am being beaten up at
night by these men who beat me
while I’m in bed
Emotion:
Physiological
Anger
arousal
Behaviour: Aggression
Interaction
Behaviour: Confrontation;
rushing interactions; attending in
twos; using male carers
Emotion:
Apprehension
Thoughts: He’s cunning and
evil!; best to get in and out
as quickly as possible; got
Care giver to use force to protect
yourself at times
Figure 24.3 Mr A’s cognitive behavioural therapy
formulation.
of the aggression, and then assist the nurses to adapt their
approaches to the situation, making their interactions more
functional.
Through formulation, key elements to the treatment
were to reduce Mr A’s risk of falling during the night, pro-
vide him with painkillers first thing in the morning, reduce
the number of staff attending to his personal care, and in the
morning, ensuring the initial nurses were female that sup-
ported his physical and cognitive needs respectively. In the
following section, we will take a look at intervention strate-
gies for the treatment of BC, before focusing in more detail
on carer communication.
24.2.2 TREATMENT APPROACHES
There are five main treatment approaches with respect to
BC, two pharmacological and three psychosocial. Some of
these treatments are the foci of chapters within this book
therefore are not addressed here in detail. One’s choice of
strategy must be completely aligned with the identified
causes of the behaviour.
The first of the medication regimens involves the iden-
tification and appropriate prescribing of drugs to treat
common triggers for distress and agitation, such as pain,
constipation, delirium, diabetes, thyroid disorders, anxi-
ety, psychosis, etc. The second pharmacological strategy
makes use of the sedating, calming and tranquilizing pow-
ers of antipsychotics, benzodiazepines and mood stabilizers
(Ballard and Howard, 2006). While such drugs are crucial
within a treatment ‘tool-box’, particularly in cases of high
levels of distress and risk (Ballard et al., 2008; Barnes et al.,
2012), their problematic side effects mean these classes of
drugs need to be used with great caution (see Chapter 25).
In terms of psychosocial approaches, these can be
roughly categorized as psychological, environmental and
carer–client interactions. Psychological treatments (Hulme
et al., 2010; Gitlin et al., 2012; Whitaker et al., 2014) con-
tain a broad church of interventions (cognitive stimulation
therapy, reminiscence, exercise, reality orientation, valida-
tion, music, aromatherapy, animal assisted, etc.). With rela-
tively few exceptions their evidence base remains limited,
and they are often used in preventative capacities rather
than to treat behaviours once they have emerged. In other
words, the use of these approaches makes it less likely that a
BC will be triggered, rather than treating it once it has been
triggered.
The second group – environmental strategies – involves
Arousal
designing the architecture and locality to reduce levels of
confusion and distress. Simple things such as having access
to a garden, using good signage, appropriately designing
rooms, equipment and utensils (adaption of shape, colour,
texture) can reduce levels of agitation markedly (King’s
Fund, 2009).
The final set of strategies – optimizing carer approaches
to the person with dementia – are perhaps the most impor-
tant in relation to interpersonal relationships between the
person with dementia and caregivers. Further, no mat-
ter what the cause of the behaviour (biological, social or
psychological), appropriate interactions can serve to de-
escalate problematic situations. Indeed, it has long been rec-
ognized that highly competent carers are those who are best
able interact, connect and engage with people with demen-
tia (Levy-Storms, 2008). Such caregivers are able to de-
escalate highly charged and problematic situations, through
their verbal and non-verbal skills. As such, researchers have
attempted to teach staff, with some success, how to commu-
nicate with people with dementia (Eggenberger et al., 2013).
Unfortunately to date, while it has been shown that carers
can be taught to communicate better, these improvements
are not reflected in reductions in BC. Owing to the impor-
tance of carer interactions, we will discuss the latter topic
further below in the context of agitation and anger.
24.2.3 CARER INTERACTIONS AND
COMMUNICATION WHEN
DEALING WITH AGITATION AND
ANGER
The most frequent BC clinical referrals are related to agita-
tion and aggression rather than more passive expressions
of BC such as refusal to eat, inactivity, and apathy. This is
mainly due to the fact that the latter activities are less dis-
ruptive and therefore less of a challenge to the system in
which they are performed. The circumstances that pro-
duce aggression and agitation in people with dementia are
248 Dementia

similar to those affecting people who do not have dementia.
An example of this was Mr A, whose anger led to an aggres-
sive response. Beck and colleagues (Beck, 1976; James, 1999;
James and Hope, 2013) have recognized that anger occurs
when we perceive our rights are being unjustly infringed,
such as when we think we are being taken advantage of
(James, 2011). When we have such thoughts, anger will
occur in all of us; therefore it is not uniquely a feature of
dementia. Of course, dementia can reduce people’s ability
to cope with and control anger when executive function-
ing is affected, although another key difference for people
with dementia is that in some situations they are more likely
to perceive their rights are being infringed; the reasons are
two-fold.
First, their view of a situation may sometimes conflict
with that of the caregivers as they are using degraded
information to process their world. For example, owing to
memory difficulties, a care home resident may believe she
needs to go and see her deceased mother immediately. This
brings her into conflict with her carer who is repeatedly
attempting to convince her that her mother died 20 years
ago. Such a scenario is common and frequently leads to
confrontation. Second, it can be a carer’s intended actions
to keep the person with dementia safe or clean that trig-
ger conflict (e.g. not letting him go out at night; prevent-
ing her driving her car; asking him to get out of a soiled
bed). Indeed, because the person with dementia does not
always share the same reality as his/her caregiver, they
can often perceive such management strategies as restric-
tive practices, which evokes anger and aggression. BCs are
sometimes conceptualized as the by-products of strategies
carers’ employ to manage the lives of people who are con-
fused, impulsive and disorientated.
As behaviours can be the consequences of our man-
agement strategies, they can be reduced significantly if
we respond to the person with dementia in a skilful way
that takes account of his/her needs, strengths and deficits
(Brechin et al., 2013). The impact that management strate-
gies play in the triggering, maintenance and resolution of
problem behaviours cannot be overstated, and is well repre-
sented in Table 24.2.
Figure 24.2 and Table 24.2 demonstrate that problem
behaviours are not single actions, rather they are dynamic
interplays. It is important to capture these patterns of action,
in order to understand the causes and develop potential
treatments.
We will summarize some of the key issues that we have
tried to highlight above. First, BCs are not solely features
of cognitive impairment. Indeed, the same fundamen-
tal mechanisms underpinning BC operate for everyone,
including those without dementia. However, owing to their
cognitive difficulties people with dementia can see things
differently, and this can result in disagreements. Further,
owing to them being vulnerable, risk management strate-
gies that run counter to the person’s ability to exert control
over their environment may need to be introduced and this
can also result in confrontations.
Observational studies (Levy-Storms, 2008; Eggenberger
et al., 2013) inform us that skilful carers are those people who
are able to communicate with someone who is getting upset in
a manner that reduces the likelihood of conflict. To optimize
the possibility that carers will have sensitive and appropriate
interactions with people with dementia who are distressed
and potentially challenging, two types of information are
required that enable them to ‘put themselves in the shoes’ of
the person with dementia: (1) a detailed understanding of the

Table 24.2 T
 he triggering of problem behaviours through poor management strategies (MSs) of people with
dementia (PWD)

3a. MSii in Response to the

1. Carer’s MSi
Locking exit door to prevent
the person with dementia
from wandering the busy
street
Increasing volume of TV
owing to care home
residents’ hearing
problems
Trying to get someone to
wash after 5 days of
refusing to do so
2. Behaviour of PWD
Triggered by MSi
Kicking exit door to get out
Shouting and yelling, owing
to high volume of the TV
Refusing to agree to wash
self, or be assisted to be
washed
PWD’s Behaviour That
Reinforces Problem
Behaviour
Taking the person to
another room in the care
home
Tell the person with
dementia not to be so
selfish. Explaining to her
that the other residents
need the higher volume
to hear the TV
Tricking the person to go
into the bathroom, and
not letting her out until
she has let you wash her
3b. Resolution
Escorting the person with
dementia while they go
for a walk outside
Encourage the residents
who have hearing
problems to sit nearer the
TV
Helping maintain her dignity
by giving her a flannel and
assisting her to wash
herself under cover of her
dressing gown
 Treating problem behaviours in dementia by understanding their biological, social and psychological causes 249
person’s behaviour, its dynamics and likely triggers, and (2)
knowledge about both the person they are caring for (his-
tory, likes, dislikes, etc.) and the context/environment. From
a clinical perspective, the value of these two types of infor-
mation is recognized (see the case of Mr A), and assessments
tools have been devised to capture these details. These assess-
ment tools are discussed in the next section.
24.3 METHODS AND TOOLS
Over the last 6 years, many countries have published
national dementia strategies, routinely endorsing the use of
a more holistic approach to treating BC. While commend-
able, the dementia strategies have been uniformly poor at
being specific about how to implement evidence-based
alternatives to psychotropic medication. Hence, the follow-
ing section operationalizes the conceptual ideas expressed
earlier and describes the assessment tools and protocols
used in clinical settings.
24.3.1 INFORMATION REQUIRED
We have already highlighted the need for caregivers to
know detailed information about both the behaviour and
the person. However, the rule of parsimony must be used
in this area, whereby sufficient information is gained to
guide treatment, but not so much that assessment materi-
als become over-burdensome and thereby inefficient. In this
section, we will examine the type of information that it is
useful to collect, and tools through which the details can be
collected and conceptualized.
24.3.1.1 Background of person
Figure 24.1 outlines some of the background information one
can usefully obtain to understand the reason for a person’s BC,
and Figure 24.2 outlines how to formulate a case of aggression
(Mr A). This framework is taken from the Newcastle concep-
tualization, which is part of a 10- to 12-week package of care
known as the Newcastle model (James, 2011). Adherence to
the model involves the following phases.
24.3.1.1.1 PHASE 1. BACKGROUND ASSESSMENT
The gathering of information relating to the person’s back-
ground from friends, family, carergivers and from case files
and relevant databases. Assessment material can be gath-
ered by a specialist worker or can be a task assigned to a key
worker or named nurse.
24.3.1.1.2 PHASE 2. ASSESSMENT OF TRIGGERS AND
BEHAVIOUR
Information is obtained to determine the events or situa-
tions that are likely to elicit the behaviours through discus-
sion and completion of behavioural charts. These charts also
provide in-depth information regarding the event itself.
24.3.1.1.3 PHASE 3. FORMULATION MEETING
(INFORMATION SHARING SESSION)
A specialist clinician who has collated the assessment infor-
mation meets with the people involved in the person’s care
(including staff, family and other professionals) to develop a
shared understanding of why the person presents with BCs.
The session is intended to refocus the group from problem to
solution-focused through increasing empathy and improv-
ing understanding of the person’s BC. The formulation ses-
sion is the mechanism through which the group comes to
refocus their attention on the needs of the resident/patient
rather than on the challenge they experience. The formu-
lation session can be facilitated by a specialist challenging
behaviour clinician or experienced ward or home staff.
24.3.1.1.4 PHASE 4. INTERVENTIONS
Interventions are based on the group’s suggestions, then
developed and refined during the formulation session with
the facilitator’s help. Further ongoing support is then pro-
vided for 4–6 weeks (negotiated with the individual care
home/service) to ensure appropriate implementation of the
treatment strategies, and tweaking is undertaken where
necessary.
The Newcastle model (James, 1999, 2011) is well
respected and has received empirical support, being used
in the Focussed intervention training and support (FITS)
trial (Fossey et al., 2006; Fossey and James, 2007). The use
of this model serves at least two functions, summative and
formative. The summative function is the establishment of a
bespoke formulation of the person and his/her presentation.
To obtain this a practitioner typically works with caregivers
to collect personal and contextual information, including
data about physical and mental health status, medication
and social environment. A detailed analysis of the behav-
iour is also undertaken using behavioural charts.
The formative function occurs in those caregivers who
participate in the data collection. Their monitoring and care-
ful observation facilitates their own pattern recognition and
hypothesis development with respect to the BC, and can
result in the development of a more positive attitude towards
the person with dementia. Thus, the process of collecting
data to inform the conceptual model frequently enhances
carer attitude, leading to a process termed repersonalization
(Kitwood, 1997).
There are a number of other conceptual models direct-
ing the treatment of BC (Kitwood, 1997; Cohen-Mansfield,
2000; Volicer and Hurley, 2003; Aberdeen, 2010) – see James
(2011) for a review. The best developed of the latter is the
Cohen-Mansfield ‘unmet needs’ perspective, which has a
satisfactory evidence base (Cohen-Mansfield et al., 2007).
In addition to obtaining extensive biographical information
about the person with dementia, this approach suggests that
a BC is typically a poorly executed communication of an
unresolved ‘need’.
Cohen-Mansfield identified three potential links: BCs
aimed at addressing the need (e.g. stealing food to assuage
250 Dementia

hunger), BCs aimed at communicating the need for assis-
tance (e.g. continuous shouting or buzzing for help) and
BCs when being thwarted at attempting to meet a need (e.g.
an aggressive response when attempting to maintain one’s
self-esteem or when being prevented from leaving the build-
ing). Once the potential causes of the BCs have been estab-
lished, the next step is to ask how we can help the person to
meet their need in a more functional manner.
A number of stand-alone tools have also been devised
to assist in the collection of personal information, such as
Dementia Passports (Alzheimer’s Society, 2013). These are
biographic booklets compiled collaboratively by family,
with the aid of professionals – detailing personal history,
preferences, likes and dislikes. The booklets are carried rou-
tinely by the person with dementia, aiding positive interac-
tions and facilitating communication.
24.3.1.2 Behavioural charts
BC tend to have patterns, made up of contexts and cues
that typically trigger the person to act in a certain man-
ner. In the past, antecedents–behaviour–consequence
(ABC) charts have been used to analyse BC in detail. In
more recent times, these charts have been tailored and
elaborated upon. Such charts are extremely helpful, but
require staff training in order to be completed appropri-
ately. Without adequate training and reinforcement the
charts can be burdensome and misleading. An example
of a bespoke chart (Figure 24.4) seeks to gain informa-
tion about the person with dementia’s emotional states in
relation to behaviour and context; in keeping with a CBT
perspective.

Behavioural chart for …………………………..

Target behaviour ……………………………………

Please record any episodes of the above behaviour (day/night).

Aim—To record frequency and circumstances of incidents.

Date and time What was the person doing just before the incident? (A—antecedent)

Where did the incident

occurred?

What did you see happen? (B—actual behaviour)

Which staff were

involved (initials)?

What did the person say at the time of the incident?

How did the person appear at the time of the incident? (may be more than one tick)

Angry Frustrated
Anxious Happy
Bored Irritable
Content Physically unwell
Depressed Restless
Despairing Sad
Frightened Worried

How was the situation resolved? (C—consequences)

A—Antecedents are the features happening just prior to the emergence of the behaviour that may have
served to trigger or reinforce it.
B—Behaviours are simply the factual acts witnessed by the staff. The staff are taught not to interpret the
behaviour, rather provide factual details.
C*—Consequences are the responses of others to the behavioural disturbance. An analysis of this aspect
helps to determine what the person might be achieving by acting this way. Also by examining the
consequences, one can check the behaviour is not being inadvertently reinforced.

* Answers in this column give therapists ideas for interventions, and provide clues about which staff are
dealing with the situation well (or not so well).

Figure 24.4 Behavioural chart.

 Treating problem behaviours in dementia by understanding their biological, social and psychological causes 251
24.3.1.3 Behavioural analytical tools
A Cochrane review (Moniz-Cook et al., 2012) recently dem-
onstrated the positive value of analysing the behaviours in
detail to help determine causes and then derive treatments.
Three useful behavioural analytical tools are Dementia
Care Mapping (DCM) (Kitwood, 1997), Bird’s Treatment
Protocol (McCabe et al., 2015) and Cohen-Mansfield’s
Treatment Route Exploratory Agitation (TREA) (Cohen-
Mansfield, 2000). DCM is a multipurpose observational
tool, useful for assessment and training purposes. It links
negative and positive care practices with levels of client
well-being. Bird’s protocol consists of an eight-page ques-
tionnaire designed to be used with an informant. Questions
are asked about the person with dementia’s physical health,
setting, triggers, strengths, weakness and guides the carer
in the direction of the likely causes of the BC.
In contrast, TREA was developed through a statistical
methodology. It is used in the treatment of different types
of ‘agitation’ (verbal agitation [VA], physical non-aggres-
sion and aggressive behaviours) and suggests that these
behaviours have different aetiologies reflecting underlying
‘needs’, requiring different treatment strategies. For exam-
ple, Cohen-Mansfield’s (2000) empirical data suggest that
the needs that typically underlie VA are related to personal
discomfort, lack of social contacts and physical pain; with
inactivity and depression also playing a role (Figure 24.5).
The TREA approach utilizes a decision tree to arrive at
the most likely cause of the BC based on assessment of the
behaviour, the environment and information about the
individual’s past preferences and needs. The decision tree is
used to guide the caregiver to ascertain the need that is most
likely to be contributing to the behaviour.
24.3.2 TREATMENT PROTOCOLS
In 2013, Brechin et al. reviewed the above literature, and
other work relating to the treatment of BC, and developed
a Stepped-Care approach for the treatment of problem-
atic behaviours. The document produced to support the
Need for social
Causes interaction?
Try social interaction:
Intervention
real or taped
Figure 24.5 Examples of approaches to the management of verbal agitation, from the Treatment Route Exploratory
Agitation model.
approach is both a guide and a literature review of inter-
ventions (Brechin et al., 2013). It outlines four steps and
details when and where to use various physical, psycho-
logical and social approaches. It also provides guidance on
when comprehensive formulation strategies should be used
in contrast to less intensive methods of intervening. All of
the steps invite practitioners to develop their assessments to
look at the ‘under the surface’ elements of the Iceberg model
(Figure 24.1).
Step 1: The Stepped-Care model suggests that, as a matter
of course, the initial approach should be recognizing
common physical causes for changes in behaviour. For
example, the person should be screened for infection,
diabetes, constipation, thyroid disturbance and so on.
This may provide options for quick and targeted treat-
ments while those caring for the person monitor their
physical condition and behaviour, and remain vigilant
to risk.
Step 2: At this stage, emphasis is placed on examining
and changing environmental and caregiver practices.
Thus, the interventions develop from an assessment of
possible environmental and management causes for
the behaviour. Typical assessments tools would include
the use of behavioural charts and diaries such as those
in Figure 24.4.
Step 3: At this stage, specially trained health and social
care staff should be working with caregivers to assess
for potential causal factors. Assessments might
include the use of specific dementia-related observa-
tional tools such as DCM and would always include
systematic information gathering about the person’s
personal context and current behaviour and a review
of previous interventions and outcomes. The use of
decision trees, such as Cohen-Mansfield’s (2000)
TREA model (see Figure 24.5), and Bird’s Treatment
Protocol (McCabe et al., 2015), may lead to new and
more specifically targeted interventions. At this point,
‘as required’ medication may be considered if there is
high risk to others.
Verbal agitation
Need for stimulation?
Need for control?
Boredom?
Identify meaningful Offer choices; provide
activities/physical tasks that allow for
exercise control
252 Dementia
Step 4: This stage requires the involvement of specialist
practitioners using psychological formulation models
to assess the needs of both the person with demen-
tia and the care staff. This step is a more systemic
approach and the mechanism of change includes alter-
ations in the attitudes and attributions of care staff as
well as their caregiving behaviour. All of the elements
in the Iceberg model are brought together in this step
as the dynamic between the person with dementia and
their physical, social and care environment is targeted.
The specialist practitioner will develop a ‘formulation’
(see Figure 24.2), which is a story or hypothesis about
the person’s behaviour taking into their personal and
environmental context.
The formulation is developed using psychological models
to understand behaviour; such as CBT or systemic therapy
models. In most cases, the practitioner shares formulations
with the caregivers via a meeting often referred to as an
Information Sharing Session/Shared Formulation Session
(James, 2011; Jackman, 2013).
In such meetings, the caregivers are guided through the
person’s difficulties in context and invited to make links to
the needs their behaviour might represent. The practitioner
also considers how any current caregiving practices (i.e.
management strategies) might be counterproductive to this
task taking into account the dynamic interplays described
in Table 24.2. The latter processes are designed to foster col-
laboration between the caregivers and practitioner to give a
sense of ownership regarding the assessment, formulation
and subsequent interventions.
Caregivers and/or specialist clinicians would target their
interventions at the appropriate step based on the person’s
presentation, with more severe and complex cases entering
immediately at Step 4. However, in some cases occasionally
the nature of someone’s difficulties may lead them to prog-
ress through the stages, as outlined for illustration purposes
in the following case study.
24.4 CASE STUDY
The following case study illustrates how the Stepped-Care
approach helps to define and address causal factors, delivering
interventions more accurately targeted at these causes. At each
step, the ‘under the surface factors’ – the person’s individual
biography, beliefs and preferences (Figure 24.1) – are taken
into account as part of the assessment process. You will notice
that, unless there are high levels of risk, antipsychotic medica-
tion is not recommended until the higher steps are engaged
(Barnes et al., 2012), unless there is evidence of psychosis.
Mr B is an 83-year-old gentleman with mixed Alzheimer’s/
vascular dementia who lives in care. Over the last 3 weeks,
staff working with him have noticed a change in his behav-
iour. They describe him walking around the unit in an agi-
tated manner trying to open doors and kicking them when
they are locked. He refuses food and he is becoming distressed
with staff providing care to him in the bathroom, sometimes
trying to push them away and swearing at them.
Step 1 – Recognition: A physical assessment demonstrated
that Mr B was constipated. He was prescribed laxative
medication and staff were given advice about improving
his diet and exercise regime. Although Mr B’s constipa-
tion resolved over the following few weeks, he contin-
ued to display agitation. He started to pace around the
lounge and refuse medication. He was verbally hostile
and flicked his tie when people approached him.
Step 2 – Low Intensity Interventions: An assessment of
environmental factors associated with Mr B’s behav-
iour showed that he was largely showing this disturbed
behaviour in the lounge area, but was relatively calm
elsewhere. Behaviour charts also suggested that there
were only a few members of staff who experienced
this continued agitation and these caregivers tended
to employ some restricted practices on the unit. For
example, these staff preferred to have all of the resi-
dents in one place just before lunch so the medication
could be easily given out.
  Mr B was often so upset around lunch time that
his appetite was affected. His family told staff that he
was not a sociable person and had problems mixing
with other people. They wondered if he might feel
intimidated by the behaviour of the other residents. As
a result of the remarks made by the family, Mr B was
given a dining table to himself and allowed to eat later
than others, at a time when more assistance could be
given. Here, we see caregiving practices beginning to
take into account Mr B’s interpretation of his environ-
ment and consequent emotional state.
  After an initial improvement, Mr B’s behaviour
worsened. He started to ‘interfere’ with other people’s
belongings, ‘targeting’ particular staff he did not like.
He was repetitive and perseverative in speech and
swore at visitors. He was often tearful and distressed,
especially in the mornings.
Step 3 – High Intensity Interventions: At this stage, trained
health and social care staff were brought in to work
with caregivers to assess for other causal factors. Mr B
was reassessed by clinicians who reviewed his previ-
ous interventions. Bird’s Treatment Protocol was used
to help identify potential causes. Via Bird’s checklist
it was thought that some of his symptoms might be
related to an unresolved depression and so an antide-
pressant was prescribed. Alongside this, it was noted
that Mr B’s memory and general cognitive functioning
had declined. He had become dysphasic when at his
most symptomatic, and it was at these times that he
became most distressed and threatening.
  DCM was also used to help understand the envi-
ronmental impact on his behaviour, and it was fed
back to carers that they were making quite heavy cog-
nitive demands on him at times. For example, giving
 Treating problem behaviours in dementia by understanding their biological, social and psychological causes 253

him complicated instructions such as ‘if you could
wait here a moment, we’ll bring your tablets and then
have you seated for your lunch’, which he misunder-
stood, leaving him frustrated and embarrassed. On
reflection the staff noted that he had been an English
teacher who was used to being articulate and able, and
hypothesized that his communication difficulties may
be a further source of frustration. Information about
dementia was provided to staff in a teaching session to
help them make sense of Mr B’s overall presentation.
  Despite using the above tools and strategies,
Mr B continued to display acute high levels of agita-
tion at least once a day. As such it was felt that a Step 4
approach was required, involving the development of
a bespoke formulation. This approach usually requires
the assistance of specialist clinicians, who adhere to
specific treatment protocols, resulting in the develop-
ment of formulation-led targeted interventions.
Step 4 – Specialist Interventions: Mr B was reviewed by
a specialist clinician trained in the use of evidenced-
based protocols, such as the Newcastle model
(James, 2011) and Cohen-Mansfield’s needs-led frame-
work (Cohen-Mansfield, 2000). In this particular case,
the Newcastle model was chosen. Via this approach
the clinician gathered information about Mr B’s life
and experiences and presented this to the caregivers
in an information sharing session (ISS) along with
information about his cognitive impairment and
physical health problems. During the presentation, the
staff were invited to consider the contrast between the
previous life of this independent, proud and articulate
man, with his current position where he had little
control over his environment and deficits, mean-
ing he could not express this frustration or despair
appropriately. The caregivers were able to agree that
his ­agitation was probably caused by his need to regain
some control over his life, his need to express his
distress and his need to have some private and quiet
time. As a result, successful care plans were devised
that recognized his individual needs (Table 24.3) but
which also reflected the high level of risk he could pose
when distressed.

Table 24.3 ‘Traffic Light’ care plans for Mr B

Well-being care plan Mr B is prone to infection, which can leave him feeling tired and out of sorts. Staff should
(green) regularly check his urine markers for infection.
Mr B suffers from constipation. A bowel movement chart should be kept. He should be offered
more high fibre foods at times when he is constipated. He does not like high fibre foods but
will recognize the need if you explain that he is constipated.
Mr B used to describe himself as a loner and does not like to eat with others. Mr B should be offered
a quiet area to eat his meals although accommodated in the main dining room if he prefers.
Mr B often feels low in mood especially in the mornings when he misses his family. His mood lifts
if he has access to activities he enjoys. As he has always enjoyed domestic tasks, staff should
engage Mr B in clearing breakfast away and setting tables for lunch. Mr B is then to have an
opportunity to have a drink with staff after helping.
Mr B has some difficulty understanding instructions and conversation. All staff should use
simplified language with Mr B and allow him time to respond to any requests or questions. NB.
DO NOT USE CHILDISH EXPRESSION OR TONE.
Mr B has always had control over his own life and this is difficult for him now. Staff should provide
opportunities wherever possible for Mr B to be involved in decision making.
Address escalating Mr B shows us he is feeling frustrated or crowded by flicking his tie and making growling noises.
problems (amber) At these times, staff should monitor the business of the environment and offer Mr B the
opportunity to move somewhere quieter. If he refuses, staff should offer others in the area an
alternative place to spend time.
Mr B may enter other people’s rooms and take their belongings. This is a sign that he is lost and
searching for familiar objects. This usually happens on days when his understanding is not so
good. Staff should adapt requests or tasks to his lowered level of functioning at these times.
For example, distract him from other people’s rooms by offering alternative objects rather than
by giving instruction.
Consider using an ‘as required’ dose of a Benzodiazepine. Ensure this is recorded monitored and
reported to the senior member of staff and family.
Risk management (red) At times when Mr B has become extremely distressed, it may be difficult to calm him. Provide 1:1
observation from a distance until the distressed period is over. Then approach and offer
reassurance.
If Mr B seems distressed by specific residents, ensure that another member of staff moves with
them to an alternative environment.
Mr B sometimes responds well to his son’s visits. Consider telephoning Mr B’s family for support.
254 Dementia
Teams using the Newcastle model have found it help-
ful to develop specific care plans to meet well-being needs
(thereby avoiding the person’s need to communicate dis-
tress) to recognize the onset of an episode of distress (and
to take immediate opportunities to intervene on the envi-
ronment or through different levels of care) and to manage
highly risky situations. Sells and Shirley (2010) refer to these
as ‘Traffic Light’ care plans. An example for Mr B appears
in Table 24.3.
Cases frequently do not present themselves in such
an orderly and progressive fashion, but the case has been
used to clarify the various steps. Importantly, the four-
step framework encourages people providing interventions
to consider some basic strategies first to address the most
common causes of BC. The later steps continue to incorpo-
rate these basic physical and environmental causes as well
as looking more closely at the meaning the person with
dementia might be making of their environment.
24.5 TRAINING
In the United Kingdom, two-thirds of people with dementia
are cared for at home, in many other countries the figure is
far higher. Hence, supporting family carers is an essential
part of any treatment regimen in BC. By keeping carers fit
and mentally healthy, they can deal better with the tasks of
supporting and caring for the person through any challeng-
ing period. Moniz-Cook et al.’s recent Cochrane review on
the use of behaviour therapy (functional analysis [FA]) of
BC has shown that 66% of the 15 quality studies have been
conducted within ‘own-home’ settings. The overall findings
of this systematic review demonstrated that the use of FA
behavioural methodologies can significantly reduce care-
giver burden.
Carer interventions take various forms. The psychother-
apeutic approaches may use either a formal 1:1 therapy or
a group format, while education and training approaches
can be used to enhance skills, improve knowledge and atti-
tudes (Mittelman et al., 2004, 2007; McCabe et al., 2007).
It is relevant to note each of the approaches has a different
goal. The formal therapeutic approaches tend to be used
to tackle psychiatric disorders, such as carer depression
and anxiety. The teaching methods enhance coping abili-
ties, and help the carers to develop practical caring skills.
One of the few approaches to have an empirically validated
manual for the treatment of BC is Teri’s Staff Training in
Assisted Residences (STAR) programme (Teri et al., 2005a,
2005b, 2012). STAR teaches staff to understand and modify
their interactions with residents by identifying ABCs. The
programme also involves teaching on dementia, communi-
cation skills and use of activities. Teri has conducted two
Randomized Controlled Trials using STAR; one for families
and one in a 24-hour residential setting (Teri et al., 2005a,
2005b). Both of these studies are included in Moniz-Cooks’
Cochrane, which shows that of the five quality studies
conducted into residential care settings, none employed
CBT, despite all aiming to change staff attitudes (Proctor
et al., 1999; Teri et al., 2005b; Fossey et al., 2006; Visser et al.,
2008; Chenoweth et al., 2009).
There has also been a number of systematic reviews
regarding caregiver training and support programmes
(Sörensen et al., 2002; Cooper et al., 2006). Despite Cooper’s
review examining only anxiety in caregivers of people with
dementia, her categorization of the types of interventions
is a helpful summary of the approaches used. Here are the
types of projects she identified, together with the num-
ber of trials she found under each heading: five CBT trials
(Gendron et al., 1986, 1996; Wilkins et al., 1999; Hébert
et al., 2003; Akkerman and Ostwald, 2004); four coping
strategy/professional support; four alternative placements;
three behavioural interventions; three respite; two relax-
ation/yoga; two exercise; one group counselling and one
information technology support.
Her conclusion from the review was somewhat disap-
pointing with only Akkerman and Ostwald’s CBT study
showing significant effects in terms of anxiety. This was
a 9-week CBT intervention that reduced anxiety in fam-
ily carers of people with dementia. Their approach also
included training in relaxation when appropriate.
The picture around the efficacy of training is compli-
cated due to the potential mismatch between attendee
reports of the benefits and the actual improvements in out-
comes for residents (McCabe et al., 2007). The growth in
dementia-related training, following an increase in interest
from governments around the world, also raises problems
for measurement of effectiveness due to the lack of stan-
dardization of the programmes. Further, we lack clarity
around what mechanism is responsible for translating staff
training to a change in the behaviour of the person with
dementia.
The approach we have described in this chapter suggests
that enhanced knowledge about dementia, coupled with a
greater understanding of the individual and their needs,
enables staff in care homes to more effectively (1) establish
appropriate interventions to address the cause of the per-
son’s behaviour and (2) to recognize their own role in main-
tenance cycles. Measurement of this change in focus of care
staff is difficult as there are no well-established measures
of attributional change for people working with this client
group (Shirley, 2005).
Finally, the evidence for the benefits of training aimed
at reducing BC has repeatedly demonstrated that train-
ing on its own is not sufficient to produce lasting effects.
In a recent randomized control trial across Australian and
New Zealand care facilities, McCabe et al. (2014) found
that improvements in levels of BC after training were only
maintained for the group receiving post-training clinical
support. Likewise, when community nurses were trained
to support families caring for people with dementia whose
behaviour challenged, the effect relied on extensive train-
ing and ongoing clinical supervisions and support (Moniz-
Cook et al., 2008).
 Treating problem behaviours in dementia by understanding their biological, social and psychological causes 255
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 25
Treatments for behavioural and psychological
symptoms in Alzheimer’s disease and other
dementias

ANNA BURKE, WILLIAM J. BURKE AND PIERRE N. TARIOT

●● Aggressive (e.g. physical, such as hitting or slapping, or

25.1 INTRODUCTION verbal, such as obscenities or name calling)

Merriam et al. (1988) asserted that Alzheimer’s disease (AD) As Table 25.1 indicates, half or more of patients with
is ‘the most widely encountered cause of psychiatric pathol- dementia will show some feature of agitation at some point
ogy associated with a specific neuropathological substrate’. in the course of illness.
This is consistent with phenomenological studies and litera-
ture reviews, which generally converge on the conclusion Table 25.1 Summary of literature regarding
that roughly 90% of patients with dementia will develop psychopathology of dementia (per cent of patients
significant behavioural problems at some point in their affected among studies reviewed)
­illness (Tariot and Blazina, 1993). The ‘behavioural and
­psychological signs and symptoms of dementia’ (Finkel et al., Range Median
1996) do not typically meet criteria for discrete ­psychiatric 1. Disturbed affect/mood 0–86 19
disorders. They do, however, tend to occur in clusters of 2. Disturbed ideation 10–73 33.5
signs and symptoms that may vary among patients and over 3. Altered perception
time (Tariot and Blazina, 1993). Examples of these clusters Hallucinations 21–49 28
are provided in Table 25.1, based upon a review of published Misperceptions 1–49 23
studies regarding psychopathological changes in dementia 4. Agitation
that was performed in 1993. With experience, these clus- Global 10–90 44
ters of signs and symptoms can be both predicted and rec-
Wandering 0–50 18
ognized, and can be used as guideposts in the selection of
5. Aggression
appropriate therapy.
Verbal 11–51 24
This chapter will focus on agitation, which Cohen-
Mansfield and Billig (1986) defined as ‘inappropriate Physical 0–46 14.3
verbal, vocal, or motor activity unexplained by apparent Resistive/uncooperative 27–65 44
needs or confusion’. Cohen-Mansfield and Billig (1986) 6. Anxiety 0–50 31.8
empirically categorized agitated behaviours into three key 7. Withdrawn/passive behaviour 21–88 61
groups: 8. Vegetative behaviours
Sleep 0–47 27
●● Disruptive but not aggressive (e.g. attempts to leave, Diet/appetite 12.5–77 34
robes and disrobes, repeated complaints or questions) Source: Tariot, P.N. and Blazina, L. In J. Morris (ed.), Handbook of
●● Socially inappropriate (e.g. disrobing or urinating in Dementing Illnesses, New York, Marcel Dekker Inc.,
public) pp. 461–475, 1993.

257
258 Dementia
25.2 A RATIONAL APPROACH
This chapter proposes a systematic general approach to the
evaluation and management of agitation that is based on
an elaboration of prior work (Leibovici and Tariot, 1988;
Tariot, 1996, 1999); key aspects are described as follows:
Define target symptoms. Review the available evidence
and delineate the patient’s behaviour pattern, for
example, ‘wanders without an apparent destination,
calls out repeatedly, bites and kicks during care’.
Establish or revisit medical diagnoses. It is a truism in
geriatrics that delirium is a frequent cause of incident
agitation and must always be suspected. Common cul-
prits include respiratory or urinary infections, dehy-
dration, occult trauma, electrolyte disturbances or side
effects of medications. Such medical problems should
be treated specifically and the patient monitored care-
fully, ideally without the need for other medications.
Establish or revisit neuropsychiatric diagnoses. It is also
possible that disturbed behaviour may reflect a long-
standing, recurrent or new-onset discrete psychiatric
disorder. When a specific disorder is identified, it
should be specifically treated and monitored.
Assess and reverse aggravating factors. Examples might
include deficits in hearing or vision, or an environ-
ment that is too dark, noisy or cold. Disrupted daily
routines may present a remediable factor. It is impor-
tant to look hard for environmental triggers, sleep
deprivation or biological triggers such as pain or
constipation.
Adapt to specific cognitive deficits. Some patients may
be able to respond to verbal reassurance and redirec-
tion, whereas others may not. Pain or distress may
need to be inferred from behaviour or facial expres-
sion. Some may need constant environmental cueing
to organize their behaviour. It is important to identify
each patient’s cognitive strengths and weaknesses,
attempting to capitalize on residual strengths and
avoid weaknesses.
Identify relevant psychosocial factors. It may be easy to
overlook the fact that a patient with dementia may be
suffering anxiety, sadness, denial or fury in response
to major and minor life events. In some long-term
care facilities, for instance, moving from one unit to
another can be associated with perceived loss of status
as well as contact with familiar people. It is easy to
overlook this as a precipitant of ‘agitation’.
Educate caregivers. Caregivers can learn that change in
behaviour usually has meaning and that the behav-
iours can occur in discernible patterns. This helps
caregivers interact in a more supportive manner.
In the process, caregivers can be taught to employ
essential behaviour management principles, learn-
ing, for instance, that their own behaviour is a major
determinant of the patient’s behaviour. Caregivers can
be trained to identify common triggers as well as con-
sequences of agitated behaviour and work with health
professionals to attempt to minimize the triggers and
maximize more positive circumstances.
If the behavioural disturbance is grossly aggressive or
disruptive, and frankly dangerous, it may be necessary to
use antipsychotics on an emergency basis, preferably by
mouth but sometimes parenterally. In rare cases, hospital-
ization is needed. Once the emergency is under control, it
is imperative to pay attention to the basics outlined earlier.
25.3 DEVELOPMENT OF THE
PSYCHOBEHAVIOURAL
METAPHOR
For persisting non-emergent problems where non-­
pharmacological interventions have been exhausted, we adopt
an approach that begins with a definition of a target symptom
pattern that is at least roughly analogous to a drug-responsive
syndrome. We refer to this as the ‘psychobehavioural meta-
phor’ (Leibovici and Tariot, 1988). We then match the domi-
nant target symptoms (the metaphor) to the most relevant
drug class. For example, in the case of a verbally and physically
agitated patient who is also irritable, negative, has become
socially withdrawn and appears dysphoric, we might well
first undertake a trial of an antidepressant. Conversely, if the
patient showed ‘agitation’ in the context of increased motor
activity, loud and rapid speech and lability of affect, we might
consider early use of a mood stabilizer. The ‘aggressive’ patient
whose hostile actions are associated with delusions is likely to
be treated first with an antipsychotic. Although this approach
to drug selection is face valid, there is limited empirical sup-
port for it (Lyketsos et al., 2000; Devanand, 2000; Tariot et al.,
2001a, 2002a; De Deyn et al., 2003). Thus, the validity of the
approach that we have endorsed for some years, and that is
reflected in most consensus guidelines (Doody et al., 2001;
Alexopoulos et al., 2005; APA Work Group on Alzheimer’s
Disease and other Dementias, Rabins et al., 2007; Rabins et al.,
2014), has not been established empirically. Furthermore, the
use of medications to treat any aspect of psychopathology is
not recognized by the U.S. Food and Drug Administration
and would thus be considered ‘off-label’.
The approach adopted in this chapter more or less reflects
the position of the American Geriatrics Society and American
Association for Geriatric Psychiatry consensus statement
(2003) and the American Psychiatric Association (Rabins
et al., 2007, 2014) with respect to the use of target symptoms
to guide selection of drug class. We emphasize selection of a
medication with at least some empirical evidence of efficacy
and with the highest likelihood of tolerability and safety. We
observe some general rules such as starting with low doses
and escalating slowly, assessing target symptoms as well as
toxicity and discontinuing the medication if it is harmful or
ineffective. Even when a medication is helpful at sub-toxic
 Treatments for behavioural and psychological symptoms in Alzheimer’s disease and other dementias 259

doses, an empirical trial is often performed in reverse and the Table 25.2 Selected current pharmacological treatments
patient monitored for recurrence of the problem. This type of for agitation in dementia
approach is actually mandated in the nursing home setting
Suggesting starting and (maximal)
in the United States by Federal regulations created in 1987.
Drug and class daily dose (mg/day)a
Sometimes several medications need to be tried in series
before a successful one is identified; sometimes combinations Antipsychotics
are warranted; sometimes no medication is found that is Traditional
helpful. We hold the view that best practice includes routine Haloperidol 0.25–0.5 (2–4)
use of cholinesterase inhibitors (ChEIs) and/or memantine Thioridazine 12.5–25 (50–100)
in most patients with AD as well as certain other dementias, Thiothixene 0.5–1 (2–4)
meaning that psychotropic use occurs against this backdrop. Atypical
Evidence suggests that ChEIs and/or memantine may be of Clozapine 6.25–12.5 (25–100)
benefit in reducing less severe agitated or aggressive behav-
Olanzapine 2.5 (5–10)
iours in patients with AD or possibly delaying their emer-
Quetiapine 25 (50–200)
gence (Birks and Flicker, 1998; Trinh et al., 2003; Cummings
Risperidone 0.5 (1–2)
et al., 2006 a,b; Wilcock et al., 2008). The trials conducted
Aripiprazole 5 (15)
with these agents were aimed towards obtaining regulatory
Ziprasidone Unknown
approval and not informing clinical practice regarding issues
such as the advantages or disadvantages of one agent versus Anxiolytics and sedatives
the other for relief of behavioural symptoms, or of using psy- Benzodiazepines
chotropics in combination with these agents. Practice will Alprazolam 0.5 (1–2)
outstrip evidence for the foreseeable future. Lorazepam 0.5 (2–4)
Oxazepam 10 (40–60)
Non-benzodiazepines
25.4 SPECIFIC CLASSES Zolpidem 2.5 (5)
OF PSYCHOTROPICS Buspirone 10 (30–60)
Antidepressants
The remainder of this chapter reviews the most relevant Trazodone 25–50 (200–300)
classes of agents and specific agents within those classes, SSRIs
focusing on information from about the last 5 years and on Citalopram 10 (20)
older studies that remain as crucial guides to practice. Much Fluoxetine 10 (20)
of the older literature was reviewed previously in the last Sertraline 25–50 (100–200)
edition of this textbook (Profenno et al., 2005); this chapter Anticonvulsants
builds on that as well as some of our earlier work (Tariot,
Carbamazepine 50–100 (300–500)
1999; Loy et al., 1999; Rosenquist et al., 2000; Profenno and
Divalproex 125–375 (500–1500)
Tariot, 2004). Table 25.2 provides an overview of individual
β-Blockers
agents and typical starting doses, proposed based upon a
mixture of data and clinical experience. Propranolol 20 (50–100)
Others
Selegiline 10
25.5 CONVENTIONAL Oestradiol/ 0.625/2.5
ANTIPSYCHOTICS progesterone
Source: Loy, R., et al. In I.R. Katz, Oslin, D. and Lawton, M.P. (eds.)
Within the context of the ‘metaphor’ approach, antipsy- Annual Review of Gerontology and Geriatrics: Focus on
Psychopharmacologic Interventions in Late Life. New
chotics would be used first for treatment of agitation that York, NY: Springer, 1999.
included psychotic features. In reality, antipsychotics have a Suggestions are based on published data as well as anecdotal

been used and studied in patients with a wide range of psy-
chopathology. There are two main classes of antipsychotics:
so-called conventional or first generation antipsychotics
and the newer atypical or second generation agents. Prior
reviews of the conventional agents have concluded that the
effects of these agents were consistent but modest and that
no single agent was better than another (Wragg and Jeste,
1989; Schneider et al., 1990) (Table 25.3).
Lanctôt et al. (1998) performed a meta-analysis includ-
ing some studies that were less rigorous than those included
experience, and should be regarded accordingly.
in the Schneider et al. (1990) meta-analysis. These authors
also concluded that type and potency of agent did not influ-
ence response. They reported an average therapeutic effect
(antipsychotic versus placebo) of 26%, with placebo response
rates ranging from 19% to 50%. Side effects were reported to
occur more often on drug than placebo (mean difference 25%).
These meta-analyses did not include five more recent studies
(Devanand et al., 1998; De Deyn et al., 1999; Allain et al., 2000;
260 Dementia

Table 25.3 Conventional antipsychotics

Dose (mg/day), Adverse
Study Diagnosis N Design duration Response effects
Haloperidol
Schneider Dementia 252 (in 7 Meta-analysis 2.5–4.6, Little benefit beyond Not reported
et al. DB, PC of 33 haloperidol, placebo across all
(1990) trials in neuroleptic 3–8 weeks neuroleptics;
primary trials average effect 18%
dementia) greater than
placebo
Devanand AD 71 Randomized 2–3 or 0.5–0.75, Decreased psychosis, Moderate-to-
et al. DB, PC, 6 weeks aggression, severe EPS
(1998) parallel agitation with at high dose
group higher dose only, (20%)
55%–60% response
vs. 25%–35% low
dose response vs.
25%–30% placebo
Christensen Organic 48 Randomized Mean 0.64, 6 No difference None seen at
et al. mental crossover to weeks between this low dose
(1998) syndrome alprazolam treatments on CGI,
SCAG
DeDeyn AD, 344 Randomized Mean 1.2, 13 Significantly greater EPS 22%,
et al. vascular, MC, DB, weeks improvement for somnolence
(1999) mixed parallel haloperidol vs. (18%
group placebo on haloperidol
risperidone BEHAVE-AD and vs. 4%
or placebo CMAI, decreased placebo)
physical and verbal
aggression (72%
risperidone vs. 69%
haloperidol vs. 61%
placebo on
BEHAVE-AD)
Allain AD, VD, 306 Randomized 100–300 tiapride Significantly Less EPS with
(2000) mixed MC, DB, or 2–6 improved CGI and tiapride than
PC, parallel haloperidol, MOSES irritability/ haloperidol
group 21 days aggress-iveness
sub-score for both
drugs compared to
placebo, no
differences
between drugs
Teri (2000) AD 149 Randomized 1.8 haloperidol, Reduced agitation Less EPS with
DB, PC, 200 trazodone not significantly behaviour
parallel or behaviour different between management
group management treated and techniques
techniques, placebo groups
16 weeks
Tariot Probable 284 Randomized, Mean 1.89, 8 No change in EPS, sedation
(2002a) AD with PC, DB vs. weeks psychosis, some
psychosis quetiapine decrease in
(n = 94 on agitation
haloperidol)
 Treatments for behavioural and psychological symptoms in Alzheimer’s disease and other dementias 261

Teri et al., 2000; Tariot et al., 2002a). The data from these newer
studies generally conform to the results of the meta-analyses.
Lonergan et al. conducted a pooled analysis of five randomized
trials of haloperidol versus placebo that included two studies
not incorporated in the previous meta-analysis, which found
decreased aggression but no significant improvement in agi-
tated symptoms overall among the patients treated with halo-
peridol. There was also a noteworthy increase in adverse side
effects such as rigidity and bradykinesia compared to placebo.
Reviews regarding conventional agents cite side effects
including akathisia, parkinsonism, tardive dyskinesia (TD),
sedation, peripheral and central anticholinergic effects,
postural hypotension, cardiac conduction defects and falls
(Lanctôt et al., 1998; Lonergan et al., 2002). Based on limited
efficacy and a high likelihood of toxicity, Lonergan et al. con-
cluded by recommending that haloperidol be used sparingly,
on a case by case basis, with monitoring of side effects. Most
of these data come from short-term controlled trials; evi-
dence regarding long-term safety is generally lacking. Data
available from other elderly populations, however, indicate
that caution is warranted. For instance, rates of TD are five-
to six-fold greater in older than in younger populations after
treatment with conventional agents (Jeste et al., 1995). Recent
studies also indicate higher mortality rates in patients with
dementia receiving conventional antipsychotics versus those
receiving atypical agents (Kales et al., 2012; Huybrechts et al.,
2012). For practical purposes, side effects typically guide
selection of these agents when used in patients with demen-
tia. A clinical issue that is of particular importance is demen-
tia with co-occurring extrapyramidal disorders such as
dementia with Lewy bodies, where occasional extraordinary
sensitivity to conventional agents is seen (Ballard et al., 1998).
For all these reasons, it was hoped that atypical antipsychot-
ics would have special utility in patients with dementia.
25.6 ATYPICAL ANTIPSYCHOTICS
Atypical antipsychotics are listed in Table 25.4.

Table 25.4 Atypical antipsychotics

Dose (mg/day),
Study drug Diagnosis N Design duration Response Adverse effects
Olanzapine
Satterlee et al. AD 238 Randomized, 1–8, 8 weeks No benefit vs. placebo None reported vs.
(1995) MC, PC, DB placebo
Street et al. AD, 206 Randomized, 5, 10 and 15, Decreased agitation, Dose-dependent
(2000) moderate- MC, PC, DB, 6 weeks delusions, sedation,
to-severe parallel group hallucinations on abnormal gait
NPI-NH at 5 and 10
(but not 15) mg/day
vs. placebo
Street et al. AD 105 Open as Flexible 5–15, Significantly improved Somnolence,
(2001) follow-up to 18 weeks agitation and other accidental injury,
previous symptoms by NPI/ rash
6 week DB trial NH and other scales
Meehan et al. AD, VaD or 272 Randomized, intramuscular 5, Decreased agitation at No significant
(2002) mixed with MC, PC, DB 2.5, or 1 2 and 24 h difference
acute lorazepam, between
agitation 2 h and prn placebo and any
×2 within 20 h active treatment
Quetiapine
Tariot et al. Various 184 Open, MC 12.5–800 Significant decreases Somnolence (31%),
(2000a) psychotic (median in BPRS total and accidental injury
disorders 137.5), CGI Severity (24%), dizziness
52 weeks (17%)
Scharre and AD 10 Open 50–150 (mean = Improved NPI for Drowsiness (40%),
Chang, 100), delusions and weight gain
(2002) 12 weeks agitation or (40%)
aggression
Davis and DLB 10 Open 25–150 (50 mg Significant reduction in No significant
Baskys modal), total NPI and increase in EPS
(2002) 12 weeks agitation subscales
of NPI and BPRS
(Continued )
262 Dementia

Table 25.4 (Continued) Atypical antipsychotics

Dose (mg/day),
Study drug Diagnosis N Design duration Response Adverse effects
Tariot et al. Probable AD 284 Randomized, Mean 100, No change in Sedation
(2002a) with DB, PC vs. 8 weeks psychosis, some
psychosis haloperidol decrease in agitation
(n = 91 on
quetiapine)
Ballard et al. AD, dementia 93 Randomized, Mean 100, No change in Cognitive decline
(2005) DB, PC 26 weeks psychosis, some
decrease in agitation
Tariot et al. Possible/ 284 Randomized, Mean 96.9, Improvement in Somnolence
(2006) probable MC, PC, DB 10 weeks agitation and
AD psychosis
Zhong et al. Dementia 333 DB, fixed dose Mean, 10 weeks Clinically greater No significant
(2007) improvements in difference
Positive and between
Negative Syndrome placebo and any
Scale–Excited active treatment
Component CGI-C
and CGI-C response
rates
De Deyn AD 100 Randomized, Mean 143.6, NPI frequency × None reported vs.
et al. (2012) DB, double 142, 6 weeks severity total, placebo
dummy NPI-NH version,
CMAI, CGI-S CGI
scores improved
Risperidone
Herrmann AD, vascular, 22 Case reports Mean 1.5, Improvement CGI (17) EPS (11), sedation
et al. DLB 1 week, (1), drooling (1)
(1998b) 10 months
Lavretsky and AD, vascular, 15 Open 0.5–3, 9 weeks Decreased agitation (in Sedation (5),
Sultzer PD, (concurrent all 15) akathisia (1)
(1998) Progressive psychotropics
Supranuclear allowed)
Palsy, mixed
De Deyn AD, VaD, 344 Randomized MC, Mean 1.1, Decreased physical EPS not different
et al. (1999) mixed DB, parallel 13 weeks and verbal from placebo,
dementia group vs. aggression (72% somnolence
placebo or risperidone vs. 69% (12% risperidone
haloperidol haloperidol vs. 61% vs. 4% placebo)
for placebo)
Katz et al. AD, VaD, 625 Randomized MC, 0.5, 1.0, 2.0, Dose-dependent Somnolence, EPS
(1999) mixed PC, DB, 12 weeks decrease in 21% (on 2 mg/
dementia parallel group aggression and day, compared
(lorazepam, psychosis, significant with 12% on
benzatropine at 1 and 2 (but not placebo), mild
and chloral 0.5 mg/day) peripheral
hydrate oedema in some
allowed PRN)
Brodaty et al. AD, VaD, 345 Randomized, Mean 1.0, Significant reductions Somnolence,
(2003) mixed MC, PC, DB 12 weeks in CMAI total urinary tract
aggression score infection
and BEHAVE-AD
aggressiveness
(Continued)
 Treatments for behavioural and psychological symptoms in Alzheimer’s disease and other dementias 263

Table 25.4 (Continued) Atypical antipsychotics

Dose (mg/day),
Study drug Diagnosis N Design duration Response Adverse effects
Schneider AD, 5110 Meta-analysis of Mean 0.97 ± Decreased agitation Somnolence, UTI,
et al. dementia randomized, 0.74 mg, EPS, gait
(2006a, PC, DB, 16 weeks abnormalities
2006b) parallel-
group trials
Devanand AD 180 Open Mean 0.97 mg, In patients with
et al. (2012) 32 weeks psychosis or
agitation that had
responded to
risperidone therapy
for 4 to 8 months,
discontinuation of
risperidone was
associated with an
increased risk of
relapse

Aripiprazole
DeDeyn et al. AD 108 Randomized, Mean 10 mg, No significant drug- Somnolence (in 1%
(2003) PC, DB 10 weeks placebo difference of placebo and
on primary end 8% of drug
point. Some groups)
secondary measures
showed drug-
placebo differences
at some time points.
Breder et al. AD 487 Randomized, Mean 2, 5, Significant drug- No significant
(2004) PC, DB 10 mg, 10 placebo difference differences in
weeks on primary end rates of adverse
point in 10 mg/d events across
group. Significant groups
effects on CGI-S and
total BPRS in
10 mg/d group;
significant effects in
5 and 10 mg/d
groups on CMAI
Streim et al. AD 256 Randomized, Mean 8.6 mg/ No significant drug- Somnolence (4% in
(2008) PC, DB day, 10 weeks placebo difference pla and 14% in
on primary end aripiprazole
points. groups)
Mintzer et al. AD 487 Randomized, Mean 2, 5, 10 mg/day was CVA
(2007) MC, PC, DB 10 mg, efficacious and safe
10 weeks for psychosis
associated with AD,
significantly
improving psychotic
symptoms, agitation,
and clinical global
impression
264 Dementia
25.6.1 CLOZAPINE
Only anecdotes and case reports are available; none are
new and are the same as mentioned in the previous chap-
ter. Individual patients showed partial improvement in agi-
tation or psychosis, whereas others developed side effects
including sedation and anticholinergic effects. While not
mentioned specifically in these reports, agranulocyto-
sis and seizures have been reported in other populations,
the former requiring regular haematological testing for
months. Dose–response issues are unresolved. In using this
medication, we err on the side of caution by starting at 6.25
or 12.5 mg/day. Based on the relative lack of motor toxicity
encountered with clozapine, a case can be made to select this
agent preferentially in patients with dementia and extrapy-
ramidal disorders. However, in view of the lack of informa-
tion regarding dose–response, the risk of side effects in the
elderly and the lack of controlled data regarding efficacy and
tolerability, most clinicians are likely to choose from among
the newer atypical agents first.
25.6.2 RISPERIDONE
The earliest exploratory studies indicated that doses in the
range of 0.5–2 mg/day might be best tolerated, with dose-
related risk of motor toxicity (especially in patients with
extrapyramidal disorders). Sedation, peripheral oedaema
and orthostatic hypotension were sometimes reported.
Use of risperidone can result in increased prolactin levels
in other populations, although the clinical significance
of this in patients with dementia is uncertain. We do not
routinely check serum prolactin levels and would only
take action in response to elevated levels associated with
symptoms associated with its use (e.g. galactorrhoea in
women, sexual dysfunction in men) or with symptoms
indicative of a possible hypothalamic tumour (e.g. diplo-
pia). The earlier open trials and case series indicated that
risperidone may decrease agitation, aggression or psychosis
in patients with dementia, spawning more definitive tri-
als. Three large multicentre trials of risperidone have been
completed in nursing home patients with relatively severe
dementia (Katz et al., 1999; De Deyn et al., 1999; Brodaty
et al., 2003) and one in outpatients (Mintzer et al., 2004).
A meta-analysis of results from these four studies revealed
that risperidone significantly reduced measures of agitation
and/or psychosis in comparison with placebo (Schneider
et al., 2006a, 2006b). Risperidone-treated patients displayed
positive effects on measures of psychosis. In patients with
AD who had psychosis or agitation that had responded to
risperidone therapy for 4 to 8 months, discontinuation of
risperidone was associated with an increased risk of relapse
(Devanand et al., 2012). The main side effects in these trials
were somnolence, extrapyramidal symptoms (EPS), abnor-
mal gait and peripheral oedema in addition to cerebrovas-
cular adverse events (CVAEs) and death described later.
In the aggregate, these risperidone studies comprise
the largest placebo-controlled, multicentre studies ever
conducted of any form of treatment for agitation or aggres-
sion associated with dementia. A conservative interpreta-
tion of the available evidence would be that the efficacy of
risperidone is roughly equivalent to that of haloperidol.
The tolerability of risperidone appears to be better at doses
below 2 mg/day, with low-to-moderate risk of dose-related
parkinsonism and sedation and numerically higher rates of
peripheral oedema and sedation in patients treated with ris-
peridone versus placebo.
In 2003, the Food and Drug Administration (FDA) issued
a warning titled ‘Cerebrovascular Adverse Events, Including
Stroke, in Elderly Patients with Dementia’ prompting con-
cerns regarding the drug’s safety. It referred to CVAEs
(stroke, transient ischaemic attack), including fatalities,
reported in patients (mean age 85 years; age range 73–97)
in trials of risperidone in elderly patients with dementia-
related psychosis and/or agitation. In placebo-controlled
trials, a significantly higher incidence of CVAEs was noted
in patients treated with risperidone compared to those
treated with placebo (Woolerton, 2002). Risperidone was
associated with a threefold increased risk of serious CVAEs
compared with placebo. Soon thereafter, a similar warning
was applied to olanzapine and aripiprazole. The increased
risk for CVAEs was determined from research clinical trials
and is based on unbiased estimates. However, the construct
‘CVAEs’ was defined after the trials were completed and was
based on spontaneously reported adverse events and inter-
pretation of the risk was limited by the fact that the studies
were not designed to investigate a causal link with CVAEs
(Burke and Tariot, 2009).
25.6.3 OLANZAPINE
Studies suggest benefit of olanzapine in treating agitation
in patients with dementia. A 6-week, randomized, parallel-
group, multicentre study of olanzapine in 206 nursing home
residents with dementia and agitation and/or psychosis was
completed using fixed doses of 5, 10 and 15 mg/day ver-
sus placebo (Street et al., 2000). In patients receiving 5 and
10 mg/day, significant improvement in agitation and aggres-
sion compared to placebo was seen, and patients receiving
5 mg/day also demonstrated significant improvement com-
pared with placebo in broader assessments of psychopathol-
ogy. Sedation and postural instability were observed at all
doses in at least 25% of subjects. Some of the patients from
this trial received follow-up open-label, flexible-dose treat-
ment for 18-weeks; results were consistent with the findings
from an earlier paper (Street et al., 2001).
Meehan et al. (2002) studied acute treatment of agita-
tion with intramuscular olanzapine in 272 inpatients or
nursing home residents with AD and/or vascular dementia.
Olanzapine was superior to placebo in treating agitation at
2 and 24 hours. At present, the utility of this formulation
appears limited due to restricted distribution and poten-
tially onerous side effect profiles.
Additionally, a cautionary note is warranted when
­considering using this agent in patients with dementia.
 Treatments for behavioural and psychological symptoms in Alzheimer’s disease and other dementias 265
I­n January 2004, Eli Lilly issued a warning of increased
incidence of CVAEs in patients with dementia treated with
olanzapine. The medication has also been widely criticized
for its potential to cause metabolic syndrome, at least in
younger populations, with limited data in the elderly thus
far which have come chiefly from the Clinical Antipsychotic
Trial of Intervention Effectiveness – Alzheimer’s Disease
(CATIE-AD) trial (see the following).
25.6.4 QUETIAPINE FUMARATE
Two open trials and a case series with quetiapine within
a dose range of 25–800 mg/day suggested possible behav-
ioural benefits for agitation (Tariot et al., 2000a; Scharre
and Chang, 2002; Davis and Baskys, 2002). A 10-week
multicentre placebo-controlled trial of quetiapine versus
haloperidol was conducted in elderly nursing home patients
with psychosis that was operationally defined. These crite-
ria were implemented prior to the development of clinical
criteria for the psychosis of AD (Jeste and Finkel, 2000).
This trial is notable in that it may have been the first large
placebo-controlled study of antipsychotics in patients with
dementia selected on the basis of psychotic symptoms.
Flexible doses of the medication were permitted; the mean
daily dose of haloperidol was 2 mg/day at end point, while
that of quetiapine was about 120 mg/day. None of the treat-
ment groups differed with respect to reduction in measures
of psychosis, which was the primary outcome of the trial,
whereas there was evidence of reduced agitation on some
measures with both haloperidol and quetiapine treatment
but not placebo. Tolerability of quetiapine was superior to
that of haloperidol; however, evidence of improvement in
agitation was inconsistent.
Data from studies evaluating the efficacy of quetiapine
remain mixed. Two meta-analyses (Ballard and Waite, 2006;
Schneider et al., 2006a, 2006b) that included three trials
(Ballard et al., 2005; Tariot et al., 2006; Zhong et al., 2007)
revealed modest improvement in agitation and aggression at
the 200 mg dose, but did not significantly improve psychotic
symptoms in AD patients. The lack of antipsychotic effect
may have been related to the relatively low dosing (<200 mg)
and may suggest that higher doses might have been neces-
sary. Quetiapine had more discontinuations due to lack of
response but fewer discontinuations due to adverse effects.
Both studies identified quetiapine as the atypical agent with
the lowest mortality risk and lowest risk of injury, although
an increased risk of cognitive decline was noted in one
small study (Ballard et al., 2005). A retrospective cohort
study analysing data from the U.S. Department of Veterans
Affairs for patients with dementia treated with antipsychot-
ics (risperidone, quetiapine, olanzapine or haloperidol) or
valproic acid, indicated reduced mortality rates in patients
receiving quetiapine compared with those receiving other
antipsychotics (Kales et al., 2012). A randomized, double-
blind, parallel-group study comparing the tolerability of
extended-release quetiapine with immediate-release que-
tiapine in patients with dementia identified haematological
abnormalities, including neutropenia and eosinophilia
(De Deyn et al., 2012). However, confounding factors made
it difficult to establish relationship to quetiapine treatment.
25.6.5 ZIPRASIDONE AND ARIPIPRAZOLE
There are no geriatric-specific studies of ziprasidone and
none in patients with dementia. However, case reports have
suggested both oral and injectible forms of the medication
may be well tolerated and of some benefit in the treatment
of agitation in this population.
Results from a placebo-controlled trial of aripiprazole in
208 outpatients meeting new clinical criteria for psychosis
of AD (Jeste and Finkel, 2000; De Deyn et al., 2005) showed
that the medication was generally well tolerated, with
numerically more frequent sedation in the active treatment
group. The primary outcome, a measure of psychosis, did
not show a difference between drug and placebo although
there was some behavioural benefit on secondary mea-
sures. A multicentre, randomized, double-blind, placebo-
controlled trial of three fixed doses of aripiprazole (2 mg,
5 mg and 10 mg) for the treatment of psychosis in patients
with AD indicated that 10 mg daily was safe and efficacious
revealing significant improvement in psychosis, agitation
and clinical global impression (Mintzer et al., 2007).
25.6.6 ATYPICALS: SUMMARY
The data indicate that atypical antipsychotics as a class are
likely better tolerated than typical antipsychotics and at
least as efficacious. There appear to be modest differences
within the class of atypicals in terms of effectiveness, tol-
erability and side effect profile. An Agency for Healthcare
Research and Quality (AHRQ) review in 2011 estimated
that among the placebo-controlled trials of elderly patients
with dementia reporting a total/global outcome score that
includes symptoms such as psychosis, mood alterations and
aggression, small but statistically significant effect sizes
ranging from 0.12 and 0.20 were observed for aripiprazole,
olanzapine and risperidone (Maglione et al., 2011). To
address this type of issue, the National Institute of Mental
Health conducted the CATIE-AD, which was designed to
compare the effectiveness of atypical antipsychotic medi-
cations and placebo in patients with AD and psychosis
or agitated/aggressive behaviour (Schneider et al., 2001,
2006a, 2006b). The study included 421 outpatients with
AD and psychosis or agitated/aggressive behaviour. In the
first phase of the trial, patients were assigned randomly to
masked, flexible-dose treatment with olanzapine, quetiap-
ine, risperidone or placebo for up to 36 weeks (Schneider
et al., 2006b). The primary measure of effectiveness, time-
to-discontinuation for any reason, was not significantly
different between the treatment conditions, with median
treatment durations of 8.1 weeks for olanzapine, 5.3 weeks
for quetiapine, 7.4 weeks for risperidone and 8.0 weeks
for placebo. The median time-to-­d iscontinuation due to
lack of efficacy was significantly longer with olanzapine
266 Dementia
and risperidone (22.1 and 26.7 weeks, respectively) ver-
sus quetiapine and placebo (9.1 and 9.0 weeks, respec-
tively). However, patients treated with an atypical had a
shorter time to discontinuation due to adverse events or
drug intolerability compared with placebo. Time to dis-
continuation due to intolerability occurred in 24% of
patients receiving olanzapine, 18% receiving risperidone,
16% receiving quetiapine and 5% receiving placebo. Safety
findings were generally consistent with reports of prior
studies. Although the trial has frequently been misinter-
preted as showing that these medications are ineffective, a
more accurate analysis reveals that there is a high rate of
adversity that offsets evidence of efficacy, but that a minor-
ity of patients can also show clinical benefit without toxic-
ity. Indeed, in secondary analyses of the CATIE-AD trial,
patients receiving risperidone demonstrated improvement
in a variety of behavioural ratings compared to placebo at
the time of discontinuation in phase 1 while patients tak-
ing olanzapine had improvements on measures of hostil-
ity and suspiciousness, but demonstrated a worsening of
depressive symptoms (Sultzer et al., 2008).
These results are consistent with a 2006 Cochrane
Collaboration review of placebo-controlled trials, which
concluded that risperidone and olanzapine may improve
aggression compared with placebo and that risperidone
may improve psychosis relative to placebo (Ballard and
Waite, 2006). The lower levels of agitation, hostility and
psychotic distortions in patients treated with second-gen-
eration antipsychotics in CATIE-AD also may be responsi-
ble for the significantly lower scores reported by caregivers
on both the Burden Interview and the Neuropsychiatric
Inventory (NPI) Caregiver Distress Scale compared with
caregivers of patients receiving placebo (Mohamed et al.,
2012).
During the past decade, atypical antipsychotics have
largely replaced typical agents in the treatment of psy-
chosis, aggression, and agitation in patients with demen-
tia because of perceived greater tolerability and lesser
risk for acute EPS and TD compared with typical agents
(Jeste et al., 1999; Stanniland and Taylor, 2000; Ritsner
et al., 2004; Gill et al., 2005; Burke and Tariot 2009). On
the other hand, these drugs have other acute and sub-acute
side effects in elderly persons such as sedation, postural
hypotension and in some cases, falls, especially at higher
doses. Metabolic abnormalities, which have been a major
concern among younger populations on atypical anti-
psychotics, were also evaluated by the CATIE-AD study
(Zheng et al., 2009). The authors assessed 186 male and
235 female patients with AD. Women showed significant
weight gain with olanzapine and quetiapine in particular.
This effect appeared non-significant in men. Unfavourable
changes in high-density lipoprotein (HDL) cholesterol
and girth were also noted with olanzapine. Blood pres-
sure, glucose and triglyceride levels appeared unaffected
by treatment. In addition, impairment of cognitive test
scores, gait disturbance and anticholinergic effects have
been reported in some instances. In CATIE-AD, atypical
antipsychotics were associated with worsening cognition
in multiple domains at a magnitude of one year’s deterio-
ration compared with placebo (Vigen et al., 2011). A 2006
meta-­a nalysis also demonstrated a significant increase in
respiratory tract and urinary tract infections and periph-
eral oedema in people treated with risperidone as com-
pared with placebo (Ballard and Waite, 2006).
In 2005, a U.S. Food and Drug Administration warn-
ing highlighted a significant increase in mortality risk for
patients with AD treated with atypical antipsychotic drugs
compared with individuals receiving placebo in 17 ran-
domized, controlled trials (Center for Drug Evaluation and
Research, n.d.). It stated that elderly patients with dementia-
related psychosis treated with atypical antipsychotic drugs
are at an increased risk of death compared with placebo. The
analyses of these trials revealed a risk of death in the drug-
treated patients of between 1.6 and 1.7 times that seen in
of the placebo-treated group. Although the causes of death
were varied, most of the deaths appeared to be either cardio-
vascular (e.g. heart failure, sudden death) or infectious (e.g.
pneumonia) in nature.
Subsequent studies, mainly involving large public data-
bases, have found similar or even higher death rates among
elders receiving conventional antipsychotics, which has
resulted in a second broader black box warning for all
antipsychotics in 2008. Several studies aimed at assessing
mortality risk in patients receiving atypical antipsychot-
ics (Ballard et al., 2009; Ray et al., 2009) have confirmed
an elevated risk. Subsequent studies using case controlled
methodology revealed that mortality ratios varied among
individual antipsychotic agents (Rossom et al., 2010; Kales
et al., 2012). In a retrospective cohort study, Kales et al.
reported on risks of mortality in dementia patients 65 and
older starting outpatient treatment with an antipsychotic.
Among patients taking haloperidol, olanzapine and risperi-
done, those taking haloperidol had the highest mortality
risk and quetiapine the lowest. The mortality risk was high-
est in the first 120 days for all drugs, other than haloperi-
dol where the risk was highest in the first 30 days. Valproic
acid and its derivatives, included as a non-antipsychotic
comparison, generally had morality risks higher than que-
tiapine and similar to risperidone (Kales et al., 2012). A ret-
rospective case–control study found numbers need to harm
(NNH) of 27, 40 and 50 for risperidone, olanzapine and qui-
etiapine, respectively, and corresponding increased mortal-
ity risks of 3.7%, 2.5% and 2.0%. When compared directly
with quetiapine, dose-adjusted mortality risk was increased
with both risperidone (1.7%; 95% confidence interval [CI],
0.6%–2.8%; p = .003) and olanzapine (1.5%; 95% CI, 0.02%–
3.0%; p = .047). The authors also reported a doswe–response
increase in mortality risk for these atypical antipsychotics
(Maust, 2015).
In interpreting these data it may be useful to consider
the perspective of another study that examined the effects
of conventional and atypical antipsychotic use on the time
to nursing home admission and time to death in outpatients
with mild-to-moderate probable AD. This study suggested
 Treatments for behavioural and psychological symptoms in Alzheimer’s disease and other dementias 267
that it was the presence of psychiatric symptoms rather than
the use of antipsychotics that elevated the risk of institu-
tionalization and death (Lopez et al., 2013).
Mounting evidence of possible serious adverse effects
of these medications underscores the need for caution
when considering use of atypicals. Careful evaluation of
the risks and benefits of treatment is warranted, including
assessment of the level of distress and risk of injury to the
patient as a result of insufficiently treated agitated behav-
iours. Treatment of patients with dementia should empha-
size non-pharmacological approaches, including carefully
investigating for possible delirium and for social or envi-
ronmental factors that lead to interventions that capitalize
on the patient’s residual strengths. The placebo response
rate in clinical trials of antipsychotics in dementia is rela-
tively high (generally 30%–40%), underscoring the notion
that non-specific factors such as enhanced attention can be
therapeutic in this population. However, atypicals remain a
valid consideration when other interventions have proven
insufficient.
25.7 BENZODIAZEPINES
According to the ‘metaphor’ approach adopted in this
chapter, we would, in theory, consider these agents first for
patients with prominent anxiety. Since features of anxi-
ety and depression overlap extensively, and particularly
in patients with dementia, many physicians opt to use an
antidepressant rather than a benzodiazepine if medica-
tion is needed. Benzodiazepines have been used for agita-
tion associated with dementia in several studies that have
been reviewed previously (Patel and Tariot, 1991; Loy et al.,
1999). Most of these showed, on average, a reduced level
of agitation with short-term therapy. There have been very
few studies in the past 10 years, none of which was placebo-
controlled. In the aggregate, as reviewed in the previous
version of this chapter, these studies suggest that agitation
associated with anxiety, sleep problems and motor tension
might be most likely to respond. Some of the earlier stud-
ies in which benzodiazepines were compared with tradi-
tional antipsychotics suggested that antipsychotics might
be superior.
Prior reviews indicate that side effects occur com-
monly with benzodiazepines, including sedation, ataxia,
falls, confusion, anterograde amnesia, light-headedness,
paradoxical agitation as well as tolerance and withdrawal
syndromes (Patel and Tariot, 1991). It is because of this
safety profile that we reserve the use of benzodiazepines
for situational disturbances, such as dental procedures,
for as-needed use, or situations where routine use has
been attempted and found to be convincingly safe. Drugs
such as lorazepam and oxazepam are preferred because
they are metabolized via hepatic conjugation, which is
minimally affected by age and both have relatively short
half-lives.
25.8 BUSPIRONE
There have been no randomized, placebo-­ controlled,
doubleblind studies of this agent. Reduced agitation has
been reported in some open trials that we have summarized
previously (Loy et al., 1999; Rosenquist et al., 2000), using
doses in the range of 10–60 mg/day. The medication has the
advantage of generally good tolerability, with the exception
of headache, nervousness and dizziness in a modest per-
centage of patients. There is no evidence regarding tolerance
or paradoxical effects in this population.
25.9 ANTIDEPRESSANTS
We would consider using this class of agents first in patients
with agitation accompanied by evidence of depressive
features as described in the introduction. There is some
evidence linking impulsivity to disordered serotonergic
function (Coccaro, 1996), lending support to the use of
serotonergic agents. They have also probably been more
widely assayed because of their good tolerability profile and
widespread use in other psychiatric disorders (Table 25.5).
Trazodone was one of the first studied (Table 25.5).
There has been only one published double-blind, placebo-­
controlled study, showing no relative benefit of trazo-
done over haloperidol or placebo in outpatients with
dementia and agitation (Teri et al., 2000). The trial also
included a non-blinded behaviour management arm; this
also showed no relative benefit. Among the non-placebo–­
controlled studies, doses typically reported ranged from
50 to 400 mg/day, occasionally higher. Irritability, anxi-
ety, restlessness and depressed affect have been reported to
improve, along with sleep disturbance. Reported side effects
have included sedation, orthostatic hypotension and delir-
ium. The most rigorous among these compared trazodone
(mean dose about 220 mg/day) with haloperidol (mean
dose 2.5 mg/day) (Sultzer et al., 1997). Agitation improved
equally in both patient groups, although tolerability was
reported to be better in the trazodone group. The Expert
Consensus Guideline (Alexopoulos et al., 2005) favours use
of trazodone primarily to treat sleep disturbance, relegating
it to second-or-third-line use for ‘mild’ agitation. A typical
starting dose would be 25 mg/day, with maximum doses
usually of 100–250 mg/day.
Data regarding selective serotonin reuptake inhibitors
(SSRIs) are summarized in Table 25.5. Nyth and Gottfries
(1990) performed a review of controlled studies of cita-
lopram, which suggest some beneficial behavioural effects.
Results from two open trials support this conclusion
(Ragneskog et al., 1996; Pollock et al., 1997).
A double-blind, placebo-controlled study compared
citalopram and perphenazine with placebo in patients with
various dementia diagnoses, probable AD and demen-
tia with Lewy bodies being the more common diagnoses,
268 Dementia

Table 25.5 Antidepressants – selective serotonin reuptake inhibitors

Dose (mg/day),
Study Diagnosis N Design duration Response Adverse effects
Citalopram
Nyth and AD, vascular 98 DB, PC 10–30, 4 weeks Decreased emotional Confusion (2), dizziness
Gottfries blunting, confusion, (1), sedation (1)
(1990) irritability, anxiety,
mood, restlessness
Nyth et al. Dementia (29) 149 DB, PC 10–30, 6 weeks Decreased anxiety, Tiredness (18), problem
(1992) fear-panic, concentrating (9),
depressed mood apathy (8), dizziness
in all (7), sedation (11),
tension (11)
Ragneskog AD (55), vascular 123 Open, two 20–40, 1–12 Decreased CGI or Tiredness (15);
et al. dementia (30), centres months GBS for irritability, dizziness (14);
(1996) alcoholic depression (60%), drowsiness, sleep
dementia (5), restlessness, disturbances,
NOS (3) anxiety restlessness (4),
aggression (3),
anxiety (2)
Pollock et al. AD 15 Open 20, 2 weeks Decreased agitation, Drop-outs from nausea
(1997) hostility, delusions, (1), myoclonus (1)
disinhibition
Pollock et al. Inpatient AD, 85 Randomized 20 citalopram or Significantly Similar scores among
(2002) vascular DB, PC, 6.5 mean improved all groups
dementia, parallel perphenazine, agitation for
mixed or other group up to 17 days citalopram vs.
not specified placebo
Pollock et al. Inpatient 103 Randomized 20–40 mg Decreased agitation Side effect burden was
(2007) vascular DB, PC citalopram or and psychosis in higher in risperidone
dementia, 1–2 mg both risperidone group
DLB, AD, risperidone, and citalopram
mixed 12 weeks group
Siddique AD 421 Retrospective 36 weeks Reduction of No difference in
­et al. analysis of irritability treatment vs.
(2009) CATIE-AD placebo group
Porsteinsson AD 186 Randomized 9 weeks Reduced agitation Worsening of
et al. DB, PC, and caregiver cognition,
(2014) parallel distress prolongation of QT
group interval
Fluoxetine
Auchus and AD 15 DB, PC 20, 6 weeks Neither more Anxiety, nervousness,
Bissey- parallel effective than confusion, tremor
Black, group vs. placebo for
(1997) haloperidol agitation
SertraLine
Burke et al. AD, NOS 19 Chart review 50, variable Improved on None reported
(1997) dementia duration Clinician’s Global
Impression of
Change (10/11
AD; 4/8 NOS)
Paroxetine
Ramadan AD or VD 15 Open 10–40, 3 months Verbal agitation Weight gain (5),
et al. reduced diarrhoea (1),
(2000) worsened EPS (1)
 Treatments for behavioural and psychological symptoms in Alzheimer’s disease and other dementias 269
who had at least one symptom of psychosis or behavioural
disturbance. Eighty-five hospitalized patients were treated
after 3 days of dose escalation with doses of 20 mg/day cita-
lopram or 0.1 mg/kg/day of perphenazine for up to 14 days.
Both ­citalopram and perphenazine demonstrated signifi-
cant improvement compared with placebo for agitation,
lability and psychosis. Side effects were similar in the three
treatment groups (Pollock et al., 2002).
Similarly, a 12-week randomized, controlled trial of
non-depressed patients with dementia hospitalized due
to behavioural disturbances evaluated the efficacy of cita-
lopram versus risperidone for the treatment of behav-
ioural disturbances and psychotic symptoms associated
with dementia (Pollock et al., 2007). The study concluded
that agitation and psychotic symptoms improved in both
groups, but did not differ significantly between the groups.
However, the lack of a placebo comparator limits interpre-
tation of the clinical significance of these findings. The
side effect burden was significantly increased in the ris-
peridone group.
Data from the CATIE-AD trial addressed the effec-
tiveness of citalopram versus atypical antipsychotics and
revealed no differences in time to all-cause discontinuation
for any antipsychotic versus citalopram (Schneider et al.,
2009). Times to discontinuation due to lack of efficacy, or
intolerability also did not differ by treatment group. Overall
patients showed generally mild improvement on rating
scales during treatment but changes did not differ signifi-
cantly between antipsychotics and citalopram.
A retrospective review of data from the 36 CATIE-AD
trial in which patients with AD were treated in a natu-
ralistic manner with placebo, citalopram, risperidone,
olanzapine or quetiapine, comparing scores on the irrita-
bility, apathy, delusions and hallucinations subscales of the
Neuropsychiatric Inventory suggested that the use of citalo-
pram was associated with greatly reduced irritability with-
out sedation (Siddique et al., 2009).
The Citalopram for Agitation in AD Study was a multi-
centre, randomized, placebo-controlled, double-blind and
parallel group trial that enrolled 186 patients with prob-
able AD and clinically significant agitation. A significant
improvement on both primary outcomes measures was
experienced by patients with AD over 9 weeks of treatment
with citalopram titrated to 30 mg daily. The size of effect
was comparable to that seen with antipsychotics. There
were insufficient data on efficacy for agitation at lower doses
(Porsteinsson et al., 2014). However, participants receiving
citalopram showed mild cognitive decline and QT interval
prolongation.
This reported QT prolongation with citalopram was
relevant given the 2011 U.S. FDA drug safety communi-
cation regarding abnormal heart rhythms associated with
high dosages of citalopram (FDA, 2012). This FDA warn-
ing informed health care professionals that citalopram
should no longer be prescribed at dosages above 40 mg/day
because of potential negative cardiac outcomes, specifically
QT interval prolongation and risk of torsade de pointes.
Concerns about risks of citalopram use were later revised in
2012 by the FDA to include a recommendation that dosages
>20 mg/day should not be used in adults over age 60. They
also noted that the dose-dependent QT interval prolonga-
tion seen with citalopram is approximately twice that seen
with escitalopram, the s-isomer of citalopram. In contrast,
a recently published large cohort study found no elevated
risks of ventricular arrhythmia or all-cause, cardiac or
non-cardiac mortality associated with citalopram dosages
>40 mg/day (Zivin et al., 2013). Higher dosages were associ-
ated with fewer adverse outcomes, and similar findings were
observed for a comparison medication, sertraline, not sub-
ject to the FDA warning.
It has been suggested that the potential beneficial effects
of citalopram, and conceivably other serotonergic agents,
may extend beyond its effect on aberrant behaviours.
Serotonin signalling suppresses generation of amyloid-β
(Aβ) in vitro and in animal models of AD. A small study
of healthy adult volunteers receiving citalopram versus pla-
cebo demonstrated that Aβ production in cerebrospinal
fluid (CSF) was slowed by 37% in the citalopram group com-
pared to placebo. This change was associated with a 38%
decrease in total CSF Aβ concentrations in the drug-treated
group (Sheline et al., 2014).
No benefit of administration has been reported yet for
fluoxetine or fluvoxamine, and only anecdotes have been
published regarding other serotonergic agents (e.g. sertra-
line), all suggesting possible benefit at least in individual
patients. Overall, evidence for efficacy of serotonergic anti-
depressants is mounting.
Gastrointestinal distress, loss of appetite and weight,
sedation, insomnia, sexual dysfunction and occasional
paradoxical agitation can occur with serotonergic agents,
although, as a group, they tend to be well tolerated. Because
of the suggestion of benefit and the relatively benign side
effect profile, consensus statements endorse their use in
some cases (Alexopolous et al., 2005).
25.10 ANTICONVULSANTS
Historically, we might have considered use of anticon-
vulsants first in patients with features of mania, as well
perhaps in those with prominent impulsivity, lability
or episodic severe aggression. Evidence regarding these
agents was summarized in earlier versions of this book:
we will review it briefly here. Carbamazepine at doses of
about 300 mg/day showed benefit in some, but not all,
small controlled trials for treatment of agitation (Tariot
et al., 1994; Tariot et al., 1998; Olin et al., 2001). Although
tolerability was acceptable in these trials, side effects seen
in other populations, such as rashes, sedation, haema-
tologic abnormalities, hepatic dysfunction and altered
electrolytes, would be more likely to be evident with wide-
spread use of carbamazepine in the elderly (Tariot et al.,
1995). Further, it has considerable potential for significant
270 Dementia
drug–drug interactions. Our view is that it has a limited
role in this population, but the findings suggested that it
might be beneficial to examine other, potentially safer,
anticonvulsants (Tables 25.6 and 25.7).
Valproic acid, also available as the enteric-coated deriva-
tive, divalproex sodium, is approved by the U.S. FDA for
treatment of acute mania associated with bipolar disorder.
Preliminary studies suggested that valproate might be effec-
tive and safe for the treatment of agitation associated with
dementia. The first randomized, placebo-controlled, parallel
group study of this agent was 6 weeks in duration, and sug-
gested but did not prove benefit (Porsteinsson et al., 2001) at
a mean divalproex sodium dose of 826 mg/day (mean level
46 mcg/day. Side effects occurred more frequently in the
drug group, chiefly consisting of sedation, gastrointestinal
distress, ataxia and an expected decrease in average platelet
count (~20,000/mm3).
A randomized, double-blind, placebo-controlled, cross-
over study of valproate 480 mg/day for 3 weeks was con-
ducted in patients with dementia and aggressive behaviour
(Sival et al., 2002). No significant differences in aggres-
sive behaviour in this short-term trial were seen between
placebo and active treatments according to the primary
outcome measure; there was a trend to improvement in
measures of aggression. There were significant effects on
restless, melancholic and anxious behaviours. There were
no drug–placebo differences in rate or type of adverse
events.
A multicentre, randomized, placebo-controlled, 6-week,
study of divalproex sodium was conducted in 172 nursing
home residents with dementia and agitation who also met
criteria for secondary mania. A target dose of 20 mg/kg/day
was reached in 10 days (Tariot et al., 2001a). This titra-
tion rate and dose resulted in sedation in about 20% of
the drug-treated group and a relatively high dropout rate,
leading to premature discontinuation of the study (n =
100 ­completers). There were no significant drug–placebo
differences in change in manic features, but there was a
Table 25.6 Anticonvulsants – carbamazepine
Study Diagnosis N Design
Tariot et al. AD, vascular 25 Crossover, PC
(1994) dementia (some other
psychotropics
permitted)
Tariot et al. Dementia 51 Randomized PC (no
(1998) psychotropics
except chloral
hydrate as needed)
Olin et al. AD 21 Randomized, DB, PC
(2001)
significant effect of drug on agitation. Sedation occurred in
36% of the drug group versus 20% of the placebo group, and
mild thrombocytopaenia occurred in 7% of the drug group
and none of the placebo treated patients.
A later randomized, double-blind, placebo-controlled
6-week trial in 153 nursing home patients with AD com-
plicated by agitation was conducted by the AD Cooperative
study (ADCS) (Tariot et al., 2005). This trial showed simi-
lar safety and tolerability findings as the previous valproate
studies, but failed to show benefit over placebo in the treat-
ment of agitation associated with dementia. This study was
the largest to address agitation prospectively as the primary
outcome.
The ADCS also conducted a placebo-controlled trial of
low doses (about 10 mg/kg/day) divalproex sodium in 313
people with AD not yet complicated by agitation or psycho-
sis (Tariot et al., 2011). The treatment period was 2 years,
with a 2-month placebo washout at the end of double-
blind treatment. The primary outcome was survival until
incident agitation or psychosis; key secondary measures
addressed measures of cognitive, functional and global
progression of dementia. Valproate treatment did not
delay emergence of agitation or psychosis or slow cognitive
or functional decline in patients with moderate AD and
was associated with significant toxic effects. The valproate
group had higher rates of somnolence, gait disturbance,
tremor, diarrhoea and weakness. Eighty-eight participants
underwent magnetic resonance imaging scans at baseline
and 12 months; the valproate group showed greater loss
in hippocampal and whole-brain volume, accompanied by
greater ventricular expansion.
There are no controlled studies of which we are aware
of the newer anticonvulsants, including lamotrigine and
gabapentin. There are a few case reports and case series
suggest benefit with gabapentin (Regan and Gordon, 1997;
Herrmann et al., 2000; Roane et al., 2000; Megna et al.,
2002; Hawkins et al., 2000). A small double-blind random-
ized trial comparing topiramate and risperidone suggested
Dose (mg/day),
duration Response Adverse effects
300 modal, Decreased Tics (1), sedation
5 weeks agitation
(16 vs.
4 placebo)
300 modal, Improved on Ataxia (9 vs.
6 weeks CGI (20/26); 3 placebo),
also improved dis­orientation
on OAS, (4 vs. 0 placebo),
BPRS, BRSD tics (1), sedation
388, 6 weeks Improved BPRS Diarrhoea more
hostility item common with
active treatment
 Treatments for behavioural and psychological symptoms in Alzheimer’s disease and other dementias 271

Table 25.7 Anticonvulsants – valproate

Dose (mg/day),
plasma level
(μg/mL),
Study Diagnosis N Design duration Response Adverse effects
Herrmann AD, LB, 16 Open 750–2500 Improved on Sedation, ataxia,
(1998a) vascular (mean = 1331), CMAI, diarrhoea (1)
dementia (mean level = BEHAVE-AD
459 μM/L), (11)
5-34 weeks
Kunik et al. Dementia 13 Retrospective review 500–1750 (mean Decreased None reported;
(1998) (concurrent BDZs, = 846), (mean physical not drug interaction
antipsychotics) level = 48), verbal agitation with phenytoin
duration and aggression noted (1)
variable on CMAI (10)
Porsteinsson AD, vascular 56 Randomized PC (no 375–1375 (mean Decreased Sedation and
et al. dementia, psychotropics = 826), (mean agitation by nausea, vomiting
(2001) mixed except chloral level = 45), BPRS and CGI or diarrhoea
dementia hydrate as needed) 6 weeks
Tariot et al. AD and/or 172 Randomized, DB, PC, 1000 median Significant Somnolence,
(2001a) VD with parallel-group improvement thrombocytopenia
secondary on CMAI
mania verbal agitation
subscale
Sival et al. AD, vascular 42 Randomized, DB, PC, 480 (mean level No change in Small increase in
(2002) dementia, crossover = 41), 3 weeks aggressive incidence of
other and active behavior adverse events
mixed treatment compared to compared to
dementia placebo placebo
Porsteinsson AD, vascular 46 Open extension 250–1500 (mean Decreased Fall, sedation and
et al. dementia, = 851), (mean agitation by nausea, vomiting
(2003) mixed level = 47), BPRS and CGI or diarrhoea
dementia 6 weeks

Abbreviations used in all tables

AD Alzheimer’s disease MOSES Multidimensional Observation Scale for
BEHAVE- Behavioural Pathology in Alzheimer’s Disease Elderly Subjects
AD Rating Scale NOS Dementia not otherwise specified
BPRS Brief Psychiatric Rating Scale NPI Neuropsychiatric Inventory
BRSD CERAD Behavioural Rating Scale for Dementia NPI-NH Neuropsychiatric Inventory – Nursing Home
CATIE-AD Clinical Antipsychotic Trial of Intervention Version
Effectiveness – Alzheimer’s Disease PC Placebo controlled
CGI Clinical Global Impression PD Parkinson’s disease
CMAI Cohen-Mansfield Agitation Inventory PRN pro re nata (as needed)
DB Double blind SCAG Sandoz Clinical Assessment-Geriatric
EPS Extrapyramidal symptoms Scale
GBS Gottfries–Bråne–Steen SSRIs Selective serotonin reuptake inhibitors
MC Multicentre VD Vascular dementia

comparable efficacy of topiramate (25–50 mg daily) with
risperidone in controlling behavioural disturbances in
patients with AD (Mowla and Pani, 2010).
Evidence regarding the efficacy of anticonvulsants in
the treatment of agitation associated with dementia argues
against using such agents. Nevertheless, some consensus
statements suggest a possible role as a second or third line
treatment for agitation and aggressive behaviours in patients
with dementia. We would only consider this approach if
other treatments had failed.
272 Dementia
α AND β-ADRENERGIC AGENTS
25.11 
β-Blocking agents have not been subject to rigorous study.
Most of the evidence comes from open trials conducted
over 10 years ago (Rosenquist et al., 2000). The usefulness
of β-blocking agents in this very old and frail population
is limited by the high frequency of relative contraindica-
tions to β-blocker treatment (Peskind et al., 2005). Adverse
reactions include bradycardia, hypotension, potential
worsening of congestive heart failure or asthma, reduced
adrenergic response to hypoglycaemia in patients with
diabetes, sedation, increased confusion, psychosis, depres-
sion and increased atrioventricular block. It is unclear
what role this class of medication has in the treatment of
agitation associated with dementia at this point. If it is to
be attempted at all, we would argue that it should occur
only after safer and more conventional therapies have
failed, and only with careful monitoring for side effects.
Prazosin, a non-sedating medication used for hyperten-
sion and benign prostatic hypertrophy, antagonizes norad-
renergic effects at brain post-synaptic α-1 adrenoreceptors.
A small, double-blind, placebo-controlled, parallel group
study examined the efficacy and tolerability of prazosin
for behavioural symptoms in nursing home patients with
agitation/aggression in AD (Wang et al., 2009). Subjects
received doses between 1 and 6 mg daily using a flexible
dose algorithm. Those receiving prazosin displayed a sig-
nificant improvement in behavioural symptoms compared
to the placebo group with no significant increase in adverse
effects. These encouraging preliminary results require con-
firmation in larger controlled studies.
25.12 CHOLINERGIC THERAPIES
As summarized by Cummings (2000), there is evidence that
cholinergic agents, especially ChEIs, may have modest, clin-
ically relevant, psychotropic effects in some patients with
dementia. For the most part, the studies were not designed to
address behavioural outcomes as the primary goal. A review
of 24 trials involving nearly 5800 participants found benefits
of treatment noted on measures of activities of daily living
and behaviour in patients receiving donepezil (Birks, 2006;
Birks and Harvey, 2006). The effects of donepezil, galan-
tamine and rivastigmine in people with mild, moderate or
severe dementia due to AD were also supported in a review
of 10 randomized, double-blind, placebo-controlled trials
(Birks, 2006). The reviewers found no differences in efficacy
between study medications. A meta-analysis of 29 parallel-
group or cross-over randomized, placebo-controlled trials
of outpatients diagnosed with mild-to-moderate AD meant
to quantify the efficacy of ChEIs for neuropsychiatric and
functional outcomes found that ChEIs had a modest benefi-
cial impact. No difference in efficacy among various ChEIs
was observed (Trinh et al., 2003).
Citing preliminary studies which were conducted in
patients displaying baseline low levels of psychopathol-
ogy associated with dementia, Cummings et al. (2006)
conducted an exploratory analysis of data pertaining to
the efficacy of donepezil treatment of patients with severe
behavioural disturbances. The results of these analyses sug-
gest that donepezil reduces behavioural symptoms, particu-
larly mood disturbances and delusions, in patients with AD
with relatively severe psychopathology.
A 12-week placebo-controlled, randomized trial examined
the effectiveness of donepezil for the treatment of clinically
significant agitation in patients with AD revealed no signifi-
cant treatment advantage for donepezil as compared with
placebo. Howard et al. hypothesized that the previously noted
modest but significant improvement in the overall severity of
behavioural and psychological symptoms of dementia (BPSD)
in previous trials may be explained by improvements in symp-
toms other than agitation (Howard et al., 2007). For example,
a study that examined individual items on the NPI in patients
with AD showed significant benefits for mood-related symp-
toms but not agitation (Gauthier et al., 2002).
A recent 12-week, randomized, parallel-group, ­controlled,
single-centre trial of risperidone versus galantamine
revealed that both galantamine and risperidone were effec-
tive in reducing agitation. Although risperidone showed a
significant advantage over galantamine in irritation and
agitation at week 3 and at week 12, both galantamine and
risperidone treatments resulted in improved BPSD symp-
toms and were equally effective in treating several NPI
domains (Freund-Levi et al., 2014).
By way of overview, there have not been sufficient prospec-
tive controlled trials specifically addressing whether ChEI
therapy definitely mitigates symptoms already present, or
delays emergence of symptoms in those not yet afflicted. In the
aggregate, the data available suggest that these salutary effects
may exist. Since best practice is to treat most people with AD
with these agents anyway, there seems to be little reason to
refrain from using them as first line therapy for treatment of
non-emergent psychopathology in people with AD.
25.13 MEMANTINE
Memantine is a non-competitive inhibitor of N-methyl-
d-aspartate (NMDA) receptors that may permit normal
memory formation but blocks their excitotoxic activation
(Winblad et al., 2002). Memantine has been approved for
treatment of moderate to severe AD, alone or in addi-
tion to ChEIs, on the basis of three placebo-controlled tri-
als (Winblad and Poritis 1999; Reisberg et al., 2003, Tariot
et al., 2004). A review of double-blind, parallel group,
placebo-controlled, randomized trials of memantine in
­
people with dementia conducted by McShane et al. (2006)
reported a slight decrease in the development of agitation in
patients taking memantine. This effect was slightly larger, but
still small, in moderate-to-severe AD. There was no evidence
 Treatments for behavioural and psychological symptoms in Alzheimer’s disease and other dementias 273
about whether memantine had an effect on agitation, which
is already present. A significant advantage for memantine
over placebo was also supported by a pooled analysis of three
studies of patients with symptoms of aggression/­agitation,
delusions and hallucinations (Wilcock et al., 2008).
The first completed trial designed primarily to explore
the efficacy of memantine on clinically significant agitation
in AD found no significant advantage of memantine versus
placebo in the primary outcome CMAI at week 6 or 12 (Fox
et al., 2012). Modest improvement was noted on the second-
ary measure NPI. A pooled analysis of 633 patients also
revealed better outcomes in the memantine group in terms
of behavioural and psychological symptoms, including
aggressiveness (Nakamura et al., 2014). Similar improve-
ments in NPI scores have been demonstrated with the
extended release formulation (Grossberg et al., 2013).
Howard et al. (2012) attempted a clinical trial to address
the relative benefit of continuing donepezil, adding or sub-
stituting memantine or stopping donepezil in persons with
moderate-to-severe dementia. Limited enrolment ham-
­
pered the conclusions that could be drawn (Tariot, 2012).
Participants assigned to donepezil withdrawal showed
marked decline in both cognition and daily function in
comparison with the other three treatment groups, and
memantine treatment was associated with fewer behav-
ioural symptoms.
As with the overview of the behavioural effects of ChEIs,
the available data suggest but do not prove that memantine
therapy may reduce behavioural symptoms or delay their
emergence. Since it is indicated for treatment of moderate-
to-severe AD, there is little reason not to deploy it in such
patients and observe whether behavioural symptoms are
improved.
25.14 SUMMARY
Humane treatment of patients with dementia includes vigor-
ously addressing the kinds of behavioural and psychologi-
cal signs and symptoms that are likely to occur. The main
emphasis should be on non-pharmacological approaches,
including carefully investigating for possible delirium and
searching hard for social or environmental interventions that
capitalize on the patient’s residual strengths. It is indeed this
process of attempting to ‘find what works’ that makes treat-
ment in this population so fascinating, as well as challenging.
Psychotropics should be reserved for cases where other,
simpler interventions have been attempted and deemed
inadequate. We advocate a target symptom-based approach,
which matches the most salient target symptoms to a rel-
evant drug class. Although there is no compelling empirical
support for this approach, it has the advantage of being face-
valid and logical, which are reassuring features when one is
a consultant in a confusing situation.
Much of the available data do in fact indicate that
antipsychotics as a group can show benefit for agitation
associated with psychotic features. However, these medi-
cations are not without risk. Mounting evidence as to the
cerebrovascular adverse effects and other potentially deadly
side effects of both conventional and atypical antipsychotics
has overshadowed evidence of their efficacy. Although they
remain an indispensable treatment for patients displaying
severely agitated and psychotic behaviours, this increasing
safety data emphasizes the need for vigilance when evaluat-
ing appropriate treatment options.
Emerging data regarding alternative treatment options for
agitated behaviours such as antidepressant therapy is promis-
ing, but still limited. Other literature regarding non-antipsy-
chotic medication includes anticonvulsants, anxiolytics and a
variety of other agents with less foundation. As data accrue
regarding these therapeutic approaches, we will have a clearer
sense of exactly how and when they should be deployed. In
the meantime, clinicians are obliged to deal as thoughtfully as
possible with patients on a case-by-case basis, attempting first
and foremost to avoid toxicity of therapies intended to help.
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Psychological approaches for the practical
management of cognitive impairment in
dementia
ANNE UNKENSTEIN
26.1 INTRODUCTION
A psychological approach to the management of cognitive
impairment in dementia aims to promote the best possible
quality of life for both people with dementia and their car-
ers, by offering positive, individualized and effective man-
agement. With the growing emphasis on early diagnosis of
dementia, there are increasing opportunities to provide psy-
chological interventions from the earliest stages of demen-
tia. This chapter focuses on practical and personalized
strategies. Assessment and feedback processes are outlined
and specific techniques for managing cognitive impairment
in early, moderate and later stage dementia are described.
26.2 FACTORS INFLUENCING
MANAGEMENT OF COGNITIVE
IMPAIRMENT IN DEMENTIA
Each person with dementia is unique, with a complex inter-
action of brain disease, personality, biography, health and
social psychology (Kitwood, 1993). Each person needs to
be treated as an individual. An approach that might prove
successful for one person may prove ineffective for another
(Woods and Bird, 1999). There is no single correct approach
to the management of cognitive impairment in dementia.
The help that is relevant can vary considerably.
There is a great deal of variation in cognitive function
in dementia according to the stage of dementia and differ-
ent causes and patterns of brain pathology. Dementia does
26
not imply global impairment of brain function. There will
nearly always be some retained abilities. It is important to
identify these cognitive strengths and use them positively.
Interventions can draw on retained skills in order to bypass
weaknesses.
Cognitive impairment is just one aspect of dementia.
People with dementia also experience changes in behaviour,
emotional control, personality and self-care. These changes
need to be taken into account when working on strategies
for cognitive impairment. A team approach with agreement
about realistic goals and consistent strategies is recom-
mended. Carers need to be included in management plan-
ning. Wherever the person with dementia lives, carers will
be involved. They may be relatives, friends, neighbours or
health professionals.
Not all of the person’s symptoms are directly due to brain
disease. People with dementia are very sensitive to their
physical and psychological environment. Dementia is some-
times first suspected when a person experiences a change
to his or her usual environment such as moving to a new
house or the death of a spouse. It is important to be aware
of environmental factors that may adversely affect cognitive
function and make appropriate changes to the environment
in order to enhance cognitive abilities.
Health factors can exacerbate any cognitive impair-
ment. Sensory impairment, especially of vision and
hearing, can adversely affect cognitive function. People
with dementia commonly experience anxiety, distress
and depression. Confusion can also be increased during
acute or chronic illness and with any physical discomfort
or pain. Alcohol, some medications and fatigue may
cause transient exaggeration of cognitive impairment.
It is necessary to be alert to any superimposed health
279
280 Dementia
problems and to control these to help people maintain
maximum function.
Progressive decline in cognitive function is characteris-
tic of dementia. Management strategies need to be flexible
and adapted over time. Assessment at regular intervals will
allow for the development of realistic expectations. The aim
of any strategies employed is to maintain as high a level of
function as possible by helping the individual to better uti-
lize the remaining function.
26.3 ASSESSMENT
A thorough assessment is required in order to design an
individualized approach to management of cognitive
impairment. This should include assessment of the person’s
medical and psychological status and assessment of cog-
nition. Assessment of the person’s health is important, as
there may be additional treatable medical conditions.
It is beneficial to interview the carers to gain informa-
tion about the person’s personality, interests, home environ-
ment and the history of events leading up to the assessment.
Information about strategies that the carers have already
tried and their willingness to provide support can also be
gathered.
A neuropsychological assessment provides a basis for
individual intervention. It allows for a focus on strengths
by outlining abilities that remain unaffected and also
outlines areas of cognitive impairment to be managed.
Serial neuropsychological assessment can be used to
monitor progression of symptoms over time. It can pro-
vide an objective viewpoint to the carers and to the person
with dementia with regard to the progression of symp-
toms. Part of the assessment is to check the attitude of the
person to their symptoms, as this will influence choice of
strategies.
The assessment phase will identify the problem but it is
important to go beyond this phase for a better management
of cognitive impairment. It is beneficial to share the infor-
mation gathered with the person with dementia and their
carers.
26.4 FEEDBACK AFTER
PSYCHOLOGICAL ASSESSMENT
A feedback session following psychological assessment can
serve many purposes. It provides information about how the
disease is affecting aspects of cognitive function in order to
improve understanding. While it is important to acknowl-
edge areas of loss, a positive approach can be maintained by
highlighting what the person can still do.
The carers are often the people who provide ongoing
management of the person with cognitive impairment.
Feedback can empower carers by acknowledging the success
they have had with strategies that they have already tried. It
can also provide emotional support and practical help and
assistance. Carers have access to a lot of general information
about dementia (e.g. Draper, 2011). However, specific infor-
mation that is more relevant to their particular situation can
be provided in a feedback session.
Feedback usually includes the person with dementia,
but can be given to carers alone where appropriate. The
psychologist can provide a description of the person’s
cognitive strengths and weaknesses. This information
is then used to help carers make sense of behaviour
that otherwise would seem to suggest that the person is
purposefully being annoying. For example, by outlining
the different types of memory and how each is affected,
it becomes easier to understand why a person can recall
information from their remote past but not what was
said 2 minutes ago. Furthermore, if carers know that the
person has memory impairment they are more likely to
understand why the person persistently repeats the same
question or forgets to pass on a phone message. It can be
reinforced that this is not done deliberately. Behaviour
is thus reinterpreted as related to brain disease and not
purposeful or intended. This information is also useful
when it comes to management of cognitive impairment.
For example, if carers know that forgetfulness is due to
memory loss from brain disease they are more likely to
understand that the person is unlikely to learn by repeti-
tion. They are also more likely to use strategies that avoid
reliance on intact memory ability.
A feedback session offers an opportunity to ask the per-
son with dementia and the carers how the cognitive prob-
lems manifest themselves in everyday life. This information
can be used to make strategies realistic and relevant to the
life of the person with dementia (Wilson, 2004).
A written reminder of what was discussed during the
feedback session can be useful. Both the person with demen-
tia and the carers may forget what was discussed, especially
if they are just coming to terms with the diagnosis.
An initial discussion of strategies to help manage cog-
nitive impairment can be included in a feedback session.
The types of strategies employed will vary according to
the person’s individual situation and the cause and stage of
dementia.
26.5 EARLY STAGE DEMENTIA –
MEMORY STRATEGIES
In early dementia, the most significant cognitive impair-
ment is typically in memory function. Impairment of new
learning is most prominent, including acquisition and
retention of new information. People with early demen-
tia may forget what you have just told them, forget where
they have put something, repeat the same thing as if they
have not said it before or have difficulty learning how to use
something new.
 Psychological approaches for the practical management of cognitive impairment in dementia 281
At this stage, the person often remains aware of cogni-
tive losses and may be motivated to seek methods to com-
pensate for them. The person is usually living in the family
home. Initial strategies therefore focus on the individual
with increasing involvement of family carers over time. The
aim is to maintain as much independence as possible and to
promote confidence in remembering. Family members and
friends need to avoid taking over responsibilities too soon.
Many of the strategies that are used by people experi-
encing normal memory change with ageing and are use-
ful at this stage (see Sargeant and Unkenstein, 2001, for a
detailed description of memory strategies). It is important
to ask people whether they are already using any memory
aids before explaining the use of memory strategies. People
should be encouraged to draw on strategies that they have
used in the past. They will be more likely to use strategies
if they are already familiar with them (Kotler-Cope and
Camp, 1990). Everyone has different preferences. Some
people like to use diaries while others prefer a noticeboard.
People typically need to use a range of strategies, rather
than just one technique. It is important to find out the typi-
cal things a person tends to forget and work out strategies
that will suit these specific situations and be usable for that
person. Strategy use will vary according to differing inter-
ests, lifestyles and home environments. A home visit can be
useful to help tailor strategies to particular situations.
The emphasis is on practical compensatory techniques,
which avoid challenging the person’s lost memory function.
For example, rather than asking a question that relies on
intact memory function such as ‘What show did you watch
on television last night?’, rephrase the question to ‘Did
you enjoy the show that you watched last night?’ If people
become repetitive it may be best to try distracting them
with another topic of conversation. Enhancing familiarity
is also beneficial. Developing a regular routine and doing
things at a set time of the day or week will reduce the load
on memory.
Memory strategies can be thought of as internal or exter-
nal. Internal strategies involve some form of internal mental
manipulation, for example, mentally retracing one’s steps
to remember where an object was left. External strategies
involve using some sort of external aid, for example a note
pad for writing a list or a diary. They can also involve mak-
ing changes to the environment, for instance, having desig-
nated locations in which to store particular items.
Internal strategies focus on enhancing encoding and
retrieval processes. The emphasis is on making more
efficient use of current cognitive capacity. A motivated
individual with early stage dementia may employ simple
internal strategies. These strategies typically involve one of
three main features: focusing attention, adding meaning
to the information to be remembered or reducing the
amount of information to be remembered. Simple internal
strategies such as ensuring understanding, associating
new information with information that is known well and
visualization may be useful for motivated individuals with
early dementia.
When people with dementia are supported with repeated
training sessions, they can learn and retain new informa-
tion using specific learning methods. One technique that
has been found to assist learning is spaced retrieval, which
requires people to recall information over increasingly lon-
ger periods of time. This is sometimes combined with other
learning techniques, such as the errorless learning approach,
where individuals are not allowed to commit errors when
they are receiving memory training (see Clare, 2008).
Some well-known internal strategies or mnemonic tech-
niques, such as the method of loci and peg word systems,
are quite complex. These techniques require considerable
remaining cognitive capacity including new learning and
motivation for success. People with early stage demen-
tia usually do not have the motivation or learning ability
required to use these techniques (Grandmaison and Simard,
2003).
External strategies aim to compensate for memory
impairment by reducing the demand on a person’s memory.
They are generally easier to use and more suitable for every-
day remembering than internal strategies. They may involve
written reminders, storage of objects in specially designated
places, technical memory devices and reminders from other
people.
Written reminders assist with remembering locations of
objects, a task that has to be done, appointments, shopping
items, messages, names and instructions. Calendars, dia-
ries, notebooks, notepads, noticeboards and sticky notes are
all useful. Having a pen or pencil attached reduces the load
on memory even further. Such written aids should not only
be readily visible and accessible but should also be in close
proximity to the to-be-remembered activity. For example, a
shopping list pad on the refrigerator door or instructions for
how to operate a piece of equipment permanently displayed
on that equipment.
External memory strategies can assist with orientation
in early stage dementia. It is helpful to mark off the days as
they pass on a calendar, or use a flip-top desk calendar and
turn each day over as it passes. Newspapers can also serve
as prompts. Clocks should be positioned in places where
they are readily seen and ideally should have day and date
built in.
Storing objects in specially designated places can help
with remembering the location of objects, a task that has
to be done, or something to be taken out. For example, keys
can be stored near the front door of the house. This makes
it easy to pick up the keys when leaving the house and to get
into the habit of putting them back when returning.
Leaving objects in visible locations can act as a reminder
to do something. Medications can be left somewhere obvi-
ous in the kitchen if they are to be taken with meals. Objects
that a person needs to take out with them can be located in a
special place near the front door, such as a hall table.
A useful storage device for managing medications is a
dosette box, divided into compartments that relate to the
day of the week or time of the day into which a set number
of tablets can be placed. The box has to be filled at weekly
282 Dementia
or other intervals, but is simple to use and let people know
whether they have taken the necessary tablets.
Basic alarms are useful to help people remember some-
thing they have to do. A common example is an oven timer
used as a reminder to turn the oven off. Many household
objects have built in memory aids. Most telephones have
a system that enables storage of frequently used numbers
that can then be dialled by pressing only one appropriately
labelled button. Automatic shut-off devices on electrical
and gas appliances, such as stovetops, kettles or lights can
be installed. These devices turn the power off after a period
of time if the appliances are left on. More complex electronic
memory aids, including smart phones and computers, can
be useful for motivated and insightful individuals but may
require training to know how to operate them. They usually
rely on other cognitive processes remaining intact and may
not suit the person with early stage dementia.
Reminders from other people can provide an excellent
memory back-up system. Family members can provide tele-
phone reminders or leave notes in a regular and prominent
location. Reminders need to be specific. For example, a note
saying “back in 5 minutes” does not provide enough infor-
mation. The person with dementia needs to know when the
person will return.
People with mild to moderate dementia can be taught
to use memory strategies using a range of approaches.
Cognitive training programmes typically involve repeated
practice of cognitive tasks or specific memory strategies,
whereas cognitive rehabilitation aims to improve an indi-
vidual’s everyday functioning. Bahar-Fuchs et al. (2013) and
Choi and Twamley (2013) review the efficacy of cognitive
training and rehabilitation for people with dementia.
26.6 MODERATE DEMENTIA –
WORKING WITH CARERS
As dementia progresses people can experience increasing
memory loss, language difficulties and specific disorders
such as apraxia. They may be unable to function indepen-
dently outside the home and require increasing assistance
with tasks of personal care. They could be living in their
own home or supported accommodation. By this stage
the person’s insight into their cognitive losses usually has
diminished.
With little awareness of their difficulties and increased
cognitive impairment, it becomes difficult to work on strat-
egies with the person with dementia alone. The manage-
ment of cognitive impairment, therefore, becomes focused
on working in collaboration with family members or other
carers. Carers know the person best and often come up with
strategies that work well for that person. Carers can pro-
vide reminders for the person, encourage the person to use
external memory aids and make appropriate changes to the
environment. Without this assistance the person is unlikely
to make use of memory strategies. By this stage strategies
for other areas of cognitive impairment are also required.
Providing support and information to the carers can help to
further tailor strategies to make them suit the individual’s
current cognitive strengths and weaknesses.
Carers will need to become increasingly involved in the
use of external memory strategies and can assist with set-
ting up a designated ‘memory centre’ in a visible location
in the home environment (Sargeant and Unkenstein, 2001).
Here the carer could hang a whiteboard in which the day,
date and daily schedule are written or a clock with the day
and date on it. A pin board next to the whiteboard can be
used to display other important information. The carer may
need to keep reminding the person to check the memory
centre. Carers can also develop ‘communication books’. For
this a notebook is left in a special location where visitors can
write messages. The person can be encouraged to check this
book regularly as a reminder of who has visited recently.
These strategies are a form of reality orientation, an
approach that emphasizes the use of external cues and
structures to assist the person in maintaining contact with
the environment (see Woods, 2002 for a review of reality
orientation). Carers can help to provide personalized real-
ity orientation, by identifying to which realities the person
needs or desires to be oriented. A structured programme
of reality orientation and cognitive stimulation for people
with dementia can improve memory and functional abili-
ties (Spector et al., 2010). Typically, a structured stimulation
programme would consist of several weeks of group inter-
vention sessions (see Droes et al., 2011 for a review of cogni-
tive stimulation therapy).
Carers can continue to encourage a regular routine of
familiar activities. Sudden unexplained changes or unfa-
miliar activities could cause the person distress. Carers can
help the person focus on activities that are familiar and
based on previous interests, such as gardening, walking the
dog or other household tasks. Drawing on the continued
strength of memories of procedures and lifetime memories
can provide meaningful activity. Carers at accommodation
facilities can find out about the person’s past likes, dislikes,
lifestyle and life interests from family members. This infor-
mation and any old photos available can be recorded in a
book that can be used as a cue for discussion and reminis-
cence (see Subramaniam and Woods, 2012 for a review of
reminiscence therapy).
A familiar environment will reduce the demand on the
person’s memory. Unnecessary changes such as rearranging
furniture should be avoided. If changes have to be made,
they should be introduced slowly, with explanation.
Carers may need assistance with strategies for other
areas of cognitive impairment. For example, the person at
this stage may experience apraxia, an inability to carry out
routine patterns of voluntary movement. A common prob-
lem caused by apraxia is difficulty with dressing. Helping
the carer to understand that a person can sometimes dress
automatically, but has difficulty when the movement comes
under conscious control is useful. To remove the degree of
voluntary focus from the action, avoid giving the person
 Psychological approaches for the practical management of cognitive impairment in dementia 283
direct instructions about performing the task. Specific tech-
niques include distracting the person’s attention from the
task, imitation, laying the clothes out in the order in which
the person likes to put them on and giving reassurance and
praise for each successful step. See Holden (1995) for strate-
gies for other specific cognitive disorders.
26.7 LATER STAGE DEMENTIA –
ENVIRONMENTAL ADAPTATION
In the later stages of dementia people experience marked
confusion and widespread cognitive disturbance. Most
people with advanced dementia are living in supported
accommodation with professional carers. Strategies for
management of cognitive impairment need to be focused
more on the environment in which the person is living.
Adaptations are made to the environment rather than
expecting the individual to change. Visiting the person’s
residence allows one to observe environmental cues, how
they might best be used and/or changed and how new ones
might be introduced (Kapur et al., 2004).
At this stage, people become dependent on their envi-
ronment to support them. Making adaptations to the envi-
ronment can enhance feelings of security and help people
cope with their confusion and disorientation. A ‘demen-
tia friendly environment’ provides orientation strategies
that help to reduce confusion and promote independence
(Davis et al., 2009). When one first moves into a new resi-
dence there is often a settling in period. An unfamiliar and
a new environment can increase confusion. It helps to make
the environment as familiar as possible. Possessions, such
as photos, objects and furniture can be put in the person’s
room. Assistive technology, involving sensor systems and
computers, can provide further support (Charness et al.,
2012; Kurz et al., 2013).
A routine and daily timetable should be emphasized.
Orientation information or cues can lessen confusion. For
example, having access to a window helps a person to tell
the time of the day and the weather. A good sensory envi-
ronment with adequate light is important. Making each
part of a large place unique in some way is useful for orien-
tation to the environment. Colour and furniture can high-
light the difference. Smaller spaces are less confusing than
large spaces.
Clear labelling throughout the accommodation facil-
ity can further lessen confusion. Way finding cues can be
marked on the floor or walls with coloured lines or arrows.
Individual rooms can be clearly labelled. Large uppercase
print with black against white is often best for older people
(Kapur et al., 2004). Pictures may be more easily under-
stood than written labels (e.g. a picture of a toilet on the
toilet doors). Carers can wear name badges, with their first
name only, that are large enough to read. People will require
continued instruction on how to use these orientation aids.
To maximize cognitive function it helps to simplify the
environment to avoid the person becoming overwhelmed.
If there is excessive stimulation then confusion may be
exacerbated. It helps to remove distractions, keep noise lev-
els down and not have too many people around (Robinson
et al., 2001).
It is often difficult to communicate with the individual
with this stage of dementia. Using an empathic, validating
approach that displays respect and sensitivity to feelings can
help to ensure understanding.
26.8 CONCLUSION
Improving the practical management of cognitive impair-
ment in dementia using a psychological approach is just
one part of the challenge to maintain maximum function
throughout the course of the illness (Kitwood, 1993). For
any symptom of dementia, the first step involves investi-
gating what may be causing the person to present in that
particular way. Multidisciplinary assessment will establish
whether there are any environmental factors that can be
altered or health factors that can be treated to enhance the
individual’s function. Effective management strategies that
are relevant to the stage of dementia and other individual
variables can be developed using a collaborative approach
involving the person with dementia, carers and health
professionals.
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Oxford: Oxford University Press, pp. 311–331.

Sexuality and dementia
JOE STRATFORD
27.1 INTRODUCTION
Dementia and its relationship with sexuality raises many
significant medical, ethical, cultural and relationship issues.
Our sexuality is one of the most basic aspects of our human-
ity and encompasses a wide range of elements including
gender identities, sexual orientation, intimacy, beliefs, behav-
iours and roles. Moreover, society is becoming increasingly
open about sexuality and sexual behaviour in general. As
the world’s population ages and we see associated increases
in numbers of individuals affected by dementia, the issue of
sexuality and dementia will only increase in its relevance.
This chapter addresses some of these complex issues and
highlights some approaches towards managing various dif-
ficulties raised.
27.1.1 SEXUALITY AND AGEING
Many myths about sexuality and ageing exist within popu-
lar culture in a way which would not be tolerated on grounds
of race or religion. Sexuality in older adults is often regarded
as being amusing or revolting (Kessel, 2001). Younger pop-
ulations also overestimate the degree of sexual problems,
which older people encounter (Allen et al., 2009).
Although sexual activity appears to decline with advanc-
ing age (Schiavi et al., 1990; Kaiser, 1996), it does not appear
to cease completely. In a large U.S. study, Lindau et al. (2007)
studied over 3000 older adults (age range 57–85 years) and
found that while 84% of the 57–64 year olds reported sexual
activity in the last 12 months, 39% of the 75–85 year olds
were still active. And in a study of almost 3000 community-
dwelling elderly Australian males, 11% of the 90–95 year
olds had been sexually active in the preceding 12 months
(Hyde et al., 2010).
Although overall levels of sexual activity may decrease
with age, there is evidence that the elderly are becoming
27
more sexually active than in previous years. In a Swedish
study stretching over a 30-year period looking at trends,
Beckman et al. (2008) studied four cohorts of 70-year-old
community-dwelling older people. Over 1500 subjects were
assessed at four separate intervals (1970–1971, 1976, 1992
and 2000), each assessment being identical although each
assessed a different cohort of 70 year olds. Sexual activity
(defined as intercourse within the last 12 months) in males
increased from 47% in 1970–1971 to 66% in 2000. In females,
the increase was from 12% to 34% over the same time.
Overall, older women are less likely to be sexually active
than older men. This may be in part due to the decreased
likelihood of women being in a spousal or intimate relation-
ship, often as a result of separation or bereavement. For both
sexes, sexual activity is also related to physical health. Those
who rate their health as poor are less likely to be sexually
active than those who rate their health as very good or even
excellent (Lindau et al., 2007).
Sexual activity of course does not always have to mean
sexual intercourse. As people age, intimacy with a partner
appears to be expressed in different ways and there may be
physiological reasons behind this. Touching, holding hands,
hugging and kissing can assume greater importance when
compared to activities such as intercourse or masturbation
(Ginsberg et al., 2005).
27.1.2 SEXUALITY AND RESIDENTIAL
CARE
As the numbers of ageing individuals increase, so does the
population of those living in care, be it residential or nursing
home establishments. The expression of these residents’ sexu-
ality is particularly challenging in such institutions for a vari-
ety of reasons including ill health or a lack of partners (Bauer
et al., 2009). The move into institutional residential care inev-
itably leads to a loss of privacy especially where personal care
and supervision are required (Bouman et al., 2006).
285
286 Dementia
Overall, much of the evidence related to sexuality and its
expression in residential facilities is mixed. There seems to
be a huge variation in attitudes to this issue dependent on
what kind of facility, its ‘culture’ and which staff group is
being assessed (Doll, 2013).
27.2 EFFECTS OF DEMENTIA ON
SEXUALITY AND SEXUAL
BEHAVIOUR
The onset of dementia may have a significant effect on
the sex life of the individual and their partner, although
the evidence base for such changes in sexual behaviour in
dementia remains small. Wright (1991) undertook a con-
trolled study of the impact of Alzheimer’s disease (AD) on
marital relationships. Eight of the 30 (27%) couples of the
dementia-affected group were sexually active, compared
with 14 of the 17 (82%) controls. In those individuals still
sexually active, compared with controls, sex took place
more often in couples where one partner had dementia.
Derousesné et al. (1996) in a survey of 135 married cou-
ples, one of whom had possible or probable AD, found that
80% of spouses reported a change in patient’s sexual activity.
This was not linked to the degree of cognitive impairment
or the gender of the patient. Eloniemi-Sulkava et al. (2002)
questioned the spousal caregivers of 42 demented patients
over a 7-year period. At the onset of dementia, 32 (76%)
couples engaged in regular sexual intercourse. By the sev-
enth year, seven (28%) couples continued to engage in such
activity. While 25 caregivers (60%) reported some negative
behavioural changes in the sexual side of the marriage, four
(10%) reported positive changes. In most studies of this type,
sexual demands and activity seem to decrease following the
onset of dementia but only in small proportions do couples
report significant dissatisfaction (Dourado et al., 2010).
27.2.1 RELATIONSHIP EFFECTS
Dementia leads to an inexorable change in the nature of most
relationships, but none is more poignant than that between
partners. Partners of individuals with dementia become
carers as the disease process robs an individual of their
autonomy. This can lead to such carers being vulnerable to
depression and anxiety as carer burden increases (see other
chapters). Although not all dementia-affected couples experi-
ence a change in sexual activity, an altered sexual relationship
is a difficulty many couples face after the onset of dementia.
The diagnosis should not be assumed to herald cessation of
an active sex life, and couples should be encouraged to think
and act flexibly in order to adjust to the impact of the disor-
der (Davies et al., 1998). If sexual activity is experienced to
be problematic, it is important to stress to patients and carers
that physical intimacy, such as cuddling or simply holding
hands, can be just as beneficial and rewarding to both.
27.2.2 CAPACITY AND ETHICAL ISSUES
People with dementia should have a right to express their
sexual feelings engage in sexual behaviour in a way that is
no different to the rest of society. The difficulty which arises
within the context of dementia relates to firstly whether the
expression of such feelings conflicts with the basic rights of
those affected by such activity but also importantly, whether
the issue of capacity has been considered. Failure to do so
runs the risk of committing a sexual offence (e.g. sexual
activity without consent).
Capacity is not an all-or-nothing concept. It can vary
over time and is decision specific. The same would apply
to the capacity for an individual to engage in a sexual rela-
tionship. In the United Kingdom, the Mental Capacity Act
(2005) specifically excludes decisions about sexual rela-
tions as it is felt that this is not something that one indi-
vidual can decide for any other. This obviously leads to
complexities when addressing issues of sexual behaviour
where one (or even both) party felt a lack of capacity in
this regard.
Due to its sensitive and complex nature, the capacity of
a demented individual to enter into a sexual ­relationship
could be difficult to establish. In an attempt to address this,
Lichtenberg and Strzepek (1990) ­developed a structured
assessment technique to aid decisions about patients’ abil-
ity to consent to sexual relationships. It includes s­ections
addressing the patient’s awareness of the relationship, their
ability to avoid exploitation and an assessment of their
awareness of any potential risks that could arise from it.
The right of an individual with dementia and who lacks
capacity to make decisions about his or her sexual activity
raises some profound ethical issues. In an attempt to explore
the area, Mahieu and Gastmans (2011) helpfully suggest
considering familiar medical ethical issues of autonomy,
beneficence, non-maleficence and justice when dealing with
these issues. They also add that principles of dignity and
vulnerability need also to be incorporated.
A lack of capacity can expose an individual to the risk
of abuse in its many forms. Sexual abuse of demented indi-
viduals can occur and their vulnerability arguably makes
them even more at risk (Burgess and Phillips, 2006).
27.3 INAPPROPRIATE SEXUAL
ACTIVITY
There is no clear consensus on what constitutes inappro-
priate sexual activity in the context of dementia or even
its prevalence. This is probably in part due to the relatively
small and heterogeneous populations studied, as well as
inconsistent definitions of such sexual behaviour (Ward and
Manchip, 2013). Despite this lack of consensus, a reason-
ably large body of evidence has developed in recent years
examining the nature and range of sexually inappropriate

behaviour in dementia. The terms ‘hypersexuality’, ‘sexual
disinhibition’ and ‘inappropriate sexual behaviours’ (ISB)
are also often used interchangeably.
27.3.1 TYPES OF BEHAVIOUR
In addition to considering whether any particular behav-
iour is abnormal, we need to also try and define specific
behaviours – as the range of unwanted acts/symptoms can
be varied. As Series and Dégano (2005) note, the decision
of when a particular behaviour becomes inappropriate or
aberrant needs to be based on a judgement of what is normal
or appropriate for a specific individual in a particular situa-
tion. This may differ according to the environment or on the
level of risk or discomfort to others.
Szasz (1983) offered a framework for objectively describ-
ing ISB. This categorization splits these behaviours into the
following:
●● Sexual talk – inappropriate comments and propositions
●● Sexual acts – inappropriate touching of oneself or
others, exposure of genitals, masturbation or even
intercourse
●● Implied sexual acts – the reading/watching of porno-
graphic material
Despite the relative lack of consensus in categorizing ISB,
the literature often includes making explicit sexual com-
ments, inappropriate touching of one’s own genitals or the
genitals/breasts of others. Inappropriate disrobing or mas-
turbation in public areas right through to attempted inter-
course with a non-consenting person all have been described.
The context of such behaviour is critical as what might be
considered acceptable in private homes or bedrooms could
well result in distress, fear or even outrage in public spaces
or communal areas of residential facilities.
27.3.2 PREVALENCE
Prevalence rates of such behaviour vary significantly
between 2% (Devanand et al., 1992) and 25% (Szasz, 1983)
depending on the study, the setting and the relatively het-
erogeneous nature of the criteria used. Burns et al. (1990)
reported disinhibition to be present in 7% of a sample of
178 patients with AD. In this study there was no difference
between males and females. However, Black et al. (2005) in
their review, state that these behaviours are more common in
males. There is also evidence to show that these behaviours
can present in mild cognitive impairment right through to
advanced dementia (Alagiakrishnan et al., 2005), although
Bardell et al. (2011) suggest that they are more common
with advancing cognitive impairment. Patients with AD
have been reported as being less likely to present with such
behaviour when compared with other types of dementia
(Zeiss et al., 1996; Alagiakrishnan et al., 2005). Most stud-
ies suggest that sexual disinhibition is found in dementias
with a significant vascular component. Tsai et al. (1999),
Sexuality and dementia 287
however, in their study of 133 patients with dementia found
no such differences between dementias of various types.
27.3.3 CAUSES OF HYPERSEXUALITY
Hypersexuality can arise from a variety of causes, even in
the absence of dementia. Structural factors such as frontal
lobe damage and temporal lobe dysfunction, leading to the
Klüver–Bucy syndrome, have been associated with sexually
disinhibited behaviours. Hypothalamic dysfunction as seen
in the Kleine–Levin syndrome can result in hypersomnia,
hyperphagia and hypersexuality, especially in males. It is
important to draw a distinction as to whether this behav-
iour is simply part of a generalized disinhibition syndrome
as we often see in dementia or a true ‘hypersexual’ disorder
manifesting in markedly increased sexual drive or activity.
Pharmacological agents such as alcohol and other
sedatives can produce behavioural and sexual disinhibi-
tion in both healthy individuals and those with dementia.
Dopamine agonists can also cause hypersexuality in patients
with Parkinson’s disease as well as a range of other impulse
control disorders such as gambling (Pontone et al., 2006).
In dementia, it is not difficult to see how ISB could arise.
Social factors such as the misinterpretation of cues (e.g. dur-
ing the delivery of personal care such as washing or being
aided to dress/undress) and premorbid patterns of sexual
activity may also all play a part in the development of sexu-
ally inappropriate behaviour (Series and Dégano, 2005).
27.4 MANAGEMENT OF ISB
Any strategy to manage sexually inappropriate behaviour
needs to begin with a comprehensive assessment of the
behaviour. This will involve a description of the behav-
iour but also a consideration of the frequency and context.
Careful and sensitive exploration, where possible, of an
individual’s sexual history, behaviour and attitudes may
well shed light and provide an insight into current problem-
atic symptoms Another vital consideration is how much of
a problem this behaviour presents and to whom, as well as a
comprehensive risk assessment (Series and Dégano, 2005).
A critical element of the assessment is to try and deter-
mine whether these unwanted behaviours occur within the
context of other challenging behaviours of dementia such as
agitation or aggression or if the hypersexuality per se is the
primary issue. This may provide clues not only to the aetiol-
ogy but also could dictate the treatment strategy.
Knight et al. (2008) have developed a validated rating
scale to evaluate ISB in people with cognitive impairment
and brain injury, but other tools exist such as the Manchip
Rating Scale (Ward and Manchip, 2013) to specifically
examine these difficulties in the context of dementia. Such
scales are useful in identifying target symptoms, which in
turn if used at intervals, can be used to measure the efficacy
of any intervention.
288 Dementia
27.4.1 NON-PHARMACOLOGICAL
APPROACHES
Ward and Manchip (2013) note that non-drug approaches
need to take into consideration the environment, culture and
attitudes of carers. If the setting is a care home, then provid-
ing adequate space for privacy may well lessen the need or
impulse for individuals to engage in ISB in more public areas,
etc. Staff need to remain sensitive to the needs of their resi-
dents in expressing their sexuality in appropriate ways, and
not discouraging discussion or attempts to address the issue.
Specific interventions to reduce such unwanted behav-
iours have been suggested (Jensen, 1989; Howell and Watts,
1990). Most rely on behavioural modification, including
removing reinforcement during the undesired behaviour
and increasing reinforcement of appropriate alternative
behaviours. Bardell et al. (2011) found that consistently
applied distraction techniques were effective in reducing
such behaviour. Other more practical strategies such as
the use of same-sex caregivers if appropriate, or the use of
clothing specially designed to prevent inappropriate disrob-
ing (e.g. with buttons at the back) may have a value and offer
simple yet effective means to address such difficulties. The
utility of these approaches such as these has not been fully
established and most evidence exists in the form of indi-
vidual or multiple case reports.
Finally, before any consideration is given to additional
medication that may be directed towards target symptoms,
common sense suggests it would be advisable to consider
the removal of any medications, which could be causing or
at least exacerbating the problem. Drugs such as benzodiaz-
epines and dopamine agonists would fall into this category
(Joller et al., 2013).
27.4.2 PHARMACOLOGICAL APPROACHES
Despite the most comprehensive assessment and detailed
behavioural management strategies, some sexually disin-
hibited behaviour can continue leading to the prescription
of medication. Currently, no medication has been licensed
either in the United Kingdom (Series and Dégano, 2005) or
in the United States (Kettl, 2008) for this specific purpose.
While there have been no double-blind, placebo-controlled
trials for any of the drugs used to combat such symptoms,
their use has been reported in the literature and again exists
mainly in the form of case reports or series and retrospec-
tive case control series. A summary is outlined below.
27.4.2.1 Antidepressants
Antidepressants are among the commonly prescribed
psychotropic medications. Their relatively favourable
side effect profile makes them ideal first-line medications
for addressing ISB (Cross et al., 2013). Selective serotonin
reuptake inhibitors (SSRIs) such as citalopram or parox-
etine are thought to act by not only their negative effect
on the libido but also via their anti-obsessional properties
(Series and Dégano, 2005). The sexual dysfunction, which is
sometimes seen with the use of such medications (Stimmel
and Gutierrez, 2006) in everyday clinical practice, could well
be the mechanism behind the beneficial effect seen in cases
of ISB. Case reports suggest that these agents can be effec-
tive even after a variety of other psychotropic medications
have failed (Tucker, 2010). Leo and Kim (1995) also found
that clomipramine – a tricyclic antidepressant but with sig-
nificant serotonergic properties – was effective in treating
two dementia patients exhibiting sexual disinhibition.
27.4.2.2 Antipsychotics
Antipsychotics have been used in attempts to manage a vari-
ety of challenging behaviours within the context of demen-
tia, not just sexually disinhibited behaviour. These drugs
exert their anti-libidinal effect through dopamine receptor
blockade (Black et al., 2005) but have been the subject of sig-
nificant debate given their potential and serious side effects
including cerebrovascular risk (O’Brien, 2008). Macknight
and Rojas-Fernandez (2000) report the beneficial use of
quetiapine in an 85-year-old man with dementia and par-
kinsonism who presented with excessive masturbation ‘to
the point of self-injury’. The patient had previously been
tried on cyproterone acetate (CPA) and paroxetine with no
success. Within 2 days of the quetiapine being commenced,
the sexual behaviours had improved with no worsening of
his parkinsonism. Case reports with positive outcomes have
also been seen with haloperidol, zuclopenthixol, olanzapine
and risperidone (Tucker, 2010; Bardell et al., 2011). Reeves
and Perry (2013) describe how a 61-year-old male with fron-
totemporal dementia and excessive sexual vocalizations was
successfully treated with aripiprazole after a variety of psy-
chotropics either failed or were not tolerated.
27.4.2.3 Anti-androgens
These agents can be further subdivided into hormonal and
non-hormonal groups. They both act to decrease serum
testosterone levels with the aim of reducing sexual drive,
although the extent to which serum testosterone corre-
lates with hypersexual behaviour is not clear (Levitsky and
Owens, 1999). The issue of using medication to suppress the
libido in a dementia patient is a complex and an ethical issue.
CPA is a progestogen and exerts its effect by both inhib-
iting testosterone release and blocking androgen receptors.
Haussermann et al. (2003) describe the successful reduction
in ISB following treatment with CPA. Huertas et al. (2007)
conducted a study comparing CPA against haloperidol
admittedly looking at non-sexual aggressive behaviours.
Twenty-four patients completed the study that revealed a
significant reduction in such behaviours favouring the CPA.
Medroxypreogesterone acetate (MPA) acts in a simi-
lar manner to CPA, although it is less potent in its mode
of action (Guay, 2008). Cross et al. (2013) reported on
a series of 10 individual cases of elderly males with
dementia and exhibiting ‘inappropriate hypersexuality’.

Positive outcomes in terms of a reduction in unwanted
behaviour were found in 7 out of the 10. This was after
antidepressant and antipsychotic trials failed to achieve
improvements in 7 and 6 of the group, respectively.
Luteinizing hormone releasing hormone (LHRH) ana-
logues such as leuprorelin, triptorelin and goserelin inhibit
gonadotrophin release suppressing ovarian and testicular
hormone production and resulting in a “chemical castration”
(Guay, 2008). Amadeo (1996) found beneficial effects of leu-
prorelin in three subjects with dementia exhibiting sexual
disinhibition. Ott (1995) also reports the successful treatment
of a demented patient with Klüver–Bucy syndrome.
Oestrogens such as diethylstilbestrol (DES) have also
been used in this context. They act by reducing lutein-
izing hormone (LH) and follicle stimulating hormone
(FSH), which, in turn, leads to a reduction in testoster-
one production (Black et al., 2005). Lothstein et al. (1997)
reported marked improvements in behaviour in 38 out of 39
demented subjects who were exhibiting sexually inappro-
priate behaviour, when treated with DES.
Care must be taken to consider the side effect profile of
these medications, which can include elevated thromboem-
bolic risk, fluid retention, osteopaenia and bone pain. Cross
et al. (2013) suggest that MPA should be considered before
oestrogen and LHRH analogues due to its more favourable
level of adverse effects and ease of administration/dosages, etc.
Other drugs with anti-androgenic properties such as
cimetidine (a histamine H2 blocker), ketoconazole (an anti-
fungal) and spironolactone (a potassium-sparing diuretic)
have also been studied. Wiseman et al. (2000) reported on
20 demented patients with sexually inappropriate behav-
iour. Fourteen of the 20 patients responded favourably
to the cimetidine while the remaining six responded to
combinations of cimetidine and ketoconazole, spironolac-
tone or both. Na et al. (2009) described how finasteride, a
5α-reductase inhibitor commonly used for treating benign
prostatic hyperplasia, successfully extinguished ISB in 6 out
of 11 men with vascular dementia.
27.4.2.4 Cognitive enhancers
If the dementia pathology lies behind the aetiology of ISB, it
might be reasonable to predict that drugs shown to be effec-
tive in treating cognitive impairment such as cholinesterase
inhibitors or memantine may also have an important role in
managing these behaviours. At present, however, the evidence
remains conflicting. While Canevelli et al. (2013) report the
improvement of sexually inappropriate behaviour in an elderly
dementia patient given rivastigmine, Freymann et al. (2005)
found that such behaviour was made worse by galantamine.
Case reports have also been published showing how donepezil
led to ISB (Chemali, 2003; Lo Coco and Cannizzaro, 2010).
While memantine has been shown to be an effective
treatment for agitation in the context of dementia, so far
no evidence has been published showing its efficacy specifi-
cally in ISB. Despite this, there is evidence that memantine
Sexuality and dementia 289
is being used by old age psychiatrists for this purpose (Ward
and Manchip, 2013).
27.4.2.5 Other medications
Finally, in addition to those described above, there are case
reports indicating beneficial effects of other medications
including carbamazepine (Freymann et al., 2005), gabapen-
tin (Alkhalil et al., 2003), buspirone (Tiller et al., 1998) and
pindolol (Jensen, 1989). The sparse nature of the published
evidence reflects the uncertainty that remains on which
pharmacological strategies are the most effective. For a com-
prehensive review of the medications used in the treatment of
ISB, see Tucker (2010) and Ward and Manchip (2013).
27.4.2.6 Ethical issues of drug management
There are complex ethical considerations when drugs are
used to combat sexually inappropriate behaviour in patients
who are unable to provide informed consent. Central to this
issue is the concept of human rights both those belonging to
the perpetrator and those on the receiving end of such behav-
iour. Any medication decision must be made in the light of an
assessment of risk to all parties and involving all relevant indi-
viduals. This decision should form part of a multidisciplinary
care plan that should be reviewed at regular individuals.
27.5 CONCLUSIONS
Clearly, the impact of dementia upon the sexuality of an
individual has profound implications for the patient, their
partner and all those involved in caring for them. When
difficulties do occur, they can be significant and a compre-
hensive assessment of all the relevant factors needs to be con-
sidered. If specific management is required, then this needs
to take account of sometimes complex ethical issues such as
capacity, consent and basic human rights. Professionals of
all disciplines need to be alert to these problems and offer
support and help when necessary.
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Residential care for people with dementia
DAVID CONN, JOHN SNOWDON AND NITIN PURANDARE
28.1 A GLOBAL PERSPECTIVE ON
RESIDENTIAL CARE PROVISION
Availability of residential long-term care (LTC) facilities for
people with dementia and physical disabilities varies from
country to country and within countries. In many areas of
the world, relatively little funding is allocated to the LTC
sector. Even between developed nations there is considerable
variation in the types, organization, funding and policies of
residential facilities. Hence, caution needs to be exercised
when considering generalizations about how residential
care is or should be provided for people with dementia.
Ribbe et al. (1997) noted that there are no universally
accepted definitions for the different LTC services. They
compared provision of residential care in 10 developed
countries based on an understanding that nursing homes
provide nursing care 24 hours per day, while residential
homes provide personal care and social involvement for
people unable to manage adequately at home, but who need
no more nursing than visiting nurses can offer. They found
that, in spite of having similar age distributions, the propor-
tion of those aged 65 years or more in the Netherlands who
were in nursing homes was half that found in the United
States, but the proportion in residential homes was four
times higher. In France, nobody was in a nursing home but
4% of the elderly were in residential homes. In 2004, of those
over 65 years in the United States, 3.63% were in nursing
homes, in a total nursing home resident population of 1.49
million (National Nursing Home Survey, 2004).
The most reliable comparative international data on LTC
come from the Organization for Economic Co-operation
and Development (OECD, 2011). On average, LTC expen-
diture (including homecare) accounts for 1.5% of gross
domestic product (GDP) across the OECD. The LTC work-
force (mostly women, often working part-time) is about
1.3% of the total OECD workforce. There is significant
cross-country variation in the resources allocated to LTC
292
28
in line with observed differences in utilization. This varia-
tion reflects differences in care needs, in the structure and
comprehensiveness of formal LTC systems, as well as in
family roles and caring cultures. Most of the cost of LTC
resides within the institutional sector with the exception
of four OECD countries (Denmark, Austria, New Zealand
and Poland), where expenditure of home care exceeds that
of institutional care.
Worldwide, the population of older people, especially the
very old, is expected to rise considerably. There is a steep
rise in the prevalence of dementia in late old age. In Japan,
a doubling of the proportion of people aged over 80 years,
from 2.8% to 5.7%, was expected to occur between 1993 and
2010, with a further rise to 9.7% by 2025. Substantial rises
in the proportion aged over 80 years are occurring in many
countries (Ribbe et al., 1997). The fact that the worldwide
number of persons with dementia is anticipated to increase
from 24.3 million in 2001 to over 81.1 million by 2040 (Ferri
et al., 2005) has startling implications regarding funding,
policies and planning of LTC for people with dementia. In
the United Kingdom, the demand for LTC beds is expected
to rise from 450,000 in 2000 to 1.1 million in 2051, with
quadrupling of the annual LTC cost from £12.9 billion to
£53.9 billion (Wittenberg et al., 2004).
28.2 PREVALENCE OF DEMENTIA IN
LTC FACILITIES
Researchers in diverse countries have reported varying rates
of dementia in LTC facilities. A recent review of 30 studies,
dating back to 1986, noted a median prevalence of 58.6%
(Seitz et al., 2010). A large UK study found that 62% of LTC
residents had dementia (Matthews and Dening, 2002). Recent
nursing home studies have shown rates of 69.5% in Helsinki
(Hosia-Randell and Pitkälä, 2005), 78% in Sydney (Brodaty
et al., 2001) and 80.5% in Norway (Selbaek et al., 2007).

The proportions with Alzheimer’s disease (AD), vascular
dementia (VaD), mixed (AD + VaD), dementia with Lewy
bodies (DLB), frontotemporal dementia (FTD), alcoholic,
traumatic or other types of dementia have not usually been
reported. Cases of young-onset dementia (including FTD
and human immunodeficiency virus [HIV]) are relatively
uncommon in nursing homes but may well require special
attention because of a greater incidence of behavioural prob-
lems or the difficulty of providing age-appropriate activities
and involvement.
The prevalence of dementia in residential homes has gen-
erally been reported as lower than that in nursing homes,
though in Maryland (United States) the difference was
small. There, 67.7% of assisted living residents (74% response
rate) fulfilled criteria for dementia and an additional 6.6%
had clinically significant cognitive dysfunction (Rosenblatt
et al., 2004). Small facilities had higher percentages with
dementia (81% versus 63%). Some 83% of those with demen-
tia had exhibited neuropsychiatric symptoms in the pre-
vious month. Residents with dementia required twice the
amount of staff time given to those without dementia.
A report commissioned by Alzheimer’s Australia illus-
trates the huge economic impact of dementia and its poten-
tial workforce demands (Access Economics, 2009). The cost
implications of the projected increase in need for LTC of
people with dementia are considerable. Of 230,000 people
with dementia in a population of 21 million in Australia in
2008, 90,200 were living in residential care facilities, cared
for by 78,000 full-time equivalent (FTE) staff. There were
0.9 and 0.8 FTEs per high care (nursing home) and low care
(residential home) resident, respectively. Modelling in the
report suggested that, in the absence of changes of policy or
other arrangements, there will be a shortage of 71,000 FTEs
within two decades. There is already difficulty in recruiting
staff skilled in dementia care, partly attributable to unat-
tractive rates of pay, and this has obvious impact on the
quality of care provided in LTC facilities.
The quality of care in U.S. nursing homes in the last three
decades has been described as poor, largely attributable to
inadequate staffing and a poor mix of skills (Harrington,
2001). This is in spite of legislation (the Omnibus Budget
Reconciliation Act, 1987; OBRA-87) brought in to ensure
higher standards of care and the development of best prac-
tice guidelines. The government was said to be reluctant to
impose higher standards for staffing because of concerns
over cost. Furthermore, Harrington (2001) commented
that fraud and financial mismanagement were widespread
throughout the nursing home industry.
To provide good care in such facilities, ‘one must battle
against nihilism, cynicism and resistance to change which
is often present in geriatric institutions’ (Conn, 2007).
OBRA-87 mandated formal psychiatric assessments of nur­
sing home residents suspected of having mental disorders
but it was observed that this further entrenched a pattern
of relative neglect of patients with dementia in formal men-
tal health services planning (Borson et al., 1997). It is evi-
dent that money alone cannot ensure a high standard of
Residential care for people with dementia 293
dementia care in LTC facilities – though it can help. Factors
that can contribute to good care will be discussed later in
this chapter.
28.3 BEHAVIOURAL AND
PSYCHOLOGICAL SYMPTOMS OF
DEMENTIA IN LTC FACILITIES
The prevalence of behavioural and psychological symptoms
of dementia (BPSD) in nursing homes varies between 24%
and 93% in the United States (Beck and Shue, 1994; Gruber-
Baldini et al., 2004). Selbaek et al. (2007) reported that 65.2%
of residents in Norwegian nursing homes exhibited one or
more clinically significant behavioural symptoms and that
frequency of delusions, hallucinations, aggression/­agitation,
apathy, disinhibition and aberrant motor behaviour
increased with progression of dementia. An English study
reported that 79% of residents with dementia in both nurs-
ing and residential homes had clinically significant BPSD
(Margallo-Lana et al., 2001).
Brodaty et al. (2001) reported that 80% of nursing home
residents showed behavioural disturbances with persons
who did not have dementia being rated nearly as highly on
behavioural disturbance scales as those with dementia. This
raises questions about the relative importance of organic
and environmental factors in development of BPSD. Brodaty
et al. (2001) found a three-fold difference in the prevalence
of different BPSD across nursing homes, but size accounted
for only 3% of the variance. The extent of the difference is
difficult to explain. Some nursing homes may be reluctant to
accept ‘difficult’ referrals. The study did find greater func-
tional incapacity to be associated with increased rates of
behavioural disturbance, including aggressiveness.
In Assisted Living facilities, 49% of residents with demen-
tia were observed to exhibit one or more behavioural symp-
toms at least once weekly, 19% showing aggressive and 34%
physically non-aggressive behaviour (Gruber-Baldini et al.,
2004). Rates were higher in facilities with fewer residents.
Reliable and valid measurement of BPSD is of great
importance in both clinical practice and research. A recent
review described 83 different instruments that have been
utilized to assess and track BPSD (van der Linde et al., 2014).
Examples include the Neuropsychiatric Inventory (NPI),
the Cohen-Mansfield Agitation Inventory (CMAI) and the
Behavioral Pathology in Alzheimer’s Disease Rating Scale
(BEHAVE-AD) (Reisberg et al., 1987; Cohen-Mansfield
et al., 1989; Cummings et al., 1994). Tracking of behaviours
utilizing basic charting approaches, such as documenta-
tion of antecedent–behaviour–consequences (ABC) can
also be very useful for identifying triggers and designing
interventions.
Brodaty et al. (2001) noted positive associations between
ratings of behavioural disturbance and psychosis and
depression. Wancata et al. (2003) reported that 38% of newly
admitted residents with dementia had marked or severe
294 Dementia
non-cognitive symptoms of dementia, including 30% with
depressive symptoms and 12.7% with ‘aggressive-psychotic
symptoms’; one-third remitted from these symptoms within
6 months. Menon et al. (2001) analysed data from residents
with dementia newly admitted to Maryland nursing homes.
Nursing staff observed physical aggressive behaviours in
10.5% and verbal aggressive behaviours in 10.4%. The rates
varied with degree of cognitive impairment, with physical
aggression displayed by 15% of those with severe demen-
tia and 2.4% with mild dementia, and verbal aggression by
13% and 5.4%, respectively. They found that those manifest-
ing physical or verbal aggression (mainly those with more
severe cognitive impairment) were more likely to be rated
as depressed.
Studies have found the prevalence of depression in LTC
facilities to be much higher than that reported among
older people living at home. Depression levels were some-
what higher in nursing homes than in residential homes
(Snowdon and Fleming, 2008). Of residents newly accom-
modated in Maryland nursing homes (assessed 21–65 days
after admission, thus minimizing the effect of relocation
stress on results), 23.6% of demented and 22.3% of non-
demented subjects were recorded as depressed (Kaup et al.,
2007). Among those with dementia, depression in residen-
tial homes was not significantly less prevalent than in nurs-
ing homes (Gruber-Baldini et al., 2005). Most residents with
anxiety symptoms are also depressed (Parmelee et al., 1993).
Evers et al. (2002) drew attention to the high prevalence of
major depression among residents in the last 6 months of
life, both those with dementia and those without.
Among nursing home residents, the evidence regard-
ing an association of depression with cognitive impair-
ment is unclear. Some have observed no association (Katz
and Parmelee, 1994). Others have reported depression to be
more prevalent among those with mild-to-moderate demen-
tia (Evers et al., 2002; Jones et al., 2003). In contrast, Teresi
et al. (2001) diagnosed major depression in 5.8% of nursing
home residents with little or no cognitive impairment, but in
22.8% of those with moderate-to-severe dementia. Gruber-
Baldini et al. (2005), examining scores on the Cornell
Scale for Depression in Dementia (Alexopoulos et al., 1988)
among residents of nursing homes and residential homes,
found that participants with depression were more likely to
be severely or very severely cognitively impaired. The asso-
ciation of behavioural symptoms with Cornell Scale scores
was significant, though it was much stronger among those
with dementia in residential homes. Barca et al. (2008), who
conducted a factor analysis of ratings on the Cornell, noted
that scores on the mood sub-scale did not differ across var-
ied levels of dementia severity, but on the other four sub-
scales increases were associated with severity of dementia.
In an earlier factor analysis (Kurlowicz et al., 2002), a clear
separation had been noted between somatic/vegetative
features and a ‘core depression factor’, raising questions
about the scale’s validity in a population with high levels of
dementia, medical illness and/or functional disability. Some
symptoms of depression as rated by the Cornell overlap
with those of dementia. Nursing home resident scores on
the Cornell Scale and on the Neuropsychiatric Inventory
(Cummings et al., 1994) correlated highly (r = 0.7) (Barca
et al., 2009). Apathy (which needs to be distinguished from
depression) is common early in AD and becomes more
severe as cognitive impairment worsens.
Examination of the factors associated with depression,
agitation and other behavioural and mental disorders in
LTC facilities is relevant to discussions concerning optimal
management, interventions and therapy for these disorders.
For example, depression among residents with dementia has
been reported as more common in for-profit than not-for-
profit nursing homes (Gruber-Baldini et al., 2005). To what
extent are depressive symptoms a result of demoralizing
situations and circumstances? To what extent is disruptive
behaviour attributable to neurobiochemical or structural
brain changes, maybe interacting with environmental fac-
tors? Outcome studies exploring whether medications, psy-
chological therapies or environmental adjustments appear
to be related to reduction in symptoms will provide clues.
The finding that, in a 1-year study of residents with demen-
tia in LTC facilities, 45% of agitation cases, nearly 60%
with delusions and over 60% of depression cases resolved
independently of pharmacological treatment (Ballard et al.,
2001) should provoke consideration of what factors specific
to LTC situations contribute to development of these condi-
tions. This also highlights the self-limiting course of certain
BPSD, and therefore the propriety of regular reviews of med-
ication, with attempts to cease unnecessary prescriptions.
The fact that, in an LTC facility in California for people
with cognitive impairment, 40 residents scored >12 on the
Cornell Scale soon after admission, but that only 6 of them
were still depressed after 6 months (in contrast to worse out-
comes elsewhere), raises questions about factors that main-
tain depressive symptoms (Payne et al., 2002). Commenting
on a decrease in depressive symptoms from 41.3% to 28.9%
during the first 6 months of admission to Dutch nursing
homes, Smalbrugge et al. (2006) suggested that adaptation
to pre-admission factors, facilitated by the nursing home
environment, may explain the fall. When the prevalence
does not fall (as in the study by Scocco et al., 2006), reasons
should be sought.
28.4 RECOGNITION OF DEPRESSION
IN CASES OF DEMENTIA IN LTC
FACILITIES
Cohen et al. (2003) have commented on the evidence (e.g.
Bagley et al., 2000) that depression in nursing homes is
frequently overlooked and undertreated. They found that
despite using the Minimum Data Set (MDS) in U.S. nurs-
ing homes, 75% of major depressive disorders and 87% of
all types of depression escaped recognition; further, only
33% of those identified as depressed were treated with anti-
depressants. These authors showed that use of the Cornell

Scale resulted in a significant increase in the percentage of
residents given antidepressants. Before screening, only 16%
of patients who scored 5 or more on the Cornell were pre-
scribed antidepressants, whereas after routine screening
was introduced 36% were given antidepressants. They rec-
ommended mandatory screening and suggested that refer-
rals to staff psychiatrists of all those scoring 5 or more on
the Cornell would not impose an undue burden on them.
The American Geriatrics Society and American Asso­
ciation of Geriatric Psychiatry (2003a), in a consensus
statement, recommended that residents should be screened
for depressive symptoms within the first 2–4 weeks of
admission to an LTC facility, and subsequently at least
every 6 months. Use of the Cornell Scale was supported
for residents with moderate or severe dementia, and of
the Geriatric Depression Scale (Yesavage et al., 1983) for
residents with no more than mild-to-moderate cognitive
impairment. However, limitations should be recognized as
discussed in Section 28.3. Somatic items comprise 37% of
the Cornell. The prevalence of depression may be overes-
timated in patients with physical problems. Kurlowicz et
al. (2002) called for research to establish whether an intra-
psychic sub-scale of the Cornell may be more useful than
the global scale for measuring depression among those
with dementia, physical illness and/or disability. Greenberg
et al. (2004) found that in palliative care cases the psychia-
trist’s diagnostic assessments did not correspond well with
Cornell Scale scores and concluded that there was no scale
valid and reliable enough to effectively ascertain depres-
sion in the most severely demented patients. A short form
of the Geriatric Depression Scale (GDS-15), validated by
Herrmann et al. (1996), has been found useful in screening
for depression among residents with only mild-to-moderate
cognitive impairment (Gerety et al., 1994), and in such cases
correlates more closely than does the Cornell with psychia-
trist assessments on other depression rating scales, such as
the Montgomery Åsberg Depression Rating Scale (MADRS)
(Montgomery and Åsberg, 1979; Snowdon and Fleming,
2008). Even if such scales are not valid in all cases, use of
the GDS-15 and/or Cornell, as appropriate, in LTC facili-
ties, is strongly recommended, with the intention that, if
pointers to depression are identified, staff and doctors will
be prompted to discuss possible causation and appropriate
interventions.
The challenge of preventing and identifying depression in
this population has been highlighted by several recent stud-
ies. A Dutch study evaluated the effects of a 2-year stepped
care programme designed to prevent the onset of major
depression. After 2 years, the incidence of depression was not
significantly lower in the intervention group than in the con-
trol group although there was some evidence that completers
had benefitted. Of note, the drop-out rate was very high at
44% (van Schaik et al., 2014). In an Australian study of six
sessions of staff training to improve recognition of depres-
sion, the trained group performed no better than controls
(McCabe et al. 2013). In another study, use of the Cornell
Scale for depression in dementia had very limited impact on
Residential care for people with dementia 295
the likelihood of staff initiating or calling for interventions
when residents were rated as depressed. File notes showed
that less than one-third of the residents with high scores
were monitored for evidence of depression by staff following
the assessment. Only 18% of residents with high scores were
referred for further assessment of depression, while 10%
received a treatment change (Davison et al., 2012).
28.5 MANAGEMENT OF DEMENTIA IN
LTC FACILITIES
Prevention and management of dementia, BPSD and dep­
ression in cases of dementia are discussed in chapters 7, 8,
23, 24, 25 and 53. Aspects specific to care in LTC facilities
will be discussed here.
Little will be said about short-term residential care
(respite) because of the dearth of relevant data and studies.
It has proved effective in reducing the subjective burden and
depression experienced by family caregivers of people with
dementia (Donath et al., 2009). However, studies around the
world have shown low utilization of such care, even when
caregivers were well aware of its availability.
28.5.1 PHYSICAL AND SOCIAL
ENVIRONMENT AND STAFF
TRAINING
First it is appropriate to re-emphasize the importance of
environment and of care arrangements in relation to pre-
vention or development of mood and behaviour distur-
bance. Guidelines are available (e.g. American Geriatrics
Society and American Association for Geriatric Psychiatry,
2003b; Conn and Gibson, 2007) to advise on how, and in
what settings, optimal care can be provided. Koopmans
(2005) recommends accommodating residents at similar
stages of dementia together, but notes that a drawback is
the need to move them when their dementia progresses.
Others advocate ageing in place. There is also an argument
for housing people with early-onset dementia together. The
major need surely is to look at the needs of the individual
and what suits that person best.
As stated earlier, funding varies between jurisdictions,
both in relative amount and how it is allocated. However,
Conn and Gibson (2007) pointed out that countries that
have residential care facilities for older people commonly
face challenges that include ‘inadequate staffing levels, lack
of staff training regarding mental health issues, aging and
poorly designed LTC homes, failure to identify and assess
residents in a timely fashion, inappropriate use of psycho-
tropic medications and limited availability of mental health
consultants’.
Management of dementia in LTC settings is optimized
by having available a multidisciplinary team that can
coordinate care. Facility-based staff members may take
296 Dementia
on mental health interest roles, such as recognition and
coordination of management of depression, and may be
designated to have a role liaising with doctors and visit-
ing mental health professionals. Some LTC facilities make
arrangements for a consultation-liaison old age mental
health service to be accessible to work with facility staff and
primary care doctors in dealing with the range of psychi-
atric and behavioural problems associated with dementia.
An Australian model for dealing with challenging behav-
iours blended clinical consultation with staff training and
educational interventions (Turner and Snowdon, 2009). A
UK study found that few LTC facilities had visits from psy-
chologists or social workers, and only one-third received
visits from old age psychiatrists (Purandare et al., 2004).
Snowdon (2010) reviewed models of mental health service
delivery to LTC homes concluding that prompt recognition
of mental health problems among residents is required, and
this is facilitated by availability of a team working within
the facility to deal with these problems. Provision of opti-
mal mental health care in LTC settings is dependent on
adequate funding, availability of expertise and education,
positive and caring attitudes, recognition of needs and sup-
portive teamwork.
Citing Canadian national guidelines relating to men-
tal health issues in LTC homes, Conn and Gibson (2007)
discussed organizational and systems issues. The first con-
cerned LTC homes developing the physical and social envi-
ronment as a therapeutic milieu through the intentional
use of design principles. Verbeek et al. (2009) declared that
traditional institutional care has been arranged according
to the medical model, with emphasis given to the treat-
ment of the underlying pathology. They contended that this
model has become outmoded. They said that a shift towards
a psychosocial model has occurred, this approach being
person centred and aimed at supporting the well-being and
remaining strengths of older people with dementia.
It has been recognized that a facility’s architectural and
physical environment influences dementia care, and studies
have suggested that small, domestic-style environments are
beneficial for older people with dementia. Verbeek et al. (2009)
reviewed and compared 11 concepts, from various countries,
that have adopted a home-like philosophy of care in a small-
scale context. They referred to CADE (confused and disturbed
elderly) units in Australia, the Cantou in France, Group Living
and Small-scale Living in Sweden and the Netherlands and
Belgium, Green Houses in the United States and comparable
concepts developed in Japan, Canada, the United Kingdom
and United States. In all of the 11, residents are encouraged
to participate in the household as far as possible, with activi-
ties (such as cooking) being planned according to residents’
wishes. Residents are stimulated, encouraged and supported,
with an emphasis on autonomy and choice. Care staff function
as part of the household, and thus need to have skills and atti-
tudes that suit the philosophy. In Green Houses, staff (certified
nursing assistants) receive 120 hours of additional training for
an expanded universal role, that includes cooking, cleaning,
laundry, shopping and more (Ragsdale and McDougall, 2008).
The Green House model of care was developed by Dr
William Thomas, who had introduced the Eden Alternative
in the 1990s. This model aimed to reduce loneliness, bore-
dom and helplessness among nursing home residents. To
enhance quality of life, nursing home staff were encouraged
to integrate plants, animals and children into the daily life
of residents.
A review of the literature on the impact of environmen-
tal design for LTC concluded that designers may confidently
use unobtrusive safety measures; vary ambience, size and
shape of spaces; provide single rooms; maximize visual
access and control levels of stimulation. There was less evi-
dence on the usefulness of signage, homelikeness, provision
for engagement in ordinary activities, small size and the
provision of outside space (Fleming and Purandare, 2010).
Impetus towards developing the above ideas may have
been accelerated by reports such as that from Sloane et
al. (1991). They found that the development of special-
ized dementia units (whether areas within nursing homes
or entire facilities) apparently led to less use of physi-
cal restraints but no reduction in use of pharmacological
restraint.
However, a Cochrane review concluded that there are
no identified RCTs investigating the effects of Special
Care Units on behavioural symptoms in dementia, and no
strong evidence of benefit from the available non-RCTs.
The authors concluded that it is probably more important to
implement best practices than to provide a specialized care
environment (Lai, 2009).
28.5.2 PSYCHOTHERAPEUTIC
APPROACHES AND PERSON-
CENTRED CARE
A person-centred approach argues that much of what is
described as ‘challenging behaviour’ is a rational response
to an untenable situation and can be a response to unmet
physical or social needs (Downs et al., 2005). Cohen-
Mansfield (2001) suggested an environmental vulner-
ability model and a behavioural and learning model.
Non-pharmacological treatments for behavioural distur-
bance, based on these models, are discussed in Chapters
23 and 24. Snoezelen and aroma therapy are examples of
strategies used by nursing home staff to reduce agitation.
Chenoweth et al. (2009) have presented evidence of the
effectiveness of dementia-care mapping and person-centred
care in reducing agitation among residents of LTC facilities.
A recent review of non-pharmacological interventions for
neuropsychiatric symptoms of dementia found that 16 of 40
included studies reported statistically significant results in
favour of the interventions (Seitz et al., 2012). These inter-
ventions included staff training, mental health consultation
and treatment planning, exercise, recreational activities
and music therapy or other forms of sensory stimulation.
Many of the studies had methodological limitations that

placed them at potential risk of bias. Most interventions
required significant resources from services outside of LTC
or significant time commitments from LTC nursing staff for
implementation. A study of the barriers to providing non-
pharmacological interventions concluded that awareness
of this information provides a tool by which to tailor inter-
ventions so as to anticipate or circumvent barriers, thereby
maximizing intervention delivery (Cohen-Mansfield et al.,
2012).
It has been stated that most agitated behaviours of people
with dementia are manifestations of unmet needs (Camp
et al., 2002). The goals of treatment should be to uncover and
address such needs; the person has been unable to fulfil them
because of a combination of perceptual problems, commu-
nication difficulties and an inability to manipulate the envi-
ronment through appropriate channels (Camp et al., 2002).
Cohen-Mansfield (2001) categorized non-­pharmacological
interventions, but Cody et al. (2002) detailed some of the
challenges to their use in nursing homes. They even sug-
gested (and this was long after OBRA-87 was introduced)
that staff members often see the sedating effects of psycho-
tropic drugs as desirable – and might prefer their use to
resident activity. Attitudes and the quality of care in LTC
facilities are largely determined by the leadership, example
and training provided in those facilities, in addition to their
design and philosophy.
There is good reason to examine factors that might be
responsible for demoralization among LTC residents who
become depressed. Higher levels of mastery and greater
satisfaction with available social support have been shown
to have effects in lessening depression and in buffering the
adverse impact of disability (Jang et al., 2002). Blanchard
et al. (2009) have discussed the processes of adjustment
needed to overcome the multiple losses of function, abili-
ties, roles and relationships that may occur in old age. They
referred to construction and consolidation of a new under-
standing of oneself, with emergence of meaning to life,
goals and something to hope for. Losses in one domain are
compensated for through strengths in other domains. The
relevance to LTC facility care is striking.
Testad et al. (2014) provided a systematic review of evi-
dence for the value of psychosocial interventions for BPSD.
There is good evidence that personalized pleasant activities
are effective in the treatment of agitation, and that reminis-
cence therapy can improve mood. Van Bogaert et al. (2013)
found that six to eight sessions of reminiscence therapy
reduced depressive symptoms in this population. A ran-
domized trial of humour therapy provided by professional
clowns, supported by trained staff, has been carried out in
Australia with evidence of significant reductions in agita-
tion as well as improved mood (Low et al., 2014).
Bharucha et al. (2006) reviewed 18 studies of psycho-
therapy provided in LTC settings. A majority showed ben-
efits on instruments measuring depression, hopelessness,
self-esteem, perceived control and on other variables. They
commented that a perception that psychotherapy is a ‘medi-
cal’ intervention is a serious obstacle because of the lack of
Residential care for people with dementia 297
availability of consultants to do this work. They suggested
the possibility of psychiatric nurse practitioners being
trained as depression care managers or masters-level mental
healthcare specialists, who could also provide staff training
in management of ‘difficult’ patients and coordinate group
therapy. Another model (Restore, Empower, Mobilize) for
brief individual psychotherapy to treat depression in long-
term care residents with mild-to-moderate dementia has
been presented by Carpenter et al. (2002).
28.5.3 PSYCHOTROPIC MEDICATIONS
Use of antipsychotic medication to suppress behavioural
disruption has varied between countries and over time.
Extensive comparisons will not be presented here. However,
a major catalyst for discussions leading to OBRA-87 was
concern about misuse of psychotropic medication in U.S.
nursing homes. Introduction of federal antipsychotic drug
regulations led to a 36% reduction in prescriptions for
neuroleptics in Baltimore nursing homes over 6 months
(Rovner et al., 1992), and other studies (cited by Hughes
et al., 2000) showed comparable results. Data from various
countries showed that in the mid-1990s over 20% of resi-
dents in Iceland, Italy and Sweden, but only 14.4% of U.S.
nursing home residents, were taking antipsychotic drugs
(Hughes et al., 2000).
In Sydney nursing homes in 1993, 27.4% of residents were
taking typical antipsychotic medication regularly, while 15
years later, 28% were given antipsychotics regularly, 7.4%
typical and 21.8% atypical (Snowdon et al., 2011). Two-
thirds of those given antipsychotics had dementia or cere-
bral disease and not schizophrenia (Snowdon et al., 2005).
The percentage of residents regularly taking anxiolytics fell
progressively from 1993 to 2003 (8.6% to 4.1%) then rose
to 4.7%, and similarly there was a fall in regular hypnotic
use (26.6% to 11.3% and then 11.1%) (Snowdon et al., 2006,
2011). Use of antidepressants increased, but not as much as
in U.S. nursing homes (Snowdon et al., 2006). The changes
have been attributed to increased availability of best prac-
tice information in Sydney. In the early 2000s in Norway,
21.8% of nursing home residents were taking antipsychotics,
24.5% anxiolytics, 30.6% hypnotics and 39.5% antidepres-
sants (Barca et al., 2009). Antipsychotics were more com-
monly prescribed for those with severe dementia, reflecting
the fact that psychotic and aggressive symptoms increase
with severity of dementia (Selbaek et al., 2007). In Sweden,
26.3% of residents of LTC facilities for older people were tak-
ing antipsychotics, their use being higher among those with
aggressive, verbally disruptive and wandering behaviour
(Lövheim et al., 2006). In Helsinki, in 2003, a remarkable
43.3% of residents with dementia and 41% of those with-
out were given antipsychotics, while 41.4% of those with
dementia and 51.9% of those without were given antide-
pressants (Hosia-Randell and Pitkala, 2005), and there was
a high use of anxiolytics and hypnotics. In Dutch nursing
homes, antipsychotic and antidepressant drugs were more
often prescribed for residents with severe dementia, while
298 Dementia
anxiolytics and sedatives had no association with dementia
stage (Nijk et al., 2009). Both antipsychotic and anxiolytic
use were associated with agitation.
Several studies have shown considerable variation between
nursing homes in the extent of prescribing of antipsychotic
medication. Kleijer et al. (2014) found that facilities with a
high prevalence of such prescribing had higher proportions
of residents who were physically dependent and cognitively
impaired, though levels of BPSD were not much greater than
those recorded in the other facilities. They were larger, their
residents were more depressed and consumers (relatives and
residents) were less satisfied with staffing and personal care.
Concern about overprescribing of psychotropic medications
in LTC settings persists and in some countries, e.g. England,
national targets have been set for reduced utilization with a
focus on antipsychotics (Banerjee, 2009). There is some evi-
dence that significant reductions have already occurred
(Martinez et al., 2013). Evidence that antipsychotic medication
is associated with increased rates of death and cerebrovascular
events as well as other adverse effects underline the need for
fully informed consent prior to initiation of treatment.
Use of other types of medication in managing scream-
ing, hypersexuality and other behavioural problems has
been discussed elsewhere in this book, as has the use of anti-
cholinesterase inhibitors. Frequency of use of the latter in
nursing homes varies markedly between countries.
It is relevant to note that the evidence showing effective-
ness of antidepressants in both community (Roose et al.,
2004) and LTC (Snowden et al., 2003) settings is limited,
and that a systematic review found no clear evidence for
efficacy of antidepressants in dementia (Bains et al., 2009).
Depression levels reduced in only one third of depressed
residents treated with antidepressants for 2 months (Boyle
et al., 2004). Several studies showed that residents with
dementia responded less well than those without dementia
(Snowden et al., 2003). Depression among residents with
dementia develops in response to a complex mix of factors,
some ongoing, so that non-response to antidepressants may
seem understandable. When symptoms are common to
both depression and dementia, difficulty suppressing symp-
toms may be because antidepressants have no effect on the
underlying dementia (Purandare et al., 2001).
28.5.4 OPTIMAL PSYCHOTROPIC
PRESCRIBING APPROACHES
Many factors combine during the decision-making process
related to prescribing of a new psychotropic medication in
the LTC home. Although the physician makes the final deci-
sion other team members play a critical role as well. A vari-
ety of approaches have been tested to determine how best to
optimize overall prescribing patterns. A Cochrane review
of psychosocial interventions for reducing antipsychotic use
found that reductions can be achieved through education
and training of staff and/or multidisciplinary team meet-
ings (Richter et al., 2012). Another Cochrane review focused
on interventions to optimize prescribing in LTC homes
(Alldred et al., 2013). The approaches included medication
review, multidisciplinary case conferencing, staff education
and use of clinical decision support technology. The authors
concluded that the interventions did lead to the identi-
fication and resolution of medication-related problems.
However, evidence of an effect on resident-related outcomes
was not clearly established. Ideally LTC home leaders will
develop quality improvement projects focused on how to
optimize psychotropic prescribing.
28.6 STANDARDS OF CARE IN LTC
FACILITIES
Useful advice on standards to be achieved in nursing home
care has been provided by Koopmans (2005). Physicians
specially trained in nursing home medicine are employed
by Dutch nursing homes, with a ratio of one doctor per
100 patients. Availability of doctors and specialists to visit
or work in LTC facilities varies between jurisdictions, as
does the availability of psychologists. Standards of care are
largely dependent on staffing, and how well the staff work
with residents. Standards regarding regular screening of
mood, behaviour, physical function and use of medica-
tion are desirable, and capacity to respond to special needs
should be one of the standards. Dufey and Hope (2005) have
listed a number of standards for nurses to achieve when car-
ing for people with dementia.
A Dutch-led multidisciplinary and multinational strat-
egy resulted in the publication of a set of unique quality
indicators (QIs) that aims exclusively at assessing the qual-
ity of psychosocial dementia care. It is hoped that following
implementation, these QIs will assist dementia care profes-
sionals to individualize and tailor psychosocial interven-
tions (Vasse et al., 2012).
28.7 PALLIATIVE CARE
Hertogh (2005a) has discussed issues to be addressed dur-
ing end-of-life care, which in due course applies to most
people living in nursing homes. Quality of life needs to be
assessed. Provision of high-quality palliative care in the
nursing home setting is essential (Engel et al., 2006); next of
kin are generally opposed to use of feeding tubes. Advance
directives should be discussed with a care provider at the
time of admission. However, Hertogh (2005a) pointed out
that euthanasia in cases of dementia is almost an unthink-
able option due to impaired cognitive skills and inability
of such patients to provide informed consent. Opiates are
frequently used in Dutch nursing homes for symptom con-
trol, but the administration of medications specifically
intended to cause death was found to be uncommon (2%)
(van der Steen et al., 2005). These issues are discussed in
Chapter 37 too.

28.8 USE OF TECHNOLOGIES IN
RESIDENTIAL CARE
A range of technologies are beginning to be incorporated
into LTC settings. These include a variety of monitoring
devices; tools to enhance activities of daily living; robots;
provision of care via telemedicine and approaches designed
to enhance social connectedness. Monitoring devices
include falls detection and prevention systems, mobility
aids, activity and sleep monitors and medication compli-
ance systems (Czaja et al., 2013). Videoconferencing can
connect residents in LTC with family and friends, result-
ing in reduced isolation and loneliness. Telepsychiatry has
proven valuable in the care of nursing home residents,
providing virtual assessment and follow-up (Rabinowitz
et al., 2010). The use of video-simulated presence (with
pre-recorded video by a family member) appears to assist
in reducing resistance to care (O’Connor et al., 2011). There
is some evidence that companion robots can have a posi-
tive effect on quality of life of people with mid-to-late stage
dementia. Two randomized trials looked at the use a com-
panion robot and suggested benefits on scores of pleasure
(Moyle et al., 2013) and loneliness (Robinson et al., 2013).
The introduction of new technologies can be challenging
and Niemeijer et al. (2010) have provided useful commen-
tary on the ethical and practical concerns associated with
the introduction of surveillance technologies in residential
care as well as an ethnographic field study on how staff actu-
ally incorporate these technologies into practice (Niemeijer
et al., 2015).
28.9 GOOD CARE
Hertogh (2005b) has discussed elements of an ‘ethic of
care’ in LTC for people with dementia. Caregivers are
encouraged to move beyond a simple custodial approach
to caring and focus on the residual abilities and subjec-
tive experiences rather than functional deficits of people
with dementia. The ethic of care ‘allows criticism of a soci-
ety that is too unilaterally oriented towards the maxims
of individual autonomy and independence’. Central to the
ethic are safety and self-esteem. Caregivers should afford
people with dementia meaningful choices that allow them
to enhance their self-esteem and personhood. Good care
recognizes the fear and anxiety experienced by people with
dementia due to loss of control and progressive threaten-
ing of their identity. They need a safe haven where they can
feel ‘at home’ and secure.
‘Bringing together of functional caring and empathetic
treatment is exactly what defines the specific competency
needed for caregiving in dementia’. There is also a need
to care for the carers and attention to the morale of those
working and living in LTC facilities. Adequate funding for
well-integrated care is vital.
Residential care for people with dementia 299
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Design and dementia
JUNE ANDREWS
29.1 WHY ATTENTION TO BUILDING
DESIGN AND TECHNOLOGY IS
VITAL FOR THE PERSON WITH
DEMENTIA
Good design and technology promotes independence for
people with dementia and decreases the burden of care for
families or health and social care workers. It can reduce the
cost of care by postponing institutionalization and decreas-
ing adverse incidents. In addition, because the dementia-
friendly recommendation may even be less expensive than
what the architect or planner would otherwise propose, the
financial savings for care providers can start even before the
project is functioning.
Dementia is a symptom of a primary disease process.
The ‘dementia’ is the extent to which that process (e.g.
Alzheimer’s disease or vascular disease) renders the per-
son less able to remember or learn or work things out and
leaves them with a reduced ability to cope with the stress
caused by reduction in that capacity. The dementia symp-
toms are not necessarily in direct proportion to the extent
of the disease process. Most people with dementia are
older, or very old, and their capacity to deal with the com-
mon changes of aging is reduced by environmental stress,
the behaviour of other people, other physical illness and
fatigue.
There are three levels of support for design recommen-
dations:
●● Research involving people with dementia
●● Generalizing from sensory and physical impairment
research
●● Sharing examples of good practical solutions based on
an understanding of cognitive impairment and expert
consensus
304
29
29.2 HOW THE BUILT ENVIRONMENT
AFFECTS THE PERSON WITH
DEMENTIA
29.2.1 IMPAIRED MEMORY
When you do not remember where you are, it is as if you
are in the building for the first time. You may ask people
where you are, and why, and try to leave to identify any
familiar landmark. If people stop you from getting out, you
may become stressed and redouble your efforts to exit. The
dementia-friendly building aims to compensate for this
problem by requiring you to remember less. Every location
important to you is obvious and easy to find.
29.2.2 IMPAIRED REASONING
Anyone can momentarily forget where they are or how
to use an everyday object. Usually, we can work it out. A
dementia-friendly building makes this easier. For example,
the soap, tap, flush handle and the paper holder in the toilet
will be very easy to understand, an objective best achieved
by using familiar or traditional designs.
29.2.3 IMPAIRED LEARNING
Because of acquired learning problem, the person with
dementia has difficulty with any new environment. Good
design provides cues to support residual capacity, reducing
distraction that impairs concentration. Design cues can help
with orientation and prevent the person straying into unhelp-
ful situations. An example is the hazard of frequent exiting
through the fire escape door in the absence of a fire. Design
can make this less likely. We need to balance the continuous
risk of random hazardous exiting with the theoretical risk of
the exit not being found by staff and visitors in a fire.

29.2.4 ORDINARY CHANGES OF AGEING
The majority of people with dementia are old or very old and
have age-related difficulties. The building needs to compen-
sate on their behalf. The person may need help, but forget
to use the call assist button. Technology such as a passive
infrared beam can alert carers to the fact that the person
is on the move and so that they can offer timely assistance
even if no help is requested.
29.2.5 HIGH LEVELS OF STRESS
The stress created by never knowing where you are or why
you are there and never being even vaguely familiar with the
environment in which you find yourself is unfathomable.
This is made worse by meaningless noise and activity. Good
building design can conceal background jobs like deliv-
ery of laundry and reduce necessary noises. Incorporating
outdoor spaces for leisure, gardening and exercise helps to
reduce stress.
29.3 SOME PRACTICAL IMPLICATIONS
Staff or lay people who are consulted about design of facili-
ties for people with dementia need an understanding of
dementia and of planning in order to prevent their involve-
ment becoming tokenistic, or even unhelpful. The use of
an audit tool to inform design decisions can help ensure
that evidence rather than fashion informs decisions. It
is important that any architect or designer is trained in
dementia-friendly principles to ensure best value in the
project and secure reduced running costs for the build-
ing. Such expertise can be used at every stage – planning,
building or refurbishment.
29.3.1 AT HOME
A familiar home environment with least alteration is best.
Poor short-term memory means that the person may not
remember endorsing any ‘­improvement’. People often as-
sume they have been robbed, or that someone is trying to
infuriate them by moving belongings round, or that they
are in the wrong house. So you have to balance the potential
benefit of change against the more certain risk that it will be
perplexing. The most productive change is to improve the
level of lighting (McNair et al., 2013). You must increase the
power of all light fittings, clear shrubs from outside win-
dows, clean the glass and make sure drapes can be opened
wide. Low-energy light bulbs must be replaced regularly
when their luminosity fades. Assistive technology is increas-
ingly available and affordable (Kerr et al., 2010) and can keep
the person in their own home longer. For example, a person
with dementia may forget a running tap and the flood then
causes them to be displaced to an unfamiliar setting while
home repairs are undertaken. Use of a flood detector built
Design and dementia 305
in to an alert system or an adapted plug that allows water to
drain away by being triggered by the weight of water above
can help reduce the risk of a costly and potentially perma-
nent move.
29.3.2 IN HOSPITALS AND CARE HOMES
It is never too soon in a new build to consider incorporat-
ing dementia-friendly features, as simple features in the
architectural plan can improve the building at no extra cost
(Fuggle, 2013). Examples of what design might do include
the following.
29.3.2.1 Night care
Problem – The person might not sleep well and may fall,
giving rise to injury, disruption of others and organi-
zational consequences.
Solutions – Due to the yellowing of the ageing eye,
the day/night cycle can be disrupted because of poor
daylight exposure during daylight hours (Koncelik,
2003). Morning access every day to a garden or
bright daylight can help to reset the body clock.
Space and quiet available throughout the day can
support meaningful activity to create healthy fatigue
by bedtime. Reduced noise levels and slowed activity at
bedtime can promote falling off to sleep (Kerr et al.,
2008). Glass panels in bedroom doors in conjunction
with extraneous light can wake the person up and
unhelpfully tempt them out of their room. Passive
infrared sensors could better warn staff if necessary
that the person is awake and moving about and can
switch on lights to cue the person to use the toilet
and go back to bed. The positioning of the bed head
so that the lavatory pan can be seen is crucial for
this. The use of vibrating pagers for call alerts can
reduce the meaningless noise of buzzers in the night
(and day). One simple design change to assist people
with dementia at night is the use of an analogue
clock set to the right time. The current generation
of older people with dementia may have forgotten
what a digital clock is and therefore be unable to
tell the time (Fleming et al., 2008). An appropriately
positioned and well lit clock can reduce the need
for someone with dementia to get up to orientate
themselves.
29.3.2.2 Hygiene
Problem – The person with dementia may not use the toi-
let appropriately and require extra help with hygiene.
Solutions – Incontinence can be caused by failing to
reach the toilet in time, so make sure that the floor
coverings are smooth, matte and self-coloured to
encourage the person with dementia to walk more
swiftly to the right place (Perritt et al., 2005). Make
306 Dementia
the door easy to find by using bright contrasting
colour to the surrounding wall and signage at low
height, so that the person does not have to look up
(Dementia Services Development Centre, 2011). The
sign should include words and pictures that make
sense to the generation who is using the toilet, i.e. the
matchstick man/woman sign is a recent identifier for
toilets. The fixtures and fittings should be culturally
appropriate and recognizable in traditional designs
and contrasting colours. This could currently mean
offering a bar of coloured soap and a cotton towel,
against strict infection control guidance. Some inde-
pendent hand-washing is better than dependence on
staff, or worse, no hand-washing.
Shiny bathroom surfaces and floors can cause visual prob-
lems leading to falls. Mirrors may cause distress if the per-
son does not recognize their reflection. If the bathroom has
to be used as a store for shiny metal lifting equipment and
boxes of continence pads, it reduces the capacity of the per-
son to work out where they are and why they are there. That
could give rise to resistance to the idea of being undressed,
making bath times stressful and difficult for staff. Laying
out of clothes in the order they are to be put on to aid inde-
pendent dressing is easier if there is a place to do that in the
bathroom.
29.3.2.3 Unwanted exiting and walking
Problem – There is a perceived danger that the person will
walk into danger or cause a nuisance.
Solution – The design solution depends on the reason why
it’s a problem. Do staff need to know where everyone
is all the time? Do residents need to burn off energy to
reduce their own stress? Is the problem that families
need to feel that their relative is safe?
Discreet electronic equipment can assist with monitor-
ing movement, minimizing the use of staff time and use of
restraint. Unwanted exiting requires all hazardous exits to
be designed to be less attractive to the casual observer. This
includes the use of lighting and floor covering and paint
work to conceal them and to make the approach to these
areas less interesting. Vision panels in exit doors literally
offer a window into a more interesting world than where the
resident is. Turn their attention the other way. A safe garden
is a good alternative for the inquisitive, as long as it is fulfill-
ing and interesting.
Any design features that reduce stress will help. Making
the purpose of the room clear and obvious and keeping the
size at a domestic scale is useful. High levels of noise and low
levels of light have been shown to make people with demen-
tia restless. Designing in the ability to locally control the
temperature allows staff to support the person to find one
individual place that suits them. Pain may be a root cause of
restlessness and a comfortable quiet place to sit would help
(McClean and Cunningham, 2007).
Exercise is of great value, and designing a space where
dance, or music and movement can happen, in addition
to outside activities, may reduce the pacing behaviour
(Forbes et al., 2013). If the purpose of the pacing is a futile
attempt by the person to find their own room, there are
many design solutions that will help. A lack of everyday
household spaces and objects can lead to anxious old peo-
ple, with no motivation to do anything or who spend the
whole day running their hands across tabletops, having
nowhere familiar to do what they have always done to pass
the time. Given a kitchen, they can happily spend hours
keeping the surfaces clean or mopping the sink. In some
units, the kitchen is reserved for occupational therapy
activity and only available to certain patients at certain
times, which is a missed opportunity. Washing poles and a
line in the garden with an adjacent sink, some grass to cut
or an old car in the garden to tinker with can be planned
into the design.
29.4 CONCLUSIONS
Buildings can help people with dementia to function at their
best (Dementia Services Development Centre, 2012 and
2013). In dedicated facilities, dementia care, which is com-
plex and challenging, can be made easier by design, which
also helps families to feel more comfortable when visiting
and supporting their relative. The building can demonstrate
that people with dementia and the staff are valued and
respected. Providing people with dementia with the chance
to make good decisions with helpful outcomes through
design environments that compensate for their impair-
ments will enhance the quality of their lives.
REFERENCES
Dementia Services Development Centre (2011). Dementia
Design Audit Tool, Second Edition. Stirling, United
Kingdom: Dementia Services Development Centre,
University of Stirling.
Dementia Services Development Centre (2012 and 2013).
Virtual Environments. Available at http://dementia.stir.
ac.uk/design/virtual-environments. Accessed 27 June
2016.
Fleming, R., Crookes, P. and Sum, S. (2008). A review of the
empirical literature on the design of physical environ-
ments for people with dementia. Australia: Dementia
Collaborative Research Centres. Available in print
in the United Kingdom as part of Design for People
with Dementia: Audit tool. Stirling, United Kingdom:
Dementia Services Development Centre, University
of Stirling.
Forbes, D., Forbes, S.C., Blake, C.M. et al. (2013).
Exercise programs for people with dementia.
The Cochrane Database of Systematic Reviews
(12): CD006489.

Fuggle, L. (2013). Designing Interiors for People with
Dementia, Fourth Edition. Stirling, United Kingdom:
Dementia Services Development Centre, University of
Stirling.
Kerr, B., Cunningham, C. and Martin, S. (eds.) (2010).
Telecare and Dementia: Using Telecare Effectively in
the Support of People with Dementia. Stirling, United
Kingdom: Dementia Services Development Centre,
University of Stirling.
Kerr, D., Wilkinson, H. and Cunningham, C. (2008).
Supporting Older People in Care Homes at
Night. York, United Kingdom: Joseph Rowntree
Foundation. Website Download Correct as of
31.09.09. Available at http://www.jrf.org.uk/publica-
tions/supporting-older-people-care-homes-night.
Accessed 27 June 2016.
Design and dementia 307
Koncelik, J. (2003). The human factors of ageing. In R.J.
Scheidt and P. Windley (eds.), Physical Environments and
Ageing. Canada: Hawthorn Press Canada.
McClean, W. and Cunningham, C. (2007). Pain in Older
People with Dementia: A Practice Guide. Stirling,
United Kingdom: Dementia Services Development
Centre, University of Stirling.
McNair, D., Cunningham, C., Pollock, R. and McGuire,
B. (2013). Light and Lighting Design for People with
Dementia, Third Edition. Stirling, United Kingdom:
Dementia Services Development Centre, University
of Stirling.
Perritt, M., McCune, E.D. (ed) and McCune, S.L. (2005).
Research informs design: Empirical findings suggest
recommendations for carpet pattern and texture.
Alzheimer’s Care Quarterly, 6: 300–305.

Legal issues and dementia
HUGH SERIES AND ROBIN JACOBY
30.1 JURISDICTIONS
Law varies across the world. Anglophone jurisdictions
(including the United Kingdom, the Commonwealth, the
United States and Hong Kong) incorporate much com-
mon law – law made by judicial precedent – in addition
to statute law made by legislatures. However, many other
countries have a civil law legal system which is based on a
code, derived from Roman law, in which judges apply the
code rather than develop binding case precedents. This
chapter focuses mainly on the anglophone system.
30.2 CAPACITY
Many of the legal issues that arise in dementia focus on
the affected person’s mental capacity or competence. In
the United Kingdom, ‘competence’ tends to be used in a
­non-legal context and ‘capacity’ in a legal one, whereas in
the United States it is the other way round. In this chapter,
the words will be considered interchangeable and should be
understood to refer to mental capacity.
Capacity is specific to a particular decision. Having the
capacity to make one kind of decision does not necessarily
mean having the capacity to make another. For example, a
person with dementia may no longer be competent to man-
age his financial affairs, but may still be competent to donate
power of attorney (see Section 30.3.1 ).
Capacity is also time specific. A person must have
capacity to do the task at the time he does it, irrespec-
tive of whether he lacked capacity before or afterwards.
For example, someone with dementia could be in hospital
with a serious infection that causes delirium and renders
him incompetent to make a will. He is given antibiotics,
the delirium remits, and he regains the capacity to make
the will.
308
30
Many countries have statute law about capacity, which
is usually separate from legislation about the compulsory
treatment of those with mental disorders. Northern Ireland
is unusual in considering the introduction of a combined
mental health/mental capacity act. In England and Wales,
the relevant statute is the Mental Capacity Act 2005 (MCA),
which sets out what is meant by capacity, how decisions
may be made for people lacking capacity, what steps a per-
son may take to retain a degree of autonomy for his own
future care, as well as the legal framework for the Court
of Protection, which oversees the care of people who lack
capacity. Its application is not by any means restricted to
people with dementia, but it is critical legislation for them.
30.2.1 GENERAL REQUIREMENTS FOR
CAPACITY
To make a decision with capacity a person must be able to:
●● Understand the information relevant to the decision
●● Retain that information
●● Use or weigh that information as part of the process of
making the decision
●● Communicate his decision (whether by talking, using
sign language or any other means)
The MCA begins with five general principles:
1. A person must be assumed to have capacity unless it is
established otherwise.
2. Everything possible must be done to assist the person
to be able to make the decision himself.
3. A person should not be treated as lacking capacity
simply because he makes an unwise decision.
4. An act done for a person lacking capacity must be
done in his best interests.
5. An act done for a person lacking capacity must be the
least restrictive act possible.

It seems that the first principle has not always been
appreciated by doctors. In a survey of 2100 physicians, sur-
geons and psychiatrists, Markson et al. (1994) found that
72% erroneously considered that dementia automatically
conferred incapacity, 66% thought the same for depression
and 71% for psychosis, although psychiatrists were more
likely than others to respond correctly. It is not correct to
assume that a person lacks capacity simply because he has
dementia – or any other condition or diagnosis.
A person with borderline capacity for a task may be
tilted towards having capacity by optimizing the situa-
tion and providing assistance. Allowing adequate time for
an assessment and sitting opposite the person so that he
can lip-read and hear better are not only standard require-
ments for any examination of an older person but may also
maximize the chance that he will be competent to make
the decision that is needed. It is necessary to ensure that
the person can understand the language used (simple lan-
guage, use an interpreter if necessary) and can hear prop-
erly (a quiet side room instead of a noisy general hospital
ward, a hearing aid).
It can be very tempting to assume that if a person makes
an unwise decision then that shows that he lacks capacity,
so that, instead of accepting the decision, it can be assumed
that he lacks capacity and a best interests decision can be
made on his behalf. On the third principle in the MCA, set
out above, this would not be correct. However, an unwise
decision may well flag up the possibility of lack of capacity,
which would require further assessment (or ‘anxious scru-
tiny’ as one judge eloquently put it).
In English law, and in many other jurisdictions, an act
done for a person lacking capacity must be done in his best
interests (principle 4), and must be the least restrictive step
possible (principle 5). This may still leave a very wide set
of possible decisions. It is not always clear who the relevant
decision maker might be, but the MCA sets out what mat-
ters he should take into account in making the decision
(MCA section 4). Very often this will be clear from the situ-
ation: if the decision is whether the person should have a
bath, the decision maker will be the carer offering the bath.
If the decision is whether or not to have a particular medical
procedure, the decision maker will usually be the doctor in
charge of the treatment. However, if the decision is whether
or not the person should be removed from his home to go
into a care home, the decision is likely to involve many
people, and the local authority may well be involved. The
MCA requires that appropriate people should be consulted
before a complex best interests decision is made, and a help-
ful way to do this is by means of a best interests meeting,
held to bring together the key parties such as family and
professionals. Such a meeting should be carefully set up,
chaired, and minutes taken. It may only go ahead once it
has been confirmed that the person lacks capacity. There is
no requirement that the same person who confirms the lack
of capacity should make the relevant decision. For decisions
about major medical treatment, or about where a person
should live, where there is no close friend or relative who
Legal issues and dementia 309
can speak on behalf of the person, an Independent Mental
Capacity Advocate (IMCA) may be appointed. An IMCA is
not the decision maker, but speaks on behalf of the person
who lacks capacity to ensure that his perspective is prop-
erly considered. If a decision is significant and cannot be
reached informally it may be necessary to refer the matter
to the Court of Protection.
30.2.1.1 Maintaining autonomy
Much capacity legislation is built on the principle of enhanc-
ing a person’s autonomy, that is, allowing him to make deci-
sions for himself wherever possible. This may mean, as we
have seen, supporting him to make decisions in the present.
But it also means setting up mechanisms to allow the per-
son to make decisions in advance. These may be in the form
of specific advance decisions, or the person may prefer to
appoint someone whom he trusts to make decisions on his
behalf. In England and Wales, this is known as a Lasting
Power of Attorney (LPA). It is ‘lasting’ because, unlike a
general power of attorney, the power continues after the
person loses capacity to understand the power. LPAs may
relate to property and financial affairs, or to personal wel-
fare matters. A given type of LPA does not give authority
to make decisions over matters which are not included in
the power. In the United States, similar arrangements exist
but may vary by state. Lasting powers are usually referred
to in the United States as ‘durable’, and the attorney as an
‘attorney-in-fact’. Some powers cover financial affairs only,
others cover health and welfare matters.
Many people think that the next of kin or nearest rela-
tive has a particular right to make decisions on behalf of
an incapacitated person. This is not usually the case, except
in very specific circumstances, such as when a person is
detained in a psychiatric hospital under the Mental Health
Act for treatment of mental disorder. Close family members
can have a very important role in decision making as they
have detailed knowledge of the person’s previous wishes and
views, and their views will need to be very carefully consid-
ered. However, they will not generally be the legal decision
maker where statutory authorities (health or social services)
are involved, unless they have been appointed under an LPA.
30.3 SPECIFIC CAPACITIES
30.3.1 MANAGEMENT OF FINANCIAL
AFFAIRS
Capacity is relative to the complexity of the matter to be
decided. Consider the theoretical case of two people with
exactly the same degree of dementia. The first has an occu-
pational pension from which his rent and utility bills are
paid by direct debit from his bank account, and a small
amount of money in a savings account. He is assessed by an
old age psychiatrist who judges him competent to manage
310 Dementia
his limited financial affairs. The second person is a mil-
lionaire with a variety of share portfolios, joint trusts and
other complex financial instruments. The same psychiatrist
judges him to be incompetent to manage his affairs.
For people who lack the capacity to manage their financial
affairs most countries have legislated for some sort of power
of attorney, such as the LPA for property and affairs dis-
cussed above. ‘Attorney’ here and elsewhere in this chapter
means the person nominated in a power of attorney, and not
necessarily a lawyer; attorneys are most commonly spouses
or adult offspring. A person who makes an LPA (the donor)
must have the legal capacity to do so at the time he makes
it. In essence, the donor of the power must understand that,
if he loses capacity, the named attorney will have the power
to do anything with the donor’s finances that he himself
could have done prior to losing capacity. Once executed, an
LPA must be registered before it becomes effective. In some
jurisdictions this usually happens immediately after the LPA
is signed, and does not indicate that the donor lacks capac-
ity. In others, the power is only registered once the donor is
regarded as having lost capacity (this is the case with English
Enduring Powers of Attorney [EPA], which were used before
the current Mental Capacity Act came into effect in 2007).
A person who retains the capacity to donate an power
may at the same time lack the capacity to manage his affairs.
This was endorsed in an English High Court ruling in the
landmark case of two elderly women with dementia (Re K
and Re F). The case concerned EPAs, but the implication of
the ruling is that in those circumstances the attorney should
take over management of the affairs as soon as the power is
executed by the donor and registered.
For people with dementia who have not donated LPA when
competent to do so and who are no longer competent to man-
age their affairs or to make an LPA, different countries have
different mechanisms for appointing someone to take over
management on their behalf. Typically, the process involves
applying to a court either for a specific decision or to appoint
a deputy to make decisions on behalf of the incapacitated per-
son. Court applications are often more complex, slower and
more expensive than appointing an attorney in advance.
An LPA has the advantage over a court-appointed deputy
that the donor chooses who does it. However, there is little
doubt that LPAs are sometimes abused, often by adult off-
spring, who cream off the assets for their own advantage.
For a review of elder maltreatment, please see Hirsch and
Vollhardt (2008).
30.3.2 MEDICAL TREATMENT
People with dementia are mostly old and are therefore at
high risk of co-morbid physical illness, often requiring
consideration of potentially hazardous interventions, such
as surgery. Any medical treatment given against his will
to a person competent to decide for himself constitutes an
assault in law. It is, therefore, essential in such a situation
to determine whether a person with dementia retains the
capacity to decide whether to accept or refuse treatment.
30.3.2.1 Power of attorney
Some jurisdictions allow a person to make a lasting power
of attorney that covers health and treatment decisions. In
England, this is called a health and welfare LPA. It works
in much the same way as a property and affairs LPA, except
that it only comes into effect when the donor lacks capac-
ity (by contrast, an English property and affairs LPA, unless
otherwise restricted, can be used as soon as it is registered,
which may well be while the donor still has capacity). At
the time the health and welfare LPA is drawn up, the donor
must decide whether or not he wishes the attorney to have
the authority to refuse life sustaining treatment on his
behalf. Both forms of LPA allow the donor to include guid-
ance for the attorney indicating the way in which he would
like the attorney to act. It is possible to appoint more than
one attorney; in that case, the donor must specify whether
the attorneys are always to act together (jointly) or may act
individually (jointly and severally).
30.3.2.2 Advance decisions
An advance decision (sometimes called a living will or
advance directive) is a decision made by a person who has
capacity to refuse a specified medical treatment at some time
in the future should he lose his mental capacity to decide
about it. Since no person can dictate to a doctor what treat-
ment he must give (a patient can request a treatment but not
demand it), advance directives are in effect advance refusals
of treatment. Very importantly, advance decisions are only
binding if they are valid and applicable to the actual future
circumstances that arise. Although several organizations
have drafted forms of words that can be used, most juris-
dictions do not provide any particular form or process for
making an advance decision. Where there is doubt about
validity or applicability, most doctors are likely to proceed
on the basis of best interests rather than follow a path that
may lead to the person’s death, unless the advance decision
is absolutely clear, unambiguous and applicable.
30.3.2.3 Values directives
A third way in which a competent person may wish to continue
to exercise a degree of autonomy even after he has lost capacity
is by means of a values directive in which the person making
it gives a statement of his values and asks that his doctors and
others adhere to it if he becomes incompetent. Although this
may be helpful in guiding future decision makers, it is very
difficult to write one in such a way that it is binding.
30.3.3 CAPACITY TO MAKE A WILL
In some civil law countries such as France, the disposition of
one’s estate after death is somewhat restricted, and offspring
cannot normally be excluded, although this was modified
by European Union legislation on cross-border inheritance
in 2015. In anglophone jurisdictions there is much greater

testamentary freedom, provided the testator is mentally com-
petent to make a will. Spouses or children may be disinher-
ited, although in some jurisdictions, for example, England
and Wales, legislation allows provision to be made for those
spouses or children who are still financially dependent on the
testator, even if they are excluded from the will.
In most anglophone jurisdictions, the leading case on
testamentary capacity is Banks v. Goodfellow the key part
of which states:
It is essential that a testator shall understand
the nature of the act [of making a will] and its
effects; shall understand the extent of the prop-
erty of which he is disposing; shall be able to
comprehend and appreciate claims to which he
ought to give effect; and with a view to the lat-
ter object no disorder of mind shall poison his
affections, pervert his sense of right and pre-
vent the exercise of his natural faculties – that
no insane delusion shall influence his will in
­disposing of the property and bring about a
­disposal of it which, if the mind had been sound,
would not have been made.
This judgment can be simplified into four limbs, which
are set out in Box 30.1.
It is not necessary for a testator (female, testatrix) to
appreciate the extent of his estate down to the last penny
(cent), but he must have a general grasp of his affairs.
However, the more complex the estate, the higher the
threshold of capacity on this limb of the legal test. For
example, let us take again our theoretical case of two indi-
viduals with exactly the same degree of dementia. The first
may be able to understand that he owns his house and has a
few thousand dollars in the bank, and would therefore have
sufficient appreciation of his estate. The second may, how-
ever, lack the capacity to understand the extent of his estate
because it consists of live business interests, complex trusts,
joint insurance policies, cross-national share portfolios and
foreign properties. Nevertheless, it is possible to maximize
capacity on this limb of the Banks v. Goodfellow test, as dis-
cussed below under assessment of testamentary capacity.
The capacity to appreciate the ‘moral claims’ of those who
might expect to benefit from the testator’s bounty is the one
BOX 30.1: The Banks v. Goodfellow test
A testator must be able to:
●● Understand the nature and consequences of the
act of making a will
●● Understand the extent of his estate
●● Appreciate who might have a claim on his bounty
(both those to be included and excluded)
●● Have no mental disorder and no insane delusion
directly affecting the above
Legal issues and dementia 311
that is most frequently contested after the testator’s death.
Common scenarios are the disinheritance of one child in
favour of another, or of a caregiver or charity. The grounds
on which such wills are challenged clearly vary, but allega-
tions include the following: inability to recall relatives; false
beliefs about relatives or others; and delirium supervening
on dementia.
A will may also be challenged on grounds of undue
influence, although this can be extremely difficult to prove
in some jurisdictions, notably the United Kingdom and
some Commonwealth countries, because it is necessary to
prove, not just that the testator was influenced in making
a particular disposition of his estate, but that his will was
overborne, against his real wishes, for example by threat or
force. The issue of undue influence is discussed in detail by
Peisah et al. (2009).
Paradoxically it is not necessary to prove coercion in the
equity jurisdiction that deals with contracts made when peo-
ple are alive. In such transactions courts may accept a pre-
sumption of undue influence, which theoretically, at least,
makes it easier to prove than in contested wills. However,
case law in England and Wales (Re Beaney) has established
that where the effect of a lifetime gift is to dispose of the
donor’s only asset of value, the degree of understanding
required is as high as it is for a will. One might be forgiven
for thinking that the law here seeks to avoid disputes over
undue influence in favour of those over mental capacity.
It is the common experience of old age psychiatrists that
their dementia patients are not only vulnerable to undue
influence but also actually are so influenced. However, it is
another thing to prove it in a court of law. In the United
States, where the difference between probate and equity
does not exist, it is much easier to prove undue influence.
Psychiatrists are called upon to assess testamentary
capacity in two situations: prospective, i.e. before the patient
dies; and retrospective, i.e. after death. There would be fewer
retrospective cases if lawyers were to observe the ­so-called
golden rule formulated by the late Lord Templeman
(Kenward v. Adams), which (paraphrased) recommends
that lawyers drawing up wills for elderly persons should
always seek a medical opinion on the testator’s capacity,
however embarrassing it may be to propose it to their client.
Golden rule assessments are discussed by Jacoby and Steer
(2007) and Shulman et al. (2009). As with any assessment
of capacity, examinations of prospective testators should
attempt to maximize capacity by an unhurried approach in
a nonthreatening atmosphere. If the potential testator can-
not give a full enough account of his estate, it is legitimate to
give him the information, the examiner having been briefed
beforehand by the lawyer, and to ask him to commit it to
memory. If he can do this for a sufficient length of time
to make competent decisions fulfilling the other limbs of
the Banks v. Goodfellow test, then his understanding of his
estate may be adequate. The decision on whether this or any
other aspect of the Banks v. Goodfellow test is fulfilled rests
ultimately with the court. The doctor’s role is to give his
opinion in order to assist the court in reaching its decision.
312 Dementia
Retrospective assessment of the testamentary capac-
ity of testators whose wills are subject to legal challenge
is more complex because opinions have to be given on
the basis of surviving documents and not examination of
the testator himself. Furthermore, there are often witness
statements from the opposing sides that appear to contra-
dict each other. It is within neither the remit nor the exper-
tise of a psychiatrist to decide which statements are true
or not, for this is the prerogative of the court. Although
the psychiatrist may be instructed by lawyers acting for one
or other party, his or her duty is exclusively to the court
to provide an independent, unbiased opinion of matters
within his or her expertise. Prospective and retrospective
assessments of testamentary capacity are discussed in full
by Jacoby (2013).
Most jurisdictions require a testator to have capac-
ity when he or she gives instructions for drawing up his
or her will and when he or she executes it, i.e. signs it
in the presence of witnesses. There are sometimes cases
where the testator loses the necessary capacity between
giving instructions and executing the will. In such cases,
the will might be valid if the testator can appreciate
that he is signing a will drawn up on his or her previous
instructions, known as the Rule in Parker v. Felgate: see
Jacoby (2013).
30.3.4 CAPACITY TO DECIDE RESIDENCE
Problems arise when people with dementia either lack the
insight to determine or deny the risks attendant on inde-
pendent life at home. Different countries have different
laws on involuntary committal to another place of resi-
dence, but the psychiatrist, social worker or community
nurse may need to take a variety of factors into account
when dealing with such situations. Some individuals or
authorities may lean towards ensuring safety at all costs
(public sector authorities are often highly risk-averse),
while others may lean towards taking high levels of risk.
While some families provide a selfless and unstinting level
of support to the person with dementia, others may not, or
may not be in a position to do so. Motives vary very widely
indeed, and may include a wish to keep care costs low,
possibly to protect an inheritance, or a strong p ­ reference
for the perceived safety of a care home. However, as Lord
Justice Munby has put it, ‘What good is it making someone
safer if it merely makes them miserable?’ (Munby, 2010).
Disagreements can often be resolved by patient d ­ iscussion
with the various parties and mutual acceptance of risk.
Some jurisdictions allow for objections to home care
on the part of the person with dementia to be o ­ vercome
legally so that, if necessary, the patient’s home can be
entered without the patient’s permission. Authority to
enter the house is not the same as authority to insist on
providing personal care, and in any case, even with legal
authority, it is in practice very difficult to provide care to
an unwilling person in his or her own home.
30.3.5 CAPACITY TO LITIGATE AND
STAND TRIAL
Few people with dementia are likely to litigate. In the United
Kingdom, the test for capacity to litigate is based on the case
of Masterman-Lister v. Brutton & Co. [2002], together with
the MCA. In England and Wales, if a person with dementia
lacks the capacity to litigate, he or she may be represented by
the Official Solicitor. Other countries have their own agents
for such purposes.
Fitness to plead or to stand trial is a more important
issue than capacity to litigate because a small but signifi-
cant number of dementia sufferers commit offences, some
­serious, including homicide. In England and Wales, the cri-
teria for fitness to plead are derived from the leading case of
R v. Pritchard and are explained more fully in R v. John M.
They are summarized in Box 30.2.
In the United States, the criteria for competence to
stand trial are based on the case of Dusky v. United States,
which states that the defendant requires ‘sufficient pres-
ent ability to consult with his attorney with a reasonable
degree of rational understanding’ and ‘whether he has a
rational as well as factual understanding of the proceed-
ings against him’.
It is difficult to make general statements about what hap-
pens in practice because of the variation in worldwide juris-
dictions. In the United Kingdom, the authorities are keen
to divert dementia sufferers away from the criminal justice
system at least for less serious offences, such as shop lifting.
For more serious offences, fitness to stand trial does become
an issue. Grubin (1991) studied 286 people in England and
Wales who had been declared unfit to plead between 1976
and 1988. Ten out of 286 (0.3%) were found to be suffer-
ing from dementia, six of whom died in hospital while
still considered unfit to plead. Heinik et al. (1994) studied
a group of elderly offenders referred by courts to a foren-
sic unit in Israel for psychiatric evaluation. Of the 17 with
a diagnosis of dementia, several of whom had committed
violent offences, 9 were considered incompetent to stand
trial, and the same number were considered incompetent
to be sentenced, which is not a disposal available to British
courts. So, of the small proportion of people with demen-
tia who commit serious criminal offences, many are unfit
BOX 30.2: Fitness to stand trial in England
and Wales
To be fit to stand trial a defendant must be able to:
●● Understand the nature of the charge
●● Decide whether to plead guilty or not
●● Exercise the right to challenge jurors
●● Be able to instruct lawyers
●● Give evidence in his own defence
●● Follow the proceedings in court

or incompetent to stand trial and few, if any, recover suf-
ficiently to face trial. In England and Wales, the effect of a
finding of unfitness to stand trial is that a trial of the facts
takes place in which a court will determine whether or not
the events alleged happened. If the person is found to have
carried out the act alleged, the court has a wide range of
options for disposal, including the making of a hospital or
supervision order.
30.4 DEPRIVATION OF LIBERTY
In European countries that have ratified the European
Convention on Human Rights, article 5, the right to lib-
erty and security, creates an obligation on the state to
ensure that, ‘No one shall be deprived of his liberty save
… in accordance with a procedure prescribed by law’, and
asserts that anyone who is deprived of his or her liberty has
a right ‘to take proceedings by which the lawfulness of his
or her detention shall be decided speedily by a court and
his or her release ordered if the detention is not lawful’.
A very large number of people with dementia (and those
with intellectual disabilities and many other conditions)
are deprived of their liberty because they are in care homes
or hospitals. In a very important case in the UK Supreme
Court (P v. Cheshire West and others), it has been clarified
that a person will be deprived of his or her liberty if he or
she is under continuous supervision and control and is not
free to leave. It is now necessary in England and Wales that
if such a person lacks the capacity to decide whether or
not to stay there, a formal assessment process must be fol-
lowed. If he or she is found to lack capacity, is deprived of
his liberty, and does not fall within the scope of the Mental
Health Act 1983, then formal authorization for the depri-
vation of liberty must be sought from the local authority.
The regulations governing this process are complex, but are
now established in English law, although the law on this is
currently (2016) under review. Other European countries
have different approaches to deprivation of liberty, and the
issue does not arise in the United States and other coun-
tries, which have not ratified the European Convention on
Human Rights.
REFERENCES
Grubin, D.H. (1991). Unfit to plead in England and Wales,
1976–1988: A survey. British Journal of Psychiatry,
158: 540–548.
Heinik, J., Kimhi, R. and Hes, J. (1994). Dementia and
crime: A forensic psychiatry unit study in Israel.
International Journal of Geriatric Psychiatry, 9: 491–494.
Legal issues and dementia 313
Hirsch, R.D. and Vollhardt, B.R. (2008). Elder maltreat-
ment. In R. Jacoby, C. Oppenheimer, T. Dening and
A. Thomas (eds.), The Oxford Textbook of Old Age
Psychiatry. Oxford, United Kingdom: Oxford University
Press, pp. 731–745.
Jacoby R. (2013). Testamentary capacity. In T. Dening and
A. Thomas (eds.), The Oxford Textbook of Old Age
Psychiatry, Second Edition. Oxford, United Kingdom:
Oxford University Press, pp. 797–804.
Jacoby, R. and Steer, P. (2007). How to assess capacity to
make a will. British Medical Journal, 335: 155–157.
Markson, L.J., Kern, D.C., Annas, G.J. and Glantz, L.H.
(1994). Physician assessment of patient compe-
tence. Journal of the American Geriatrics Society,
42: 1074–1080.
Munby, J. (2010). Keynote address. Paper presented at
Taking Stock: The Mental Health & Capacity Reforms
conference, Manchester, United Kingdom.
Peisah, C., Finkel, S., Shulman, K. et al. (2009). The wills
of older people: Risk factors for undue influence.
International Psychogeriatrics, 21: 7–15.
Shulman, K.I., Peisah, C., Jacoby, R. et al. (2009).
Contemporaneous assessment of testamentary capac-
ity. International Psychogeriatrics, 21: 433–439.
FURTHER READING
Harrop-Griffiths, T., Cowen, J., Cooper, C. and Hadden, R.
(2014). Dementia and the Law. London: Jordans.
Foster, C., Herring, J. and Doron, I. (eds.) (2014). The Law
and Ethics of Dementia. Oxford, United Kingdom: Hart
Publishing.
Frost, M., Lawson, S. and Jacoby, R. (2015). Testamentary
Capacity: Law, Practice and Medicine. Oxford: Oxford
University Press.
LEGAL CASES
Banks v. Goodfellow [1870] 5 LR QB 549.
Beaney v. Beaney [1978] 1 WLR 770.
Dusky v. United States (1960) 362 U.S. 402.
Kenward v. Adams [1975] The Times (London) 29
November.
Masterman-Lister v. Brutton & Co. [2002] EWHC 417 (QB).
P v. Cheshire West and Chester Council and another
(Respondents); P and Q (by their litigation friend, the
Official Solicitor) (Appellants) v. Surrey County Council
(Respondent) [2014] UKSC 19.
Parker v. Felgate [1883] 8 PD. 171.
R v. John M [2003] EWCA Crim 3452.
Re K and Re F [1988] All ER 358.
R v. Pritchard (1836) 7 C & P 303.

Driving and dementia
AOIFE FALLON AND DESMOND O’NEILL
31.1 INTRODUCTION
Driving has become an almost indispensable part of
­everyday life for older people worldwide, with falling use
of public transportation and increasing personal affluence
leading to greater access to the personal car (OECD, 2001).
These trends are particularly noticeable in rural areas,
where the proportion of older people tends to be higher and
where public transport is less accessible. It is increasingly
clear that the private car and walking are the predominant
forms of transport for not only the general public but also
older people in the developed world: even if usage of public
transport is increasing among older U.S. citizens, it is from
a very low baseline and still below 3% of trips (Lynott and
Figueiredo, 2011).
Despite increasing levels of age-related disease and dis-
ability, older drivers in general compensate and adapt to their
changing circumstances and are the safest demographic
group on the roads, with even the oft-quoted increased
crash rate per kilometre disappearing when allowance is
made for distance travelled (Langford et al., 2008b). This,
and increasing awareness of the negative effects of driv-
ing cessation on not only the older person (Marottoli et al.,
1997; Marottoli et al., 2000) but also on others (Curl et al.,
2015), has led to an attitudinal shift among clinicians to
consider mobility as the primary concern in driving assess-
ment, with due regard for safety to the same extent as other
demographic groups (Dickerson et al., 2007).
The U.S. Transportation Research Board, the
Organization for Economic Cooperation and Development
and the European Conference of Ministers for Transport
have all prepared reports on ageing and transport (European
Conference of Ministers of Transport, 2001; OECD, 2001;
U.S. Department of Transportation, 2003). Poor health is
strongly correlated with driving cessation, including vision
314
31
and cognition (Keay et al., 2009), neurological disease
(Lafont et al., 2008) and cardiovascular disease and reduced
functional status (MacLeod et al., 2014). In addition, licens-
ing policies have an important impact: accelerated renewal,
mental testing, peripheral vision testing, renewal in person
at age 70+ (as opposed to renewal by mail or online) and
restricted licensing – have a significant effect on an older
driver’s decision to reduce or cease driving (Kullkov and
Kulikov, 2010). While the knowledge base is still slender,
the issues involved have major practical, ethical and societal
implications for patients, family carers and health profes-
sionals. There are widely differing agendas on the part of
those involved: the patient, the carers, the physician, the
statutory licensing authority and the insurance companies.
Dementia is a largely age-related disorder, and the devel-
oped world is experiencing an exponential rise in the pro-
portion of older drivers among the driving population.
In the United States, there were 35 million licensed older
drivers in 2011, a 21% increase from 2002. In contrast, the
total number of licensed drivers increased by only 9% from
2002 to 2011. Older drivers made up 16% of all licensed
drivers in 2011, compared with 15% in 2002 (National
Highway Traffic Safety Administration, 2014). Over one-
third of those aged over 80 in 1990 drove at least once a
year in Ontario, Canada (Chipman et al., 1998). Although
most drive personal automobiles, this is not exclusively the
case. On the one hand, licensing regulations for drivers of
public service vehicles and heavy transport vehicles are
nearly always more restricted and use a more algorithmic
approach than for drivers of personal automobiles. On the
other hand, those who develop dementia at a younger age
are more likely to be driving heavy goods or public service
vehicles, and the abolition of mandatory retirement age in
the United States has resulted in school bus drivers being
able to continue into their mid-80s. There has been litiga-
tion concerning this group.

31.2 WHAT PUBLIC HEALTH ISSUES
ARISE WITH OLDER DRIVERS?
One of the most important, and under-recognized, public
health hazards arising from dementia is the consequence
of loss of mobility for those who stop driving (Taylor and
Tripodes, 2001). One key question about the age of the driv-
ing population is whether they add significantly to hazard
on the roads. This question is symptomatic of an ageist
approach to older driver issues; it is likely that a more signif-
icant problem is that older people give up driving without
sufficient remediation (Siren et al., 2004). The crash rate for
older drivers for a given period of time is considerably lower
than for the driving population as a whole (Langford et al.,
2008b): in some road tests healthy older drivers perform bet-
ter than younger controls (Gebers et al., 1993). Older drivers
with increasing comorbities are more likely to self-regulate
their driving, whereas comorbities in younger drivers were
shown to be associated with an increase in crash rates (Papa
et al., 2014). The increased crash rate per distance driven
noted in older populations in comparison to middle-aged
controls is not only academic while older people continue
to drive a lower mileage; it also is a product of driving a low
mileage, which is itself intrinsically risky. If younger and
older people who drive a low mileage are compared, this
apparent increase disappears (Hakamies-Blomqvist et al.,
2002). Low mileage exposes them to more dangers per mile
than high-mileage drivers as they encounter disproportion-
ately more intersections, congestion, confusing visual envi-
ronments, signs and signals (Janke, 1991), yet older drivers
cope at least as well with this.
Crashes involving older people are more likely to be fatal
by a factor of 3.5 in two-car accidents (Li et al., 2003), reflect-
ing the increased frailty and reduced reserve of older adults,
while raising suspicions that automobile design may not be
tailored for maximum safety of this group (Yoganandan
et al., 2007). However, there was a significant decline in fatal
crash involvement in the United States in those aged 70 and
older between 1997 and 2008, when compared with driv-
ers aged 35–54 (Cicchino and McCartt, 2014). In addition to
this, accident rates for young adults often arise from behav-
iour that leads to high-risk situations; older drivers tend to
avoid high-risk situations (Carmel et al., 2014) and have the
lowest proportion of crashes while under the influence of
alcohol (McGwin and Brown, 1999).
31.3 IS DRIVING WITH DEMENTIA A
PUBLIC HEALTH HAZARD?
The precise contribution of dementia to overall crash haz-
ard is uncertain. Although Johansson et al. (1997) sug-
gested a major role for dementia as cause of crashes among
older drivers on neuropathological grounds, subsequent
Driving and dementia 315
interviews with families did not reveal significant prob-
lems with memory or activities of daily living (Lundberg
et al., 1999). It has been shown that patients with demen-
tia are more likely to restrict their driving in order to avoid
complex situations than older patients with normal cogni-
tion (O’Connor et al., 2013). Early retrospective studies of
dementia and driving from dementia clinics tend to show a
high risk (Friedland et al., 1988; Lucas-Blaustein et al., 1988;
O’Neill, 1992), whereas those that are prospective and look
at the early stages of dementia show a less pronounced risk
pattern. In the first 2 years of dementia, the risk approxi-
mates that of the general population (Drachmann, 1991;
Carr et al., 2000; Eby and Molnar, 2012). The most care-
fully controlled study of crashes and dementia showed no
increase in crash rates for drivers with dementia (Trobe
et al., 1996). Likely causes of this finding include lower
annual mileage and restriction of driving by the patient,
family and physicians.
Extrapolating from special populations may skew risk
predictions. For example, epilepsy, for which most coun-
tries have relatively clear-cut guidelines, would seem to
pose a clear threat to driving ability as viewed from a
clinic setting. However, population-based studies indi-
cate that the increased risk is relatively low (Hansotia,
1993; Drazkowski et al., 2003). For cognitive function, in
a population renewing their licences in North Carolina,
the lowest decile had a very modest relative crash risk of
1.5 in the 3 years previous to the cognitive testing (Stutts
et al., 1998). A somewhat reassuring finding from this
cohort is that those with the poorest scores for visual and
cognitive function also drove less and avoided high-risk
situations (Stutts, 1998). A reasonable conclusion from
these studies is that dementia among drivers is not yet a
public health problem. Although increasing numbers of
older drivers may change this situation, it is also possible
that ‘Smeed’s law’ will operate, whereby increasing num-
bers of drivers among a defined population are associated
with a drop in fatality rates per car (Hakamies-Blomqvist
et al., 2005).
There is no evidence that mild cognitive impairment
(MCI, termed ‘mild neurocognitive disorder’ under the
Diagnostic and Statistical Manual of Mental Disorders,
5th Edition [DSM-5] classification) represents an increased
risk of crash for road users as might be expected from a
syndrome whose definition includes an absence of func-
tional impairment. Self-assessed driving skills in MCI
are preserved (Okonkwo et al., 2009): of the two studies
that seem to suggest some problems, one study combined
dementia and MCI together, which makes interpreta-
tion of the analysis difficult (Frittelli et al., 2009), and the
other showed less than optimal performance rather than
substantive impairment (Wadley et al., 2009). The key
issue is to arrange for regular review of patients with MCI
to track for the development of dementia, at which stage
the assessment and processes should be adopted for this
condition.
316 Dementia
31.4 IS THERE A ROLE FOR
SCREENING OLDER
POPULATIONS OF DRIVERS?
Despite the lack of convincing evidence for an older driver
‘problem’, ageist policies in many jurisdictions have led to
screening programmes for older drivers. In the absence of reli-
able and sensitive assessment tools, this approach is flawed, as
illustrated by data from Scandinavia and Australia (Hakamies-
Blomqvist et al., 1996; Langford et al., 2008a). There is no
reduction in the number of older people dying in car crashes
in jurisdictions with routine screening but an increase in the
number of those dying as pedestrians and cyclists, possibly due
in part to removing drivers from their cars unnecessarily. In
New Zealand, a biennial on road driving test was introduced
for all drivers aged 80 and over in 1999 and remained in place
until 2006. Analysis of data over 20 years, from 1989, showed
that there was no significant change in either licensing rates,
driving rates, injuries or pedestrian activity at the time the test
was in place (Keall and Woodbury, 2014). Denmark added
a cognitive test to older driver screening that was associated
with an increase in deaths among older unprotected road users
(Siren and Meng, 2012). A more minimalist and less medical
approach using very simple measures, such as a vision test and
a written skill examination, may be more helpful (Levy et al.,
1995); unfortunately this approach is also associated with a
reduction in the number of older drivers, a possible negative
health impact (Levy, 1995). Another approach is opportunis-
tic health screening, perhaps of those older drivers with traf-
fic violations (Johansson et al., 1996). It remains to be seen
whether these and other screening policies reduce mobility
among older people, a practical and civil rights issue of great
importance. Another problem is the uncertainty about the
outcome of screening, as there is currently a limited repertoire.
31.5 PHYSICIANS AND DRIVING
ASSESSMENT
Another problem is the relative ignorance of physicians about
the effects of illness on driving. Some of this relates to the pre-
dominantly negative tone of much of the medical regulations
for driving (White and O’Neill, 2000), and it is likely that doc-
tors are insufficiently aware of healthcare interventions that
have been shown to improve driving comfort and safety:
examples exist for arthritis, sleep apnoea and cataract (Jones
et al., 1991; George 2001; Monestam and Wachtmeister, 1997).
Doctors are unaware of the driving habits of their patients
when prescribing drugs that may affect driving (Cartwright,
1990) and also have a patchy knowledge of medical regula-
tions for driving (O’Neill et al., 1994). As the regulations,
while improving in content in recent decades, rarely fully
present the origins of their evidence base (Rapoport et al.,
2015), this ‘failure’ by doctors to acquaint themselves with the
­regulations may reflect distrust of the current official medi-
cal fitness criteria. There may also be an element of ageism by
which doctors may assume that older patients do not drive.
Drivers may not only be unaware but also may wilfully
ignore medical advice and regulations. In many countries,
they continue to drive despite failing to comply with regu-
lations for diabetes, visual disease and automatic implant-
able cardioverter defibrillators (Eadington and Frier, 1988;
McConnell et al., 1991; Finch et al., 1993). However, there
is no evidence that this under-reporting results in any
increased crash risk!
We have little information on advice given to drivers
with dementia by family physicians or physicians at spe-
cialist clinics for the evaluation of dementia. This would be
of interest because of the wide range of answers given for
patients with life-threatening arrhythmias (Strickberger
et al., 1991). It has been suggested that family physicians
are becoming more confident in managing uncomplicated
dementia (Hum et al., 2014) but have reported a number of
barriers in addressing driving with patients with demen-
tia, including a lack of resources and caregiver resistance
(Moorhouse and Hamilton, 2014). In any event, a major
shift of emphasis is required by healthcare professionals
to consider driving ability in the functional assessment of
older people.
The procedures for intervention after the opportunistic
detection of illnesses relevant to driving vary widely. In the
United Kingdom, the doctor’s duty is to inform the patient
that he/she must contact the Driver and Vehicle Licencing
Authority (DVLA); direct contact by the doctor with the
DVLA is only allowed if there is evidence of continued driv-
ing that constitutes a hazard to others and if persuasion
through other family members and carers has been unsuc-
cessful. This contrasts with the position in several states in
the United States and provinces in Canada where the doc-
tor is bound by law to report patients with certain illnesses
to the licensing authorities. This disparity is confusing, but
cross-national comparisons may prove a boon to research-
ers who wish to establish the most appropriate methods for
screening and reporting of age-related diseases.
31.6 ASSESSMENT PROCEDURES
A systematic inclusion of a question on transport and driv-
ing is now mandatory in the comprehensive assessment
of patients with memory problems (Adler and Silverstein,
2008), and it is necessary to identify whether or not the
patient drives (Bradley et al., 2000); this is important in
view of the relatively low assessment of driving in primary
care (Pimlott et al., 2006). In recent years, there has been
an introduction of resources for physicians in an effort to
increase awareness of this issue. This has been reported to
reduce avoidance of the topic of driving cessation in the

primary care setting (Moorhouse and Hamilton, 2014). The
placing of driving issues in an appropriate therapeutic con-
text is the most important task. Rather than focussing on
the difficult case of patients who present late with impaired
driving ability and insight, we must recognize that the
assessment of dementia provides the potential for a range
of interventions, one of the most important of which is the
establishment of a framework for advance planning in a
progressive disease. We need to start a process that encom-
passes an assessment, a commitment to maximizing mobil-
ity and also an awareness-raising process for the patient
and carers that the progression of the disease will inevitably
result in a loss of driving capacity.
This latter component has been termed a modified Ulysses
contract, after the hero made his crew tie him to the mast
on the condition that they did not heed his entreaties to be
released when seduced by the song of the sirens (Howe,
2000). This process has been incorporated in practice and is
now widely accepted in dementia care, that is, the diagnostic
disclosure in at least general terms – the patient who drives
needs to be told that he/she has a memory problem that is
likely to progress and hamper driving ability. In general, car-
ers are fearful of diagnosis disclosure, but older people seem
to want to be told if they have this illness. There is evidence
that such a process may facilitate driving cessation by enhanc-
ing a therapeutic dimension to disease diagnosis and advance
planning (Bahro et al., 1995). It forms the basis of a useful
patient and carer brochures from the Hartford Foundation
(Hartford Foundation, 2000) and the CanDRIVE Programme
(Byszewski et al., 2013), which are available online. This type
of approach also seems to have worked with older, visually
impaired drivers (Owsley et al., 2003).
The most useful model of assessment is that of an assess-
ment cascade (see Figure 31.1) and a helpful scheme has
been described in the context of the driver licencing system
in the United Kingdom, which can inform the process for
other jurisdictions (Carter et al., 2015), although the medi-
cal staffing, pathways and procedures in the UK DVLA are
formalized to a degree not seen in most other driver licenc-
ing agencies.
Not all levels will be required by all patients: except as an
exceptional case, a patient with a homonymous hemianopia
Physician
Occupational therapist
Neuropsychologist
Specialist driver
assessor
Socialworker
Figure 31.1 An assessment cascade.
Driving and dementia 317
is barred from driving throughout the EU and referral to
a social worker to plan alternative transportation is appro-
priate. Equally, a mild cognitive defect may only require a
review by the physician and occupational therapist (OT).
The overall interdisciplinary assessment should attempt to
provide solutions to both maintaining activities and explor-
ing transport needs. An on-road test is likely to be needed for
all but the most mild and the most severe, given the inability
of off-road tests to accurately predict driving ability. It may
demonstrate deficits to a patient or carer who is ambivalent
about the patient stopping driving. At a therapeutic level,
team members may be able to help patients come to terms
with losses associated with stopping driving. The OT may be
able to maximize activities and function and help focus on
preserved areas of achievement, whereas the social worker
can advise on alternative methods of transport.
The assessment of fitness to drive should only take place
after a thorough evaluation of the underlying medical
condition(s). Dementia may coexist with other conditions
that affect driving ease and ability. Important components
of the history and examination of theoretical relevance to
the driving task are medication and alcohol use (Doege
and Engelburg, 1986), perception, cognitive status and psy-
chomotor ability. Perception is probably more important
than vision. Cognition may be usefully measured by the
physician using one of the many brief mental status sched-
ules (O’Neill, 1993), and the elements of general clinical
assessment of older drivers for medical fitness to drive are
now described on both sides of the Atlantic (Breen et al.,
2007; Carr et al., 2010). Although the Mini-Mental State
Examination (MMSE; see Chapter 5, Screening and assess-
ment instruments for the detection and measurement of
cognitive impairment) correlates with driving performance
(Odenheimer et al., 1994; Fox et al., 1997), it is not suffi-
ciently sensitive or specific to be used as a determinant of
driving ability (Joseph et al., 2014).
The basic thrust of the assessment is to catalogue and
remedy pathologies that may be relevant to driving: vision,
cognitive function, neurological and musculoskeletal disor-
ders, as well as conditions that may give rise to transient
loss of consciousness such as diabetes and syncope. In any
one illness there may be multiple facets that affect driving:
in Parkinson’s disease, this includes motor, cognitive and
affective aspects. Each component needs to be maximally
remedied before a final decision is made.
The patient’s own assessment of driving should be
assessed and a promising approach is the Adelaide Self-
Efficacy Scale (George et al., 2007), particularly if used in
terms of a proxy assessment by a family member (George
et al., 2007). A history of any previous crashes or traffic
violations is also significant, as it has been shown that a
crash within the past 2 years is a predictor of future crashes
(Joseph et al., 2014). A collateral (witness) history of driving
abilities is important, given the often collaborative nature of
driving in later life (Vrkljan and Polgar, 2007). Caregivers
may have concerns about a patient’s driving and conse-
quently have put driving restrictions in place for the patient
318 Dementia
at an early stage (Mauri et al., 2014), but physicians should
be cognizant of the conflict of interest of a spouse who does
not drive (Adler et al., 2000). A more formalized informant
driving history, the Fitness to Drive Screening Measure,
also shows promise (Winter et al., 2015).
Medication review is important: some medications may
improve driving skills (antidepressants, anti-inflammatories
and possibly cholinesterase inhibitors [ChEIs]; Daiello et al.,
2008), while others pose hazards – in the case of neurolep-
tics, almost certainly as a marker of the nature and severity
of the underlying illness (Brunnauer et al., 2004). The signifi-
cance of benzodiazepines is uncertain (O’Neill, 1998).
31.7 FURTHER ASSESSMENT
In cases of very mild or very severe cognitive impairment, the
judgement may be relatively easy and require little supplemen-
tary testing. For those falling in between, the precise nature
of the further evaluation is not yet standardized, but neither
is the neuropsychological evaluation of dementia. A helpful
nosology of the type of the skills required at different levels of
specialization of the driving assessment has been described
in 2014 (Lane et al., 2014). Physicians may need to invoke
the assistance of a driving specialist centre, the components
of which are medical, OT, sometimes neuropsychology and
­specialist driving assessors. A Canadian study has suggested
that there is much variability between fitness to drive centres,
both in relation to testing, numbers of assessments completed
and cost (Vrkljan et al., 2013) and so it is important for doctors
to be familiar with what is available in their local area. A first
effort may be made with a suitably trained OT: postgraduate
courses in driver assessment are now organized in a number of
countries (Unsworth, 2007).
The choice of tests will be relatively arbitrary and, as in any
memory clinic where doctors will familiarize themselves with
the battery of tests carried out by the OT or psychologist in the
local area, it is likely that good communication between pro-
fessionals and familiarity with the chosen tests is as important
as the precise tests chosen. The relatively poor clinical utility of
cognitive scales in determining fitness to drive (Molnar et al.,
2007; Hoggarth et al., 2013) relates to their lack of congruity
to current models of driving behaviour and capabilities, and
in particular the concept of risk homeostasis (Fuller, 2005).
This does not mean that cognition should not be assessed, but
rather that such measures should be integrated with other fac-
tors, including an assessment of insight/anosagnosia, judge-
ment skills and strategic thinking.
While a number of screening and evaluation test batteries
have been proposed, it makes more sense to choose some
core areas of interest, and to allow some room for clinical
judgements on areas such as judgement and impulsiveness.
The task is rendered more complex by the sophistication of
models of driving, which do not conform easily to traditional
cognitive test batteries. At least five main types of model have
been explored: psychometric, motivational, hierarchical
controls, information processing and error theory. At a mini-
mum, a test battery should contain an informant history of
driving behaviour, a general measure of overall cognitive
function, a dementia grading and include tests of attention,
particularly visual attention, information processing and
perception. Some matching to dementia type will be appro-
priate (e.g. attention in subcortical dementias, judgement in
frontotemporal dementia).
Specific tests that show statistical (but not clinically use-
ful!) correlation with driving ability in more than one study
include the MMSE, the Trail Making Test (Staplin et al.,
2014) and a range of tests of visual attention, including the
Useful Field of View (Myers et al., 2000), a composite mea-
sure of pre-attentive processing, incorporating speed of
visual information processing, ability to ignore distractors
(selective attention) and ability to divide attention (Reger
et al., 2004). In a retrospective study, the Assessment of
Driving Related Skills (ADReS) as recommended for use
in older drivers by the American Medical Association was
shown not to be associated with a history of crash in the
previous 2 years, though it was acknowledged that prospec-
tive analysis is required (Woolnough et al., 2013). A range of
other tests has been assessed in single studies (including traf-
fic sign recognition [Carr et al., 1991]) and a comprehensive
review is available from the U.S. National Highway Traffic
Safety Administration (Staplin et al., 1999). In conjunction
with the clinical assessment and collateral history, these tests
will help to decide which patients require on-road testing, as
well as those who are likely to be dangerous to test.
The use of simulators to assess the driving capabilities of
patients with dementia has not been widely accepted, but
is a potentially useful research tool (Uc and Rizzo, 2008).
Simulators may have a more important role in driver reha-
bilitation of those with neurological disease (Akinwuntan
et al., 2005). Older people may be more prone to motion
sickness in driving simulators (Golding, 2006).
31.8 ON-ROAD TESTING
Given the poor correlation of nearly all psychometric tests
with driving ability, a low threshold for an on-road assess-
ment is advisable. In the United Kingdom, assessments are
available from the Forum group of driver assessment cen-
tres, with a much broader range of options through state,
not-for-profit and private organizations in the rest of Europe
(Sanders et al., 2006). In the United States, the Association
of Driver Rehabilitation Specialists (ADED, www.aded.net)
can provide a list of suitably qualified driving assessors. It
is important to emphasize to the patient that this test is not
the driving test used for learner drivers. Rather, this is an
assessment to gain insight into both the capabilities and dif-
ficulties of the driver. A good relationship with a specialist
driving assessor is important to the assessment process. The
assessor will require a full clinical report, and may use a
scoring system for on-road testing of patients with dementia

(Davis et al., 2012). These include the Washington University
Road Test (Hunt et al., 1997) and the Alberta Road Test
(Dobbs et al., 1998). The authors of the latter have classified
the errors made by drivers with dementia into categories of
increasing significance, providing a basis for future studies.
31.9 DECISION MAKING
AND INTERVENTIONS
If the assessment points to safe driving practice, the deci-
sion to continue driving entails several components. These
are as follows:
●● Duration before review
●● Possible restriction
●● Driving accompanied
●● Licensing authority reporting relationship
●● Insurance reporting responsibility
As dementia is progressive, any declaration of fitness to
drive should be subject to regular review; one study sug-
gests that a review period of 6 months is probably reason-
able (Duchek et al., 2003); sooner if any deterioration is
reported by the carer. It is also important to advise patients
and their families of the predicted decline in driving ability
on an individual basis, although 3 years from when the dis-
ease becomes clinically obvious may be a reasonable group
average (Breen et al., 2007). Nevertheless, some patients
with mild and slowly progressive dementia appear to retain
driving skills for longer than this (Ott et al., 2008). Given
evidence that the crash rate is reduced if the driver is accom-
panied (Bédard et al., 1996), it may be sensible to advise
driving to when there is someone else in the car, not as a
codriver but as both an observer and as a means of improv-
ing vigilance (Shua-Haim and Gross, 1996). There is prelim-
inary evidence that drivers with restricted driving licences
have lower crash rates (Caragata Nasvadi and Wister, 2009).
Patients should be advised to avoid traffic congestion as well
as driving at night and in bad weather. The patient and car-
ers should acquaint themselves with local driver licensing
authority requirements as well as the policy of their motor
insurance company. All this should be recorded in the med-
ical notes. Except for jurisdictions where there is mandatory
reporting of drivers with dementia, there is no obligation on
the doctor to break medical confidentiality in these cases.
31.10 WHEN DRIVING IS NO LONGER
POSSIBLE
If the assessment supports driving cessation, patients and
carers should be told and a social worker consulted to help
maximize transportation options. Giving up driving can
Driving and dementia 319
have a big effect on lifestyle. Forty-two per cent of older
people think that driving is a right as opposed to 27% who
think that it is a privilege (AA Foundation for Road Safety
Research, 1988). However, normal older drivers accept
that their physician’s advice would be very influential
in deciding to give up driving (AA Foundation for Road
Safety Research, 1988) and many patients with dementia
respond to advice from families or physicians (Adler and
Kuskowski, 2003).
For those who resist persuasion, removal of a driving
licence represents a potential breach of civil rights (Reuben
et al., 1988). The way we deal with driving reflects how we
help patients to deal with the reality of the deficits caused
by dementia. A more positive approach has been sug-
gested, whereby the issue of driving is treated as a part of
a therapeutic programme. A case was described whereby
the patient’s feelings and fears about giving up driving were
explored with him (Bahro et al., 1995). The intervention was
designed with the patient as collaborator rather than patient
and by dealing with the events at an emotional rather than
at an intellectual level. The patient was able to grieve about
the disease and in particular about the loss of his car. This
in turn enabled him to redirect his attention to other mean-
ingful activities that did not involve driving. Although this
approach may be hampered by the dementia, it reflects a
more widespread trend towards sharing the diagnosis of
dementia with the patient.
If this approach is unsuccessful, confidentiality may have
to be broken for a small minority of cases. Most professional
physician associations accept that the principle of confiden-
tiality is covered to a degree by a ‘common good’ principle
of protecting third parties when direct advice to the patient
is ignored (General Medical Council, 1985; Retchin and
Anapolle, 1993). Removal of the driving licence is not likely to
have much effect on these patients, and the vehicle may need
to be disabled or removed (Donnelly and Karlinsky, 1990) or
contact made with the local police force (some driver licenc-
ing agencies have good linkage with traffic police).
In the event of a decision to advise cessation of driving,
advice from a social worker is helpful in planning strategies
for alternative modes of travel. The availability of transport
resources within the family or of high-quality alternative
transportation is helpful (Freund and Vine, 2010), as may be
provision of support groups for driving cessation (Gustafsson
et al., 2012). This may be more challenging in rural settings.
31.11 THE FUTURE
Several developments may attenuate the problems of the
older driver with dementia. At a population level, preven-
tive strategies for dementia may lessen the burden of cog-
nitive disability and strictures on the prescribing of agents
such as long-acting benzodiazepines may reduce crash sus-
ceptibility. Improvements in highway design, signage and
Intelligent Transportation Systems may make travel safer
320 Dementia
for all. Improved assessment procedures may also main-
tain transport options (Martin et al., 2009), for instance,
in-vehicle data acquisition technology has been used to
compare drivers with early cognitive impairment to those
without over a period of 1–2 months (Eby et al., 2012).
For the individual, we do not know whether cholin-
esterase inhibitor therapy can help driving skills in early
Alzheimer’s disease. There is also a suggestion that cogni-
tive training with useful field of view can help driving skills
in non-demented older adults (Ball and Owsley, 1994); some
form of cognitive rehabilitation may be useful. Finally, older
drivers can benefit from environmental and technological
cueing (Dingus et al., 1997); developments in this technol-
ogy may benefit drivers with cognitive impairment.
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Quality of life in dementia: Conceptual and
practical issues
BETTY S. BLACK AND PETER V. RABINS
32.1 INTRODUCTION
Maximizing quality of life is a primary goal of care for indi-
viduals who have irreversible dementia, given the current
lack of disease-modifying therapies. A major challenge for
care providers is determining what makes life as good as
possible over the course of illness in the face of this chronic,
progressive disorder that affects every aspect of life. The
importance of this goal is reflected by the growing research
focus on quality of life (QoL) in dementia and the increase
in its use as an outcome measure in intervention studies.
This chapter examines how QoL in dementia is conceptual-
ized and measured, what we are learning about it and how
future research may advance our understanding of this
sometimes elusive concept.
QoL is an individual’s state of being that is determined
by the evaluation of important aspects of life based on a
set of values, goals, experiences and culture. While there
is general agreement that QoL is a broad multidimen-
sional concept, there is no consensus on how to define it or
what aspects of life should be considered when appraising
one’s QoL. For example, the World Health Organization
(WHO) defines QoL as ‘the individual’s perceptions of
their position in life in the context of the culture and
value system in which they live, and in relationship to
their goals, expectations, standards and concerns’ (WHO
QoL Group, 1995). However, as Faden and German (1994)
note, there are multiple valid and competing conceptions
of the good life, the meaning of QoL changes over a life-
time and adaptation to circumstances affects one’s per-
ception of QoL.
Lawton (1997), perhaps the most influential force in
how QoL is conceptualized and measured, argued that QoL
can and should be assessed both subjectively and objec-
tively. He defined QoL as ‘the multidimensional evaluation,
32
by both intrapersonal and social-normative criteria, of the
person–environment ­system of the individual’ (Lawton and
Herzog, 1991). He believed that there is a need for a frame
of reference against which an individual’s subjective assess-
ment can be compared and that often there are consensual
standards of quality (Lawton, 1997). Lawton suggested that
subjective aspects of QoL (e.g. psychological well-being)
and objective domains (e.g. physical safety) should be
assessed in parallel to examine congruence and incongru-
ence between the two approaches.
Health-related QoL (HRQoL) – a more narrow
­concept – focuses on aspects of life that are affected by
a person’s health conditions and the treatment of those
conditions (Kane, 2003). Although more specific than
QoL, HRQoL is also a multidimensional concept that
refers to one’s social, psychological and physical well-
being consonant with the individual’s values and culture.
This construct is broader than concepts such as mood
or function and is of interest because its primary focus
is on individuals’ subjective global assessment of their
situation. Although HRQoL is also conceptualized as a
broad construct, most researchers have concluded that it
is constructed of several domains, most commonly physi-
cal health, psychological well-being, function and social
activity (Patrick and Erickson, 1993).
While HRQoL is conceptualized as a global construct
and often examined using generic instruments, such as
the Quality of Well-Being (QWB) scale (Kaplan and Bush,
1982) or the Short Form (36) Health Survery (SF-36) (Ware
and Sherbourne, 1992), many researchers have developed
disease-specific measures because the characteristics of
diseases have a significant impact on measurement of the
construct. This approach is often advocated for dementia
because it ultimately robs a person of the ability to express
oneself due to the progressive, debilitating nature of most
dementing illnesses and because of the unique value placed
325
326 Dementia
on thought and cognition. Ettema et al. (2005b) defined
dementia-specific QoL as ‘the multidimensional evalua-
tion of the person-environment system of the individual,
in terms of adaptation to the perceived consequences of the
dementia’. They contend that successful adaptation to the
effects of the disease will lead to a sense of well-being.
Examining QoL can contribute uniquely to assessing
the effectiveness of interventions to treat persons with
dementia. Agencies that approve pharmacological agents
emphasize cognitive improvement as a necessary attribute
for drugs approved to treat cognitive disorders. However,
since these diseases also universally impair function and
social capacity, it is plausible that effective treatments
might improve non-cognitive aspects of dementia more
than the cognitive aspects and non-biological inter-
ventions may affect well-being more than medications
(Whitehouse 2006). This suggests that measuring QoL is
potentially a unique approach for examining treatment
outcomes, and improving QoL through effective interven-
tions may ease some burdens for those with dementia and
their caregivers.
32.2 GOALS OF MEASURING QoL
Measuring QoL can serve several important purposes.
Fundamentally, determining QoL increases our basic
understanding of the impact that dementia has on indi-
viduals over the course of their illness (Kerner et al.,
1998). Beyond specific aspects of the dementia syndrome,
such as cognitive and functional impairments, QoL pro-
vides a more global indicator of how dementia influences
well-being. Because dementia affects a large number of
people, has multiple causes and is non-linear in progres-
sion, QoL provides a common language for evaluating the
effects of interventions (Mack and Whitehouse, 2001). As
new medications and other therapies become available,
reliable measures of QoL are important for comparing
pharmacological agents in terms of both benefits and side
effects and for comparing non-pharmacological inter-
ventions with each other or with pharmacological agents
(Rabins and Kasper, 1997). QoL can be a key consider-
ation in evaluating service programmes or care institu-
tions (Brooker, 2005; Kazui et al., 2008) and in developing
clinical guidelines (NICE, 2006). For those whose lives
have been altered significantly by moving to long-term
care facilities, Kane (2003) believes that we have a moral
responsibility to understand and improve QoL in nursing
homes and other residential facilities. QoL is also a major
consideration in advanced dementia when decision mak-
ers are faced with choosing between aggressive interven-
tions or palliative approaches to care (Taylor et al., 2008).
Finally, we must keep issues of QoL in mind when allocat-
ing scarce resources at both the individual and societal
levels (Brod et al., 1999; Selai and Trimble, 1999; Banerjee
and Wittenberg, 2009).
32.3 CHALLENGES IN MEASURING
QoL IN DEMENTIA
The assessment of QoL in persons with dementia presents
several conceptual and practical challenges (Rabins and
Kasper, 1997). The first is whether there are domains of
QoL that are unique to dementia. Some of the hallmarks
of dementia are that it impairs memory, it can affect atten-
tion, insight, judgment, problem solving, behaviour, person-
ality, communication skills and lead to other non-cognitive
symptoms (e.g. agitation, anxiety, depression, delusions,
hallucinations) (Rabins et al., 2006). This constellation of
possible features unique to dementia can markedly influence
QoL. Howard and Rockwood (1995) emphasize the need to
employ QoL measures that discriminate between patterns
of symptoms across the illness course. An individual’s envi-
ronment also influences functioning and opportunities for
social interaction, which impact HRQoL. Measures of QoL
must be sensitive to the settings where people with demen-
tia reside or receive care, including at home in the commu-
nity, in day-care programs, in assisted living environments
and in nursing homes.
A second issue relates to the subjective nature of the
­construct. In the earlier stages of dementia when symptoms
are mild to moderate and individuals can conceptualize
this construct and express their opinions, obtaining self-
rated QoL is most appropriate, informative and of primary
interest. There is great value in capturing the perspectives –
both quantitatively and qualitatively – of those who have
dementia; there is clear evidence that it is feasible to assess
QoL directly from those in the mild-to-moderate stages
of dementia (Logsdon and Teri, 1997; Brod et al., 1999;
Logsdon et al., 2000; Selai et al., 2001a, 2001b; Trigg et al.,
2007a); and there is some support for seeking self-rated QoL
from individuals with more severe impairments (Hoe et al.,
2005; James et al., 2005). However, since individuals in late
stage dementia usually lack the capacity to self-assess QoL,
they must either be excluded from assessment or methods
must be used whereby other knowledgeable individuals can
provide an indication of the patient’s QoL.
Reliance on others to determine an individual’s QoL
raises important concerns and questions. Does another
person have the right to make judgements about an indi-
vidual’s state of well-being? If so, who is the most appropri-
ate person to serve as a proxy rater of another’s QoL? One
of the most consistent findings in the literature on QoL
in dementia is that proxy ratings are generally lower than
self-ratings (e.g. in Sheehan et al., 2012). A noted exception to
this is the finding of Ready et al. (2006) that greater patient
insight is associated with higher caregiver ratings than
patient ratings. Concordance between patients and proxy
responses is influenced by the nature/quality of their rela-
tionship, the amount of time spent together, the objective-
ness of the questions, the patient’s level of impairments and
the proxy’s well-being (e.g. caregiver burden, depression)
(Brod et al., 1999; Logsdon et al., 2002; Snow et al., 2005;

Banerjee et al., 2006; Karlawish et al., 2008b; Conde-Sala
et al., 2009; Huang et al., 2009; Moyle et al., 2012; Huang
et al., 2014). Proxy ratings have the drawback of filtering a
subjective measure through the opinion of another person
who may or may not share relevant values. This limitation
may be unavoidable, especially for those in the later stages
of dementia. However, measures consisting of items that
describe observable behaviours and expressions can help to
minimize this limitation (Rabins and Kasper, 1997).
A third major issue is establishing acceptable psycho-
metric properties of instruments that measure QoL in a
disorder in which some individuals are unable to concep-
tualize the construct. Establishing the validity of a measure
(i.e. that it accurately measures what it purports to mea-
sure) is a challenge when there is no universally accepted
definition of QoL and any definition is subject to an indi-
vidual’s interpretation and values (Rabins and Kasper,
1997). While criterion validity may not be possible, most
developers seek to establish face validity and content valid-
ity by demonstrating the relevance and comprehensive-
ness of their instrument. Reliability of a measure can more
readily be established than validity by demonstrating that
its items have internal consistency, that it has good repeat-
ability across administrations and that its use by multiple
observers produces similar results. Another psychometric
challenge for instruments measuring QoL in dementia is to
demonstrate its responsiveness or sensitivity to meaningful
change. This is a critical characteristic for its usefulness as
an outcome measure.
32.4 APPROACHES TO MEASURING
QoL
Numerous approaches have been used to assess QoL in
people with dementia. Differences relate to the general type
of instrument (i.e. generic vs. disease-specific), the scope of
the instrument (e.g. a single item vs. multiple domains), the
type of scores the measure produces and the data collec-
tion method. The approach selected by an investigator will
depend on several factors. First, the purpose for measuring
QoL may determine whether a generic or disease-specific
instrument is most appropriate. While a disease-specific
measure of QoL is most sensitive to the unique character-
istics of dementia and its impact on people’s lives, it cannot
be used to compare the well-being of individuals who have
dementia with that of people who are cognitively normal or
who have other illnesses. Naglie (2007) notes that generic
measures can be classified as health profiles or utility mea-
sures and can be helpful for health policy decision making.
If QoL is being used as an outcome measure, it is impor-
tant to consider whether the instrument’s content will pro-
vide an appropriate measure of effectiveness of the therapy,
intervention or programme being examined. Investigators
wanting to examine relationships between an intervention
and particular aspects of QoL may prefer an instrument
Quality of life in dementia: Conceptual and practical issues 327
that provides subscale scores reflecting specific domains of
QoL rather than one that provides only a single summary
score. Instruments also vary in how items are scored. In
many cases, the items of an instrument contribute equally
to either a subscale score and/or the total score, while other
measures have weighted scores based on the assumption
that the issues reflected by different items vary in their con-
tribution to the individual’s QoL.
Characteristics of the study sample can influence the
choice of methods and instruments. Some instruments are
designed to assess QoL across the course of illness. These
usually rely on proxy raters, such as family members or
formal health care providers, so that individuals with
advanced dementia can be included along with those who
are less impaired. This approach is particularly useful for
minimizing missing data in longitudinal studies if partici-
pants are likely to lose the ability to self-assess as the illness
progresses. Proxy rated instruments can vary in whether
the proxy is asked to respond based on what they think the
person’s QoL is or based on substituted judgement (i.e. what
they think the person with dementia would say). Other
instruments have been developed specifically for those with
mild-to-moderate dementia who are likely to be able to
self-assess their QoL or participate in the assessment pro-
cess along with a knowledgeable informant. Some measures
focus exclusively on QoL in severe or late-stage dementia,
often relying on formal caregivers as proxy raters or observ-
ers since many of these individuals are cared for in residen-
tial facilities.
Lawton (1997) rejected the idea that there can be only
one scale of QoL since life is composed of many facets.
Beyond the subjective measure of QoL involving self-report,
he described two types of objective measures that deal with
observable phenomena (Lawton, 1997). First are attri-
bute ratings, which are characteristics rated based on the
rater’s familiarity with or observation of the person’s typi-
cal behaviour over a period of time (e.g. the prior 2 weeks).
Instruments examining attributes (e.g. functional health,
behavioural symptoms, social interaction and affect) are
typically rated by a family member or health care provider.
The second type of objective measure is direct observation
and coding of ongoing behaviour, which can include behav-
iours of persons with dementia, their displays of affect and
interactions with care providers, or it can include aspects
of the environment. Trained researchers typically complete
observational measures.
Concerns about the high cost of dementia care increas-
ingly have led to reliance on utility-based measures of QoL
that are used to conduct cost-effectiveness analyses (Naglie
et al., 2006). Generic utility instruments provide a global
measure of an individual’s preference for a health state
using a single number usually ranging from 0 (representing
death) to 1 (representing perfect health) and allow for evalu-
ating interventions based on their cost per quality-adjusted
life year (QALY) (Naglie, 2007). Thus, QALY is a measure
of disease burden that incorporates both the quality and
quantity of life lived and is based on the relative desirability
328 Dementia
(‘utility’) of ­different outcomes (Knapp and Mangalore,
2007). Utilities can be obtained directly from individuals
or from health indexes that incorporate a health state clas-
sification ­system and a set of ­population-derived weights
that produce a utility score. Two frequently used indices
for measuring health preferences are the EuroQOL Five
Dimensions questionnaire (EQ-5D) (Rabin and de Charro
2001) and the Health Utility Index (HUI) (Horsman et al.,
2003), both of which have been used to assess QoL in p ­ ersons
with ­dementia (Jonsson et al., 2006; Naglie et al., 2006;
Karlawish et al., 2008b; Kavirajan et al., 2009; Miller et al.,
2009; Hounsome et al., 2011). The EQ-5D measures health
states according to five d ­imensions (mobility, s­elf-care,
usual activities, ­ pain/discomfort and anxiety/depres-
sion), and a later version of the HUI (HUI3) includes eight
­attributes (vision, h­ earing, speech, a­ mbulation, ­dexterity,
emotion, cognition and pain). Knapp and Mangalore (2007)
provide a ­discussion of the a­ dvantages and ­disadvantages of
using the QALY ­measurement approach.
32.5 MEASURES OF QoL IN DEMENTIA
While many investigators use generic or utility-based
­measures to examine QoL in dementia, the nine i­ nstruments
described below and summarized in Table 32.1 are ­examples
of dementia-specific measures for ­assessing QoL in people
with dementia. This is not an exhaustive list, but it includes
many of the instruments represented in the current l­ iterature
on QoL in dementia, and it illustrates the v­ ariability that
exists in the content (i.e. domains, number of items) and data
collection methods. For example, other instruments used
to measure dementia-related QoL that are not described
in detail here are the Pleasant Events ­Schedule-Alzheimer’s
Disease (PES-AD; Logsdon and Teri, 1997), the Quality of
Life Assessment Schedule (QoLAS; Selai et al., 2001b), the
Quality of Life Questionnaire for Dementia (QoL-D, Terada
et al., 2002) and the Bath Assessment of Subjective Quality of
Life in Dementia (BASQID; Trigg et al., 2007a). For selected
reviews of generic and dementia-specific instruments,
Walker et al. (1998), Demers et al. (2000), Salek et al. (1998),
Selai and Trimble (1999), Ready and Ott (2003), Ettema
et al. (2005a), Schölzel-Dorenbos et al. (2007), Banerjee et al.
(2009), Perales et al. (2013) and Bowling et al. (2015). An
online database of QoL ­instruments is available at www.­
proqolid.org.
32.5.1 ACTIVITY AND AFFECT
INDICATORS OF QUALITY OF LIFE
Albert et al. (1996, 2000) developed the Activity and Affect
Indicators of Quality of Life (AAIQoL) by adapting two
existing measures to assess QoL related to the domains
of activity and affect as rated by caregivers. The 53-item
PES-AD (Logsdon and Teri, 1997) was reduced to 15 items,
used to determine the frequency of, ­opportunity for and
­enjoyment of activities that take place either o ­ utside the
home (5 items) or indoors (10 items). Affect is ­measured
using Lawton’s Affect Rating scale (Lawton, 1994), which
consists of three positive affects (pleasure, interest,
­contentment) and three negative effects (anger, anxiety,
depression). The frequency of each affect in the previous
2 weeks is determined based on a 5-point scale. A c­ omposite
QoL indicator is then ­constructed by ­combining the affect
and activity i­ ndicators. While the developers have reported
that reliability and validity of the AAIQoL are acceptable
(Albert et al., 1996) and that it can be used in clinical and
community-based samples, they suggest that the affect
measure, which is less clearly linked to observed behav-
iours, may be a less reliable indicator of QoL when reported
by proxies (Albert et al., 2000).
32.5.2 ALZHEIMER’S DISEASE–RELATED
QUALITY OF LIFE (ADRQL)
The Alzheimer’s Disease-Related Quality of Life (ADRQL)
is a proxy rated measure of QoL of individuals who have
AD or other types of dementia for use across all levels of
disease severity (Rabins et al., 2000). It was developed using
an iterative process involving input from health care pro-
viders, informal caregivers and a national panel of experts
in dementia research and treatment. The original ADRQL
contains 47 items reflecting five domains that describe pri-
marily observable behaviours. It is administered using a
structured interview format to either a formal or informal
care provider who has knowledge of the person with demen-
tia in the previous 2 weeks, with response choices of ‘Agree’
or ‘Disagree’. One assumption underlying the ADRQL is
that the items and domains vary in their contribution to
the concept of QoL. These differences are incorporated
into the measure with preference weights to assign a scale
value to each ADRQL item. Summary scores ranging from
0 to 100 are calculated for each domain and for the overall
QoL score, with higher scores reflecting a higher QoL. The
ADRQL has good reliability and validity (Black et al., 2000;
Gonzalez-Salvador et al., 2000) and is responsive to change
(Lyketsos et al., 2003; Missotten et al., 2007; Kasper et al.,
2009). The 40-item version of the ADRQL is recommended
based on analyses of data from three settings (community,
assisted living, nursing home) that demonstrate improved
psychometric properties over the original version (Kasper
et al., 2009). The 40-item ADRQL can be derived from the
original 47 items and reflects the same five domains of QoL.
32.5.3 CORNELL-BROWN SCALE FOR
QoL IN DEMENTIA
Ready et al. (2002) developed the Cornell-Brown Scale
(CBS) by modifying the Cornell Scale for Depression
(Alexopoulos et al., 1988). The CBS was developed based
on the conceptualization that high QoL is indicated by the
 Quality of life in dementia: Conceptual and practical issues 329

Table 32.1 Dementia-specific measures of quality of life (QoL)

Instrument Content/Domains Respondent Patient Population Items

Activity and Affect Indicators of Activity Proxy–formal or Mild to severe 21
Quality of Life (AAIQoL) Positive Affect informal
Negative Affect caregiver
Alzheimer’s Disease-Related Social interaction Proxy–formal or Mild to severe 40
Quality of Life (ADRQL) Awareness of self informal
Enjoyment of activities caregiver
Feelings and mood
Response to surroundings
Cornell-Brown Scale (CBS) for Negative affectivity Clinician with Mild to moderate 19
Quality of Life in Dementia Physical complaints patient’s and
Positive affectivity caregiver’s input
Satisfaction
Dementia Care Mapping (DCM) Well-being Trained observer Moderate to severe 24
Illbeing
Personal detractions
Dementia Quality of Life (DQoL) Self-esteem Patient Mild to moderate 29
Positive affect/humour
Negative affect
Feelings of belonging
Sense of aesthetics
DEMQoL Daily activities Patient Mild to moderate 28
DEMQoL-Proxy Health and well-being Proxy Mild to severe 31
Cognitive functioning
Social Relationships
Self-concept
QUALIDEM Care relationship Professional Mild to severe 37
Positive affect caregiver
Negative affect
Restless tense behaviour
Positive self-image
Social relations
Social isolation
Feeling at home
Having something to do
Quality of Life-Alzheimer’s Physical condition Patient and/or Mild to moderate 13
Disease (QoL-AD) Mood proxy
Interpersonal relationships
Ability to participate in
meaningful activities
Financial situation
Overall assessment of self
Life quality as a whole
Quality of Life in Late Stage Activity Proxy Severe 11
Dementia (QUALID) Affect

presence of positive affect, satisfaction, self-esteem and the
relative absence of negative affect. It includes 19 bipolar
items in four categories that yield a single QoL score. The
CBS is completed by a clinician after conducting a joint
semi-structured interview with the patient and caregiver.
Based on information obtained regarding the previous
month, each item is rated on a 5-point scale from −2 to +2.
Reliability and validity have been demonstrated in a sam-
ple of outpatients with either dementia or mild cognitive
impairment, with similar properties based on data from
the mild and the more severely impaired halves of the sam-
ple (Ready et al., 2002).
330 Dementia
32.5.4 DEMENTIA CARE MAPPING
Kitwood and Bredin (1994) devised the Dementia Care
Mapping (DCM) method for evaluating quality of care
and the well-being of people with dementia in residen-
tial care settings. The DCM methodology is based on the
social–psychological theory of dementia care (Kitwood
and Bredin, 1992), which holds that much of the decline
among those with dementia is a consequence of social
and environmental factors. DCM is a structured, obser-
vational method in which the well-being or illbeing (WIB)
of patients is rated based on signs from the patient and
staff behaviours toward the patient. Trained observers
also record any personal detractors (PDs), which are any
episodes that could lead to a reduction in self-esteem for
the patient, and Positive Enhancers (PEs). Typically, five to
ten residents are rated every 5 minutes over a 6-hour time
period using 24 Behaviour Category Codes (BCC). WIB
values, which range from −5 (illbeing) to +5 (well-being),
can be aggregated to determine an overall WIB score for
the group and for each individual. Literature reviews have
described the extensive use of DCM and summarized
evidence of its reliability, validity and responsiveness
to change (Beavis et al., 2002; Brooker, 2005). DCM has
undergone several changes since its inception (Brooker and
Surr, 2006). Because of its complexity and required spe-
cialist training, others have examined the use of ‘stream-
lined’ approaches to mapping in an effort to simplify the
process and reduce the resources required to implement
this method (Fulton et al., 2006). Despite its limitations
(Beavis et al., 2002; Thornton, 2004; Sloane, 2007), DCM is
unique among the dementia-specific QoL measures in that
it also serves to examine some elements of quality of care,
is a tool for practice development and has been used as a
intervention for improving QoL.
32.5.5 DEMENTIA QUALITY OF LIFE
Brod et al. (1999) developed the Dementia Quality of Life
(DQoL), which was designed to be administered to people
with mild to moderately severe dementia. It is a 29-item
instrument developed through an iterative process i­ nvolving
a literature review, focus groups, pilot testing and ­statistical
examination of its psychometric p ­roperties. Screening
­questions are used to assess the individual’s ­comprehension
of the response format. The DQoL consists of items rated on
a 5-point visual scale that form five ­subscales. The developers
(Brod et al., 1999) have reported good internal consistency,
reliability and construct validity and suggest that reliable
data can be obtained from individuals with ­Mini-Mental
State Examination (MMSE) scores >12.
32.5.6 DEMQoL AND DEMQoL-PROXY
The DEMQoL and DEMQoL-Proxy were devised by Smith
et al. (2007) to assess HRQoL in all stages of dementia
severity. These instruments were developed based on a
multi-staged process beginning with the development
of a conceptual framework that includes five domains
(Smith et al., 2005a). The DEMQoL is a 28-item i­ nstrument
­administered to ­persons with mild-to-moderate ­dementia,
and the DEMQoL-Proxy is a 31-item questionnaire for the
caregiver to complete regarding patients with ­mild-to-severe
dementia, with higher scores i­ndicating b ­etter QoL.
The authors, who report satisfactory ­ psychometric
properties on these measures, recommend that both
­
instruments be used together, although the DEMQoL
­
­cannot be used with ­individuals who have severe cognitive
impairment (i.e. MMSE scores <10).
32.5.7 QUALIDEM
Ettema et al. (2007a, 2007b) developed the QUALIDEM to
assess QoL in individuals with dementia living in residen-
tial care settings. Content of the QUALIDEM is based on an
iterative process that involved a literature review, qualitative
research methods, field testing and psychometric analyses.
It is a multidimensional scale, rated by professional caregiv-
ers, that consists of 37 items describing observable behaviour
and making up nine subscales (Koopmans et al., 2009). The
subscale scores are linearly transformed to range from 1 to
100, with higher scores reflecting a better QoL. The devel-
opers report that 18 of the QUALIDEM items comprising
six subscales are applicable for measuring QoL in the final
phase of dementia. The QUALIDEM has satisfactory reli-
ability and validity for use in research and practice. The
authors strongly discourage the calculation of a total score
since the subscales differ in content and distinct subscale
information would be lost.
32.5.8 QUALITY OF LIFE-AD
The Quality of Life-AD (QoL-AD) was developed by
Logsdon et al. (2000) to assess QoL as perceived by both
the patient and their caregiver. The content of the QoL-AD
was derived based on a review of relevant literature on QoL
of older adults and other chronically ill populations and
the input of patients, caregivers and experts in the fields
of geriatrics and gerontology. The QoL-AD consists of
13 items used to assess seven aspects of the patient’s QoL.
An interviewer administers the QoL-AD to patients with
mild-to-moderate dementia and caregivers complete the
measure in the form of a questionnaire. Each item is rated
by the respondent on a 4-point scale, with 1 being ‘Poor’
and 4 being ‘Excellent’, and total scores range from 13 to
52. A weighted composite score is calculated by giving
greater weight to the patient’s rating than the caregiver’s
rating. The developers (Logsdon et al., 2000, 2002) report
that the QoL-AD has good reliability and validity, and it is
responsive to change (Spector et al., 2003; Karlawish et al.,
2004). The QoL-AD is widely used and frequently serves
as an indicator of concurrent validity for other dementia-
specific and generic measures of QoL.

32.5.9 QoL IN LATE-STAGE DEMENTIA
Weiner et al. (2000) developed the Quality of Life in
­Late-Stage Dementia (QUALID) for use in assessing QoL in
persons with late-stage dementia in institutional settings. The
scale items were selected from the affect and activity measure
(i.e. the AAIQoL) devised by Albert et al. (1996). A group of
­clinicians experienced in assessing persons with AD selected
the items by consensus. The QUALID, which is a­ dministered
as a structured interview, contains 11 items reflecting
­observable behaviours rated by frequency on a 5-point Likert
scale by a nursing home technician who has at least 30 hours
of exposure to the resident in the previous week. Scores range
from 11 to 55, with lower scores ­reflecting better QoL. The
developers report that the QUALID has good internal consis-
tency, adequate construct validity and is responsive to change
(Weiner et al., 2000; Martin-Cook et al., 2005).
32.6 CORRELATES OF QoL IN
DEMENTIA
Through numerous cross-sectional studies, researchers have
identified a few fairly consistent correlates of QoL, while
some relationships are less clear. For example, in a review
of findings based on dementia-specific measures, Banerjee
et al. (2009) suggest that there is little relationship between
severity of cognitive impairment and HRQoL. They cite
several studies (Logsdon et al., 2002; Smith et al., 2005a;
Fuh and Wang, 2006; Vogel et al., 2006) that found little or
no association between cognition and QoL, but they note
exceptions to this as well, such as a study by Edelman et al.
(2005) that found QoL-AD scores s­ ignificantly ­worsening as
MMSE scores decreased. Findings elsewhere reveal v­ ariable
relationships between cognitive ­function and QoL, with
some investigators identifying significant c­ orrelations (e.g.
Samus, 2005, 2006; Falk et al., 2007; Cordner et al., 2010;
Mougias et al., 2011; Sheehan et al., 2012), others reporting
no significance between the two factors (e.g. Trigg et al.,
2007b; Missotten et al., 2008; Karlawish et al., 2008a) and
still others reporting that their findings differ based on the
person’s level of cognitive impairment (i.e. mild vs. moder-
ate vs. severe) (Matsui et al., 2006; Missotten et al., 2009) or
on who rates the person’s QoL (i.e. self vs. proxy) (Edelman
et al., 2004a; Beer et al., 2010). Banerjee et al. (2009) note
that, while staff ratings of QoL usually show higher cor-
relations with cognitive ­f unction than ­self-reports or fam-
ily caregiver reports, the absolute ­correlation is generally
low, suggesting that QoL and cognition are independent
constructs.
Investigators often find that impairments in activities
of daily living (ADL) or greater physical dependency are
associated with diminished QoL in persons with dementia
(Albert et al., 2000; Gonzalez-Salvador et al., 2000; Logsdon
et al., 2002; Hoe et al., 2005; Ettema et al., 2007b; Conde-
Sala et al., 2009; Black et al., 2012; Sheehan et al., 2012),
Quality of life in dementia: Conceptual and practical issues 331
but there are also exceptions to these findings. For exam-
ple, neither Fuh and Wang (2006) nor Matsui et al. (2006)
found an association between measures of QoL and ADL
impairments, while others report findings in which proxy
ratings of QoL are associated with functional status but self-
ratings are not (Edelman et al., 2004b; Edelman et al., 2005).
Based on multiple regression analyses, Giebel et al. (2015)
found that ADL impairments had a significant impact on
QoL only in moderate dementia. Thus, studies do not reveal
a consistent pattern in the relationship between QoL and
functional status.
One of the most consistent findings in persons with
dementia is the relationship between symptoms of depres-
sion and lower QoL (e.g. Smith et al., 2005b; Banerjee et al.,
2006; Vogel et al., 2006; Ettema et al., 2007b; Trigg et al.,
2007b; Sheehan et al., 2012; Clare et al., 2014). In some stud-
ies, this is reflected by both self-ratings and proxy ratings
of QoL (Logsdon et al., 2002; Snow et al., 2005; Black et al.,
2012). A partial exception to this relationship was reported
by Hoe et al. (2005) who found that individuals with severe
dementia had QoL-AD scores significantly associated with
the mood scale on the Health Status Questionnaire but not
with the Cornell Scale for Depression in Dementia or the
depression or anxiety subscales of the Hospital Anxiety and
Depression Schedule. The generally strong relationships
among dementia, depression and QoL highlight the impor-
tance of diagnosis and treatment of depression, especially
among residents of long-term care facilities where the risk
of depression is high.
The relationship between behavioural disorders and
poor QoL in persons with dementia has been widely
reported (e.g. Samus, 2005; Banerjee et al., 2006; Samus,
2006; Hoe et al., 2007; Beer et al., 2010; Cordner et al.,
2010; Black et al., 2012). In a review, Banerjee et al. (2009)
cite studies in which behavioural disorders are associated
with decreased QoL based on staff and caregiver ratings but
not based on self-ratings (Logsdon et al., 2002; Hoe et al.,
2005; Banerjee et al., 2006; Hoe et al., 2006). They suggest
that these ­differences may be due to either the patient’s lack
of insight or differential appraisals of the impact that these
disorders have for those with dementia compared with
proxies. However, some investigators have found signifi-
cant relationships between behavioural disturbances and
QoL as rated by both the caregiver and the patient (Matsui
et al., 2006; Hurt et al., 2008). In a review of studies focused
on persons with dementia in long-term care, Beerens et al.
(2013) found associations between proxy-rated QoL and
behaviours – especially agitation – based on both ­bivariate
and multivariate analyses. Researchers have also found
significantly lower QoL in individuals with dementia who
are taking psychotropic medications (Albert et al., 1996;
Gonzalez-Salvador et al., 2000; Ballard et al., 2001; Falk
et al., 2007; Mougias et al., 2011; Clare et al., 2014). However,
since these are cross-sectional studies, it is unclear whether
medications adversely affect QoL or whether lower QoL is
due to the psychiatric and behavioural problems that are
being treated.
332 Dementia
An increasing number of longitudinal studies have
examined change and correlates of change in QoL. Lyketsos
et al. (2003) identified a small but significant mean change in
ADRQL scores over 2 years in a residential setting, with lower
baseline scores being the only significant predictor of change
in QoL. In a 12-month follow-up examination of QoL-AD
scores in a randomized controlled trial (RCT), Karlawish
et al. (2004) found that declines in functional status were
more strongly associated with diminished QoL than with
declines in cognition. Zimmerman et al. (2005) conducted a
6-month follow-up of QoL-AD scores in the Dementia Care
project and found a small but significant worsening in QoL
that was associated with greater cognitive impairment and
depression. Over 1 year, Kasper et al. (2009) found a signifi-
cant decline in ADRQL scores in a community-based sample
of individuals who had increases in ADL impairments. Hoe
et al. (2009) showed that change in QoL-AD scores in long-
term care homes was related to baseline QoL scores, depres-
sion and anxiety symptoms and an increase in depressive
symptoms and cognitive deterioration during the 20-week
follow-up. More recently in a 10-month follow-up study of
nursing home residents, Mjorud et al. (2014) determined
that change in QUALID scores was associated with base-
line QoL scores and change in neuropsychiatric symptoms.
Beerens et al. (2014) reported that change in QoL-AD scores
for residents in long-term care facilities was associated with
baseline cognition, functional dependency and depression
and with increases in dependency and depressive symptoms
over time. Other investigators have found no significant
mean change in QoL after periods ranging from 6 months
to 2 years (Hoe et al., 2005; Selwood et al., 2005; Missotten
et al., 2007; Oudman and Veurink, 2014). However, even in
studies that report little or no mean change in QoL, sizeable
proportions of their samples show increases, no change or
decreases in QoL over time (Lyketsos et al., 2003; Selwood
et al., 2005; Missotten et al., 2007; Beerens et al., 2014; Mjorud
et al., 2014). Further research is needed better to understand
what leads to these fluctuations in QoL.
32.7 QoL AS AN OUTCOME MEASURE
Relatively few intervention trials have examined QoL as an
outcome measure for persons with dementia (Takeda et al.,
2006; Schölzel-Dorenbos et al., 2007; Banerjee et al., 2009),
particularly as a primary outcome or with d­ ementia-specific
measures, but their numbers are increasing (Cooper et al.,
2012, 2013) as interest grows in improving QoL. To date,
QoL has been examined as an outcome in pharmacologic
trials less often than in non-pharmacologic studies.
Among drug trials, studies conducted by Rogers et al.
(1996, 1998a, 1998b) on donepezil showed some improve-
ment in QoL. However, the changes they observed in
QoL were not always significant or seen in the interven-
tion group and the rating scales had not been validated for
use in dementia. Lu et al. (2006) showed that testosterone
replacement therapy improved QoL in AD, but had no sig-
nificant effect on cognition. Phase 1 of the CATIE-AD trial
of three atypical antipsychotics showed some improvement
in clinical symptoms, but there was no effect on cognition or
QoL (Sultzer et al., 2008). After systematically reviewing 15
pharmacologic interventions that examined change in QoL
or well-being, Cooper et al. (2013) concluded that there is
no consistent evidence that any drug improves QoL in per-
sons with dementia. Not included in their review, however,
was a study by Larsson et al. (2011) who conducted a sec-
ondary analysis of a 24-week RCT and found that meman-
tine improved total QoL based on caregiver-rated QoL-AD
scores. More recently, Caramelli et al. (2014) reported that
a 24-week trial of galantamine improved self-rated QoL-AD
scores in mixed dementia patients. Despite the limited posi-
tive findings, drug trials should continue to include QoL as
an outcome measure.
Studies examining a variety of non-pharmacologic
­interventions and their effects on QoL have focused on
those with dementia in a range of settings – the ­community,
day-care centres and residential care (Cooper et al., 2012).
A series of studies examined the impact of cognitive
­stimulation therapy (CST) (Spector et al., 2003; Knapp
et al., 2006; Woods, 2006). Spector et al. (2003) found that a
14-session CST programme had a ­significant positive impact
on MMSE and QoL-AD scores of ­persons with dementia.
Other investigators have found that ­ community-based
occupational therapy can improve patients’ QoL and their
informal caregivers’ well-being (Dooley and Hinojosa,
2004; Graff et al., 2007; Kumar et al., 2014). Teri et al.
(2005) used the QoL-AD in an RCT to determine whether
community consultants to family caregivers could reduce
mood and behaviour problems in persons with AD. Their
STAR-C training program ­significantly reduced ­behaviour
problems, improved QoL for the patients and benefited the
caregivers. Logsdon et al. (2010) found that an early stage
memory loss ­support group improved patients’ QoL and
depression. RCTs of ­dementia care ­management (Vickrey
et al., 2006) and care c­oordination (Samus et al., 2014)
models have ­ demonstrated improvements in QoL for
­community-dwelling persons with dementia. Using DCM
in an RCT, aroma therapy with Melissa oil improved QoL
and reduced agitation in a sample of individuals with severe
dementia (Ballard et al., 2002). DCM was also used by
Rokstad et al. (2013) in a 10-month trial to p
­ revent ­agitation
and other ­ neuropsychiatric symptoms that resulted in
improved QUALID scores in the intervention group.
Lai et al. (2004) used DCM and found that r­eminiscence
­t herapy had a significant impact on WIB scores for ­nursing
home residents with ­dementia. Reminiscence therapy was
also used by O’Shea et al. (2014), who found ­significantly
improved QoL-AD scores in n ­ursing home residents
based on per-protocol analysis. Other investigators have
shown some positive effects on QoL for nursing home
residents with a therapeutic garden (Edwards et al., 2012),
an ­a nimal-assisted intervention (Nordgren and Engstom,
2014) and an awareness-based staff training intervention
 Quality of life in dementia: Conceptual and practical issues 333
involving persons with severe dementia (Clare et al., 2013).
The range of non-pharmacologic interventions shown to
improve QoL in persons with dementia in various care
settings demonstrates that there are multiple pathways to
increase patient well-being in the face of this disorder.
32.8 QUESTIONS AND ISSUES FOR
THE FUTURE
Examining QoL in dementia is an important means of
understanding the experience of people with these disor-
ders, determining the efficacy and effectiveness of phar-
macological and non-pharmacological approaches and
evaluating and improving care practices. The advancements
that have occurred over the past two decades in the study of
QoL in dementia serve as a foundation for further progress
that is needed in several areas. These include the measure-
ment of QoL, identifying predictors of change in QoL and
in the development and dissemination of interventions to
improve patients’ well-being.
Reliable and valid dementia-specific instruments are
available to measure QoL across the spectrum of severity.
Many instruments are available in multiple languages and
some have been validated across cultures. They reflect dif-
ferent conceptualizations of this construct, rely on varied
methods for data collection and obtain the perspectives of
different types of respondents to measure QoL. For some
of these measures, limited or no data are available on their
responsiveness – a psychometric property that is critical
for determining the impact of therapeutic interventions.
Related to this are the questions of how users should inter-
pret changes in QoL scores, and what is a minimally impor-
tant difference or a clinically significant change in scores
(Naglie, 2007; Schölzel-Dorenbos et al., 2007). Addressing
these issues in future research will facilitate greater reliance
on QoL as an outcome measure in RCTs.
There is a clear consensus on the importance of obtain-
ing self-assessed QoL from individuals capable of concep-
tualizing this construct and responding meaningfully to
assessment items. The value of this approach is highlighted
by the consistent differences seen between self-rated and
proxy-rated measures of QoL; differences that may be attrib-
utable to characteristics of the person with dementia, the
proxy informant and/or the QoL instrument. Correlates of
HRQoL often depend on who rates an individual’s QoL and
which measure is used (Black et al., 2012). Since the perspec-
tives of the person with dementia and the carer often differ,
proxy ratings cannot be substituted directly for self-ratings.
Clarification of criteria is needed for including self-ratings to
maximize the use and validity of self-assessment; and guid-
ance is needed to determine the most appropriate proxy for
those who lack the ability to self-assess (Naglie, 2007) since
the perspectives of informal and formal caregivers can dif-
fer. Further research should determine the aspects of cog-
nitive impairment (e.g. insight, understanding, judgment)
that impact self-rated QoL measures and what factors con-
found QoL ratings provided by patients, informal caregivers
and professional care providers.
Most published research on QoL in dementia is based
on cross-sectional data, so little is known about the ­natural
­history of QoL in dementia (Banerjee et al., 2009) or how
change occurs in QoL (Selwood et al., 2005). Available
longitudinal studies show that decline in QoL is not
­
­inevitable with disease progression and that QoL may be as
likely to improve with time as to diminish. More p­ rospective
studies are needed with larger, ­
­ representative samples
that are conducted over longer periods to i­dentify causal
­relationships and mediating factors for ­individuals with
dementia (Banerjee et al., 2009). Because our k­ nowledge of
QoL near the end of life in dementia is limited (Koopmans
et al., 2009), studies are needed to determine the impact
that care settings, approaches to symptom management and
­end-of-life care decision making have on QoL. Finally, while
progress is being made on developing methods to improve
QoL in dementia, there is also a great need for ­replicating
efficacious interventions and promoting ­ translational
research to spread the adoption of best practices in care
quality that impact QoL for persons with dementia.
We anticipate that interest in and the importance of
maximizing QoL will increase in the future as the number
of individuals with dementia grows and as investigators
seek to identify effective therapies to modify dementia’s
effects and ease the suffering of these individuals and
their caregivers.
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Ethical issues
JULIAN C. HUGHES AND DANIEL STRECH
33.1 INTRODUCTION
According to ancient tradition ethics aims at the good life.
It is about how we live our lives well, about doing the right
thing rather than the wrong thing; it’s about good and bad.
Applied at the level of individuals, decisions about the per-
son should be good decisions or the right decisions for that
individual at that time. The two words ‘ethics’ and ‘morals’
are, to all intents and purposes, used synonymously despite
semantic differences. In this chapter, we shall sketch issues
in dementia care that raise issues of right or wrong, good
or bad. It should be noted, too, that ethics and morals are
not just relevant to personal decisions, they relate to public
policy too: ethics is the foundation of politics.
The chapter will start by rehearsing some of the main
ethical theories used to think about ethical dilemmas. We
then move on to consider the spectrum of ethical issues that
arise in clinical dementia care. In the conclusion, we shall
speculate on how ethical decisions are made in practice.
33.2 ETHICAL THEORIES
The giants of ethical theory are consequentialism, deon-
tology and virtue ethics. In the field of medical ethics,
the notion of principlism has also played a dominant role.
Finally, there is a host of other ethical approaches, which we
shall mention briefly. All of these theories and approaches
are discussed more fully in Hughes and Baldwin (2006). To
highlight the differences between these theories we shall
use the notion of ‘therapeutic lying’ (Culley et al., 2013).
Therapeutic lying is the idea that sometimes it can be right
to say to the person with dementia something that is untrue
if this will make life better in some way for the individual.
For example, if a widow constantly says that she thinks her
deceased husband will be picking her up later in the day
33
from the care home, carers may feel that it is better to go
along with this falsehood rather than to contradict the lady
and cause repeated upset.
33.2.1 CONSEQUENTIALISM
Consequentialists believe that it is the consequences of an
action that determine whether it is right or wrong. In the
case of therapeutic lying, therefore, they would argue that
if the consequence of the lie means that everyone is hap-
pier, then telling the lie would be the right thing to do. It
might be, however, that while the immediate effects of the
lie are good, in that the lady is not distressed by the news
of her husband’s death, in the long run it may be that she
comes to distrust people. Her experience will be that the
reassurance she receives concerning her husband never
materializes into his appearance. Another possible nega-
tive effect of the lie is that carers might start to feel that, if
they can lie in this case, then they can lie in other cases.
Hence, there might be a general lessening of trustworthi-
ness. Society at large, hearing that healthcare and social
care workers frequently tell lies to people with dementia,
might experience a general loss of trust in professionals.
Of course, all of this may not come to pass and it may be
that there are specific instances when the consequences of
a therapeutic lie seem to be wholly good.
33.2.2 DEONTOLOGY
A deontologist is someone who stresses the importance of
duty. Deontology is often linked to the name of Immanuel
Kant (1724–1804). His idea was that there are certain
things which rational people should always regard as
imperative. He believed that it would only be rational to
make a rule that should apply to everyone and not just
to certain people. He also talked about the importance
of not regarding people solely as a means to an end, but
rather as ends in themselves. So, we should not use people
339
340 Dementia
with dementia for research to which they cannot con-
sent, which will bring them no benefit. There are some
things, therefore, which Kant would simply have regarded
as duties. One such duty was to tell the truth. His incli-
nation would be always to repudiate the need for thera-
peutic lies. He would say that once you allow that lying
is acceptable then you have undermined a whole lot of
social institutions, which rely upon the truth being told.
Contracts between people would be an example of such a
social institution, including the long-established contract
that doctors keep confidences.
33.2.3 VIRTUE ETHICS
According to virtue ethics, you will know the good thing
to do if you ask the virtuous person. A person is virtu-
ous if he or she has the inner dispositions (i.e. the virtues)
to flourish or do well humanly. The virtue words simply
describe what it is to do well as a human being. This relies
on the idea that we would all accept that the good person
is the one who is wise, courageous, humble, compassion-
ate and charitable, just, patient, honest and so on. Virtue
ethics changes the subject because it makes us think in
these different terms. On the face of it, therapeutic lying
will be bad because it involves dishonesty. But, on the
other hand, it may also involve a good deal of compas-
sion. It will require practical wisdom or sensibility in
order to decide how the virtues are to be balanced in mak-
ing these decisions; but the discussion is no longer about
rigid duties or calculations about consequences, instead
the conversation is about the honest, brave, compassion-
ate and just thing to do.
33.2.4 PRINCIPLISM
Beauchamp and Childress (2001), on the basis of the more
established ethical theories, picked out what have become
known as the four principles of medical ethics. These are
respect for autonomy, beneficence, non-maleficence and
justice. Decisions will have to be made concerning which
of these principles should be given most weight in any
particular circumstance. One immediate concern to do
with therapeutic lying, however, is that it does not seem to
respect the person’s autonomy. ‘Autonomy’ means self-rule
and a lie undermines the person’s ability to self-rule; in fact
it undermines the person’s agency and standing as a per-
son. On the other hand, beneficence, or doing good, might
suggest that it is appropriate to lie. Similarly, we may avoid
harm (i.e. abide by the principle of non-maleficence) if we
tell the therapeutic lie. The notion of justice is normally
used in connection with resource allocation. It could be
argued that therapeutic lying, if it calms the person down
who might otherwise be agitated, is a much cheaper way,
and indeed a safer way to manage the situation than the
use of drugs. So arguments could be made in favour and
against therapeutic lying using the four principles depend-
ing on the circumstances.
33.2.5 OTHER APPROACHES
There is a variety of other approaches to thinking and
dealing with ethical dilemmas and issues. Feminism, for
instance, via feminist ethics, has led to the notion of care
ethics in which the importance of relationships is empha-
sized. Narrative ethics stresses the importance of the per-
son’s story: both our understanding of and participation in
it. Hermeneutic ethics stresses the importance of interpre-
tation in a given context. Communicative ethics suggests
that the right decisions will be made if the communication
has been effective and proper. Other approaches stress the
importance of rights, community, liberty, liberal individu-
alism and so forth. This is not the place to discuss all such
approaches in detail (Ashcroft et al., 2007), but they have a
number of things in common. They all variously stress the
importance of our interconnectedness, the importance of
social and cultural contexts, the ways in which we depend
upon each other as human beings engaged in practices in
the world (Hughes, 2011).
33.3 THE SPECTRUM OF ETHICAL
ISSUES IN DEMENTIA
Strech et al. (2013) conducted a systematic review of the
English and German literature and used qualitative textual
analysis to categorize the ethical issues that emerged in clin-
ical care. They found 56 specific ethical issues, which they
then divided into seven major categories. In this section, we
shall outline this spectrum of ethical issues.
33.3.1 DIAGNOSIS AND MEDICAL
INDICATION FOR TREATMENT
First, diagnosis might be made too early or too late. If people
are seeking a diagnosis and it is made too late they will be
denied services from which they might benefit. On the other
hand, it will not always be right to make a diagnosis too
early. With the appearance of mild cognitive impairment
(MCI) and the drive to make earlier diagnoses, in particu-
lar, to make the diagnosis before dementia starts, there are
potential harms to people from inappropriate labelling,
which would of course seem less concerning if there were a
real prospect of doing good. In order to make the diagnosis
at the appropriate time it will often be very important to
take into account the views and experiences of the family,
who can otherwise be ignored during the diagnostic process
(Nuffield Council on Bioethics, 2009).
Second, there is the risk that signs of illness will be dis-
regarded, which not only means that advance planning is
not possible, but again will often leave the relative without
support. Nevertheless, the psychological burdens associ-
ated with receiving a diagnosis have to be kept in mind.
Third, having made the diagnosis, proper consideration
needs to be given to treatment decisions. There should be no

overestimation of the effect of current drug treatment and
both the benefits and harms of any form of treatment need
to be weighed up. Once again, the views of relatives must
be kept in mind. Fourth, throughout all of this process, the
patient must be properly regarded as a person, with due
weight given to their preferences and to their wishes. That
is, there must be proper respect for autonomy.
33.3.2 DECISION-MAKING CAPACITY
People must be competent to make decisions; that is, they
must have decision-making capacity (see Chapter 30).
Different jurisdictions will have different legal frameworks
for assessing competence or capacity. But there are ethi-
cal issues around the assessment of capacity. For instance,
if someone lacks capacity it is important that they should
be supported in their decision making and not allowed to
make decisions that will be harmful. Complex decisions
about capacity will often be value laden. For instance, if a
person with dementia is admitted to a medical or surgical
ward and questions are raised about whether or not they
will be able to return home, a finding of incapacity makes it
more likely that they will end up in some sort of long-term
care institution (Poole et al., 2014).
33.3.3 INFORMATION AND DISCLOSURE
This brings us back to the question of lying. We need to
respect a person’s autonomy, but there are some things, per-
haps, that a person does not wish to know, so weighing up
how much they should be told will be ethically important.
Information can be given in a helpful or unhelpful manner:
how things are done is also an ethical issue. Once again, it
will often be important to involve relatives. There will also
be cultural issues that need to be taken into account where,
for instance, families are much more closely involved in the
older person’s care and decisions about them.
33.3.4 DECISION MAKING AND CONSENT
It is a matter of ethical importance that the person should be
helped to make decisions. For instance, the United Nations
Convention on the Rights of Persons with Disabilities states
in Section 12 that people with disabilities, which would
include dementia, should be on the same legal footing as
non-disabled people when it comes to assessments of capac-
ity and they should be supported in their decision making
(United Nations, 2008). But good decision making means
that the right circumstances must obtain. There must be
good relationships, with enough time and with the right
attitude to allow the person to make a good decision. The
UN Convention would, in any case, suggest that decisions
should not be made for the person, but instead the person
him or herself should be supported to make the decision.
Information from relatives is important, so there must be
good communication and the information must be handled
appropriately.
Ethical issues 341
If there has been some advance planning, then the role of
substitute decision makers, often the family, will be easier.
Otherwise, the families might feel decisions to be burden-
some. A possible bad ethical consequence of not making an
early enough diagnosis is that the person is unable to make
reasonable plans. But advance care plans, particularly where
these are specific and where they refuse treatment, need to
be considered and weighed very carefully from an ethical
point of view. If, for instance, someone has said that they
do not wish to receive antibiotics if they were to be in the
severer stages of dementia, it can be questioned how fully
thought through such a decision might have been: did the
person have a realistic appreciation of the effects of such a
decision? ‘Living Wills’ or advance directives will need to
be interpreted correctly and then the decision as to whether
or not they should be followed will require a good deal of
ethical consideration.
33.3.5 CONTEXT AND SOCIAL ASPECTS
We have already said that relatives and carers must be given
due consideration not least because of the stresses and
strains that they have to bear. The person with dementia,
in any case, should be seen as part of this broader social
context. When people with dementia are living together in
institutions, the risks associated with harm to them and
to others need careful assessment and, at the same time,
the professionals involved in looking after them will need
support. At the societal level, the issue of the allocation of
limited resources is also important. This might impinge
on diagnosis, where certain forms of neuroimaging can be
expensive, but can also have an impact on pharmacological
and non-pharmacological treatments.
33.3.6 THE PROCESS OF CARE
Throughout the trajectory of the dementia it is important
that people are assessed to make sure that everything is being
done to maximize the benefits and minimize the harms of
any interventions. On the whole, it seems important to sup-
port people with dementia to allow them to live as indepen-
dently as possible and to be active in making decisions about
their care, as well as to keep them in a dignified state. The
process of care will often involve talking to relatives, but this
should not be to the exclusion of the person with dementia
him or herself. There will sometimes be conflicts in terms of
the interests or values of the person with dementia and his or
her family or close friends. Professional and non-professional
carers will require continuing education to allow them to ful-
fil their roles. This is also likely to decrease the risk of abuse
and neglect. All of these are clearly ethical issues.
33.3.7 SPECIFIC SITUATIONS
There are, in addition, a number of specific ethical
situations that arise during the course of dementia
(see Foster et al., 2014). First, driving can be a very emotive
342 Dementia
issue. On the whole, people should be allowed to drive as
long as possible, but the safety of others cannot be compro-
mised. Once again, how the person is told that they should
not drive and whether or not this involves specific assess-
ments are ethical issues of note.
Second, sexual relationships in the context of dementia
can cause considerable ethical concern. This is particu-
larly the case in care homes. Care home staff sometimes
have to deal with sexual disinhibition. In addition, the
person with dementia may forget that he or she has ever
been married and attachments may form with other resi-
dents. On occasions, these attachments can become quite
intimate and sexual. It is clearly important to think about
safety and often the issue that emerges is to do with one
or other partner’s capacity to consent to the sexual behav-
iour. While this is important, it is also equally important
that intimacy should be seen as part of the human condi-
tion. It is a manifestation of friendship and it would be a
good thing to encourage friendships within the commu-
nity of a care home.
Third, the issue of genetic testing frequently raises its
head in connection with dementia. The standard advice is
still that genetic testing should not be offered on a routine
basis. However, there may be particular indications when it
is more reasonable for genetic testing to take place. A very
strong history of early onset dementia, for instance, might
make genetic testing seem imperative, as would a particular
condition such as Huntington’s disease.
Fourth, the debates about the use of global positioning
systems and other forms of electronic monitoring, or indeed
the use of robots, remains a burning issue. Arguments
against electronic monitoring are often couched in terms
of the restrictions of liberty that these systems allow. Some
people have argued, however, that the bigger consideration
is the risk that technology may decrease the chances of and
necessity for real human contact.
Fifth, technological improvements, such as more accu-
rate brain imaging and tests of the cerebrospinal fluid (CSF),
mean that issues arise not only about resource allocation
and earlier diagnosis but also about the exact meaning of
any particular finding for the individual.
Sixth, in some countries physical restraints are still used.
Sometimes these are not seen as restraints, where people are
put in chairs from which they cannot arise. But any form of
restraint will raise ethical questions.
Seventh, covert medication, where medication is put into
drinks or food, often seems to be necessary, but is neverthe-
less a restriction of the person’s ability to make autonomous
decisions about their lives and clearly raises important ethi-
cal issues.
Eighth, there has been a huge debate about the use of anti-
psychotic drugs to control agitated or aggressive behaviour
in people with dementia. It is largely agreed that the more
appropriate approach should be to think of psychosocial
interventions that will be helpful in behaviours that others
find challenging. But on occasions antipsychotic medica-
tion seems the best option, although again an ethical (and
clinical) judgement will be required concerning whether
this is so.
Finally, there are a number of issues to do with the end
of life that arise in dementia care (see Chapter 34). These are
often about withholding or withdrawing treatment, e.g. in
connection with the use of antibiotics in severe dementia or
the use of artificial nutrition and hydration. A general ethi-
cal doctrine, which is often useful in thinking about issues
such as tube feeding and withholding or withdrawing
treatments, is that of ordinary and extraordinary means.
In brief, this suggests that we are only morally obliged to
provide ordinary care. This means that extraordinary care
can be given under particular circumstances, but this is not
a moral obligation. ‘Extraordinary’ is defined in terms of
whether the treatment is likely to be effective and whether
or not it is likely to be burdensome to the person and/or
his or her family. If a treatment, such as cardiopulmonary
resuscitation, is unlikely to be effective and is likely to be
burdensome, then there is no moral obligation to under-
take it.
33.3.8 SUICIDALITY
There is increasing pressure in some countries to consider
euthanasia or physician-assisted suicide. This is sometimes
put forward as a way to respect the person’s autonomy. But
broader issues to do with the effects of permissive laws must
also be considered. It seems better, in any case, to emphasize
the possibility that people with dementia can live well rather
than offer the option of death as a way, perhaps, to avoid the
difficulties of providing good quality care for people with
dementia.
Another ethical issue that arises in connection with
suicide in dementia is just the worry that the diagnosis
itself will induce suicidal wishes. The literature around
the possibility of rational suicide once again stresses the
importance of assessments of capacity. There is the fur-
ther concern that some of the motivation towards suicide
will be the stigma that surrounds dementia. Hence, there
is an ethical requirement that we should look at ways in
which we might improve the well-being of people with
dementia.
33.4 CONCLUSIONS
Having sketched the spectrum of ethical issues that arise
in the context of dementia based on a review of the litera-
ture, there is still a question about how in practice ethical
decisions are made. We have already seen that the notion
of therapeutic lying can be judged in different directions
using different ethical theories. The same will apply to
some of the other ethical approaches discussed above.
But if we take any of the particular ethical issues that we
have raised in this chapter, it will always be the case that

judgements must look at concrete circumstances. The
importance of context, of the relationships within that
context, as well as a proper understanding of the nar-
rative surrounding the individual, will always be essen-
tial to any particular moral or ethical judgement. These
judgements will require immersion in the details of the
particular case that must then be followed by the applica-
tion of what seemed to be the appropriate moral theories
or approaches. It should be possible to give justifications
for the use of any particular moral theory, to show why it
seems to be more or less relevant. This process is known
as casuistry. It is the process of looking at things case by
case. It was recommended as part of the ethical frame-
work in Dementia: Ethical Issues (Nuffield Council on
Bioethics, 2009). Casuistry has also been discussed in an
earlier edition of this volume (Louw and Hughes, 2005).
The emphasis on context, however, which means that dif-
ferent theories or approaches may seem more or less per-
tinent to different cases, suggests that what is regarded as
right or wrong demands some sort of higher justification.
There are different views about this, but one approach to jus-
tification is to consider the notion of coherence. (An alter-
native is to look for the foundations of a particular ethical
theory to find some basic principle, which will then govern
and justify everything that follows. But this is practically,
as well as theoretically, difficult.) Coherentism suggests
that our beliefs and the judgements we form on the basis of
our beliefs should cohere. That is, we must have a coherent
approach to the ways in which we deal with individual ethi-
cal problems.
One final suggestion, therefore, is that when any particu-
lar decision does not cohere with our other beliefs, this is
when our moral sense comes into play. Moral sense or moral
intuition are not particularly fashionable ideas because
they raise the problems recognized hundreds of years ago
in connection with conscience being the basis of moral
theory. Nevertheless, a through and through conscientious
approach to the ethical dilemmas and problems that arise
for people with dementia and for their carers would not be
a bad place to start.
Ethical issues 343
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Beauchamp, T.L. and Childress, J.F. (2001). Principles
of Biomedical Ethics, Fifth Edition. Oxford, United
Kingdom: Oxford University Press.
Culley, H., Barber, R., Hope, A. and James, I. (2013).
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Foster, C., Herring, J. and Doron, I. (eds.) (2014). The Law
and Ethics of Dementia. Oxford, United Kingdom: Hart
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Accessed 30 November 2014.

End-of-life and palliative care in dementia
JULIAN C. HUGHES AND JENNY T. VAN DER STEEN
34.1 INTRODUCTION
A philosophical question that arises in connection with
dementia is when should end-of-life or palliative care
begin? In the popular mind, palliative care is associated
with dying. So palliative care begins when the person
is dying, but when is that? These are both practical and
conceptual problems. They are even more pointed when
it comes to dementia. For dementia is a condition that is
variable in both its nature and progression. We can stipu-
late that end-of-life care in dementia refers to the last 6
or 12 months of life. But why should this be the case? The
person with dementia may be quite active 5 months before
he or she dies. We could, alternatively, stipulate that end-
of-life care refers only to the last few hours or days. But
this would then ignore all those decisions – about artificial
nutrition and hydration, the use of antibiotics or cardio-
pulmonary resuscitation – which are about end-of-life and
are often much better made well before the last few hours
or days. It makes much more sense, therefore, to extend
the concept of end-of-life backwards; in which case, it is
more natural to speak of palliative care.
In this chapter, we wish to take a broad view of pallia-
tive care. But the notion of palliative care in the context
of dementia is not clear. For this reason we undertook a
Delphi study involving 64 experts from 23 countries to
define a set of domains (11) and recommendations (57),
which together define optimal palliative care at least in
older people with dementia (van der Steen et al., 2014).
In the remainder of the chapter, we shall discuss pallia-
tive care and end-of-life decisions using the 11 domains
derived from the study.
344
34
34.2 THE APPLICABILITY OF THE
PALLIATIVE CARE MODEL
Most of the domains and recommendations of the Delphi
study were quickly and unanimously accepted by the
experts consulted. But the notion that palliative care is
applicable to dementia was one area where consensus was
only moderate rather than full. It is easy to understand
why. Does it not seem inappropriate, when a person is still
fairly fit, even if he or she has forgetfulness and other mild
problems, to say that the person requires palliative or end-
of-life care?
First, almost all dementias are progressive; second, they
are life-shortening. Our view is that facing the reality is
likely to improve care. It can do this in three ways. First, the
perspective of palliative care may make treatment decisions
more appropriate: what can be cured should be cured, but
sometimes the aim should be simply to maintain the person’s
functional level as opposed to cure. Second, once healthcare
professionals have it in mind that the person has a terminal
disease, when the time is right they may be more likely to
attend to important end-of-life issues, such as pain relief and
other ways to improve comfort. Finally, the palliative care
perspective is more likely to encourage appropriate advance
care planning.
In any case, the palliative care approach is always going
to be applicable to chronic and progressive diseases and
all professionals should be aware of its main tenets. The
holism of palliative care is no different from the holism of
good quality dementia care and both aim at overall quality
of life. Both approaches require attention to the biological,
psychological, social and spiritual aspects of care, which

includes involving the family and close carers in decisions.
Specialist palliative care may only be required if symptom
control is complex. The alternative notion of ‘supportive
care’ is broader still and may answer some of the concerns
expressed about ‘palliative care’ (Hughes et al., 2010).
34.3 PERSON-CENTRED CARE,
COMMUNICATION AND SHARED
DECISION MAKING
In the field of dementia we are very used to thinking about
the notion of person-centred care (Kitwood, 1997). But
person-centred care is also central to palliative care. To
understand the full impact of person-centred care, it is
necessary to have a broad view of what it is to be a per-
son (Hughes, 2011). Thus, we should regard the person as
situated in a context that involves other people, especially
close family and other carers. Good communication with
all involved will be essential, but it becomes more diffi-
cult over time; so efforts must be made to keep the person
involved. His or her currently expressed preferences must
be given due attention, but so too must the person’s pre-
viously expressed preferences (advance decision-making
is discussed in Section 34.4). This sort of weighing-up of
different aspects of the person’s life will be very impor-
tant when it comes to making decisions. Decision making
should, when feasible, be shared and the person (and/or
the ­family) involved as much as possible.
34.4 SETTING CARE GOALS AND
ADVANCE PLANNING
If early on in the disease the person is able to set out explic-
itly what they would like care to aim at, this can help treat-
ment decisions later. The benefits of advance care planning
are numerous. They allow the person to continue to man-
age his or her affairs while still able to do so. An advance
care plan also ensures that, insofar as possible, the per-
son’s wishes will be met in the future, which should bring
some peace of mind and decrease the burden on loved ones
and on the family who may otherwise have conflicting
views. Conversations about how and the extent to which
life should be prolonged are difficult and sensitive. So one
advantage of advance care planning is that these topics
arise and are given some consideration at a point where
the person is able to participate. It remains true that the
evidence that advance care planning is effective is fairly
sparse, but the process of advance care planning might in
itself be useful, even if specific items in the advance care
plan are not or cannot be met.
Advance care plans will have to be revisited with both the
patient and with the family on a regular basis and especially
when there are significant changes to the person’s health.
End-of-life and palliative care in dementia 345
It may be that eventually the person with dementia cannot
join in these discussions, but every effort should be made
to help them to participate. Indeed, the United Nations
Convention on the Rights of Persons with Disabilities specifi-
cally says that people should be supported in their decision
making (United Nations, 2008). They should certainly not
be disadvantaged on account of their disabilities. Finally,
advance care plans must be stored in a way that allows ready
access when they are required.
The aim with all such measures is to avoid inappropri-
ate interventions. What makes them ‘inappropriate’ is that
they would not be the investigations or treatments that the
person himself or herself would have wished for. In other
words, advance planning is part of person-centred care.
34.5 CONTINUITY OF CARE
People with dementia and their carers are often keen to have
continuity of care, which brings numerous advantages. It
makes communication much easier and much less frustrat-
ing for families if they are not having repeatedly to start
afresh. In particular, if the person with dementia moves into
long-term care, it can be annoying and upsetting if all the
previous relationships with health and social carers simply
stop. Yet, it may not always be possible for exactly the same
staff to be involved over the full course of the person’s demen-
tia. If this is the case, then there should at least be attempts
to make any transfers from team to team as smooth as pos-
sible. Particularly important as the end-of-life nears, moving
the person between teams may well be detrimental and is less
than supportive for the family too.
How continuity can be maintained is a challenge. If it
is not possible for a single person to co-ordinate or over-
see care throughout the trajectory of the dementia, a sense
of continuity may be maintained through careful transfer.
Some have suggested the possibility that teams or networks
of care might be virtual in that they need not exist as single
entities in a particular place (Hughes et al., 2010). However
continuity of care is achieved, the purpose is to provide a
relationship that will be sustaining for the person and his or
her close family and carers.
34.6 PROGNOSTICATION AND
TIMELY RECOGNITION OF DYING
It will always be difficult to know when and how to raise
the subject of death and dying. Talking about less traumatic
aspects of advance care planning, such as financial planning,
might start relevant conversations. It would have to be made
clear that prognostication in dementia is a challenge and that
death cannot be predicted with any accuracy. There are tools
that can help to predict mortality, however, once again with-
out accuracy. Loss of the ability to pursue activities of daily
346 Dementia
living, pneumonia, problems with food and fluid intake are
all found (more or less) to predict death. The lack of predict-
ability emphasizes that honest discussions are required early
on in order that end-of-life decisions can be as true as possible
to what the person would have wanted.
34.7 AVOIDING OVERLY AGGRESSIVE,
BURDENSOME OR FUTILE
TREATMENTS
It is often said, for good reasons, that acute hospitals are
unsuitable places for people with dementia. This is particu-
larly the case as the dementia becomes more advanced. In
general, survival is shorter for patients with dementia com-
pared with those without but who have strokes, hip fractures
and pneumonias. Decisions need to be made keeping in mind
the goals of care and the stage of the person’s dementia. The
person’s confusion may well worsen once transferred to hos-
pital and the risk of delirium is relatively high. Meanwhile,
staff in general hospitals are not always able to deal with the
specific problems of people with dementia.
Not only is hospital admission burdensome and some-
times futile for people with dementia, but polypharmacy,
that is where people are on multiple drugs, can also be bur-
densome because of the side effects of drugs as well as their
interactions. Many people with dementia will also have
co-morbidities, such as high blood pressure, heart disease,
diabetes and osteoporosis, which means that they will be on
a variety of drugs. This becomes more difficult for them if
they start to develop swallowing problems. For all of these
reasons, therefore, the goals of care should be clear.
In the early stages of dementia it is entirely reasonable,
depending on the person’s general physical state, to think
in terms of prolonging life. But when the person is nearing
the end-of-life, the use of drugs such as statins to lower cho-
lesterol levels becomes much more questionable. The same
is true of drugs that are aimed at maintaining the person’s
current functioning once patients are severely impaired.
Drugs that are intended to keep the person comfortable
should continue. Even then, the drugs will need to be moni-
tored. For instance, laxatives to prevent constipation can
cause diarrhoea, and drugs for pain may sedate the patient
or give them constipation, so should only be used when
pain is present (which is not, however, to condone under-­
treatment, as we discuss below).
The issue of artificial nutrition and hydration was another
area where the consensus of the experts in the Delphi study
was only modest rather than full. Worries about dehydra-
tion are, of course, very real in older people with dementia.
Dehydration can affect survival in pneumonia, but it also
affects the rate of healing of wounds such as ulcers. Once
someone is actually dying, however, the requirement for
hydration diminishes and eventually disappears. Avoiding
dryness of the mouth is still a priority for the sake of comfort,
but using subcutaneous rehydration or intravenous hydration
near to death is pointless and may lead to complications such
as fluid overload, which stresses the heart and can cause pul-
monary oedema. Such issues need to be dealt with in a sensi-
tive manner to reassure family and close friends.
Tube feeding is similarly an issue. A number of observa-
tional studies have shown that tube feeding does not affect
survival in dementia when it is compared to hand feeding.
There are, however, possible complications to tube feeding. It
also seems as if feeding people by hand, even when there is the
risk of aspiration and consequent pneumonia, can increase
much needed social interaction. Once again, communication
with all concerned is absolutely vital if decisions are being
made to stop feeding. Still, nutrition earlier in dementia
remains important because avoiding significant weight loss
will help with, for instance, skin integrity later in the disease.
The use of antibiotics is complicated in dementia (van der
Steen et al., 2011). They are, of course, necessary in the symp-
tomatic treatment of conditions such as urinary tract infec-
tions. But some urinary tract infections are chronic and, if
they are asymptomatic, do not always require treatment.
There is conflicting evidence about the use of antibiotics to
relieve symptoms in pneumonia. They can be used with cura-
tive intent, if this is an appropriate treatment goal, but they
are also sometimes used in a palliative way; for instance, to
decrease the stickiness of secretions, even where there is no
real hope of cure. The tendency for older people with dementia
to have recurrent episodes of infection is commonly observed.
It is a matter of delicate clinical judgement, albeit prognostic
scores can be helpful, as to whether any particular infection is
the one that will cause the demise of the patient rather than
simply make them unwell for an extended period of time.
34.8 OPTIMAL TREATMENT AND
PROVIDING COMFORT
We know that people with dementia, especially in the
severer stages, have symptoms that are not dissimilar from
those of people dying from cancer. Many will suffer from
pain, shortness of breath and agitation or restlessness. One
of the reasons for emphasizing the need for palliative care
in people with dementia is because many of these symptoms
are underdiagnosed and undertreated. Agitation, which is
counted as one of the behavioural and psychological symp-
toms of dementia (BPSD), may have a variety of causes, one
of which is pain, but it could also be caused by anxiety or
frustration. Therefore, broad and rigorous assessments are
required. Depression, too, is a form of BPSD, which can
itself cause irritable or agitated behaviour. It is reasonable,
therefore, to consider trials of analgesics or antidepres-
sants when the behaviour of people with dementia changes.
Distinguishing between sources of discomfort or distress
in severe dementia is of paramount importance if the cor-
rect management is to be pursued. It will often be helpful
to speak with those who know the person very well, either
family or those providing day-to-day care.

There is now a variety of tools to assess putative pain
in people with dementia. On the whole, they are not well
validated. A general worry with pain scales is that they do
not solely pick up pain, but actually pick up distress given
that there is no particular symptom or sign that is pathog-
nomonic of pain (Jordan et al., 2012). It is true, nonetheless,
that these scales may be useful, once a clinical diagnosis of
pain has been made, as a means to monitor the effective-
ness of treatment. If used for screening, such scales must be
combined with an adequate physical examination and pain
history. The gold standard, therefore, remains a thorough
clinical assessment, which will involve taking a history
from the person if this is possible, their family and carers, as
well as reviewing notes and carrying out observations and a
proper examination.
The first line of treatment for BPSD, however, should
almost always be non-pharmacological treatments and
psychosocial interventions. Simply sitting with a person to
give them comfort may help to alleviate symptoms. The evi-
dence in favour of many of the psychosocial interventions
has been weak, but is showing signs of strengthening, with
some encouraging findings emerging.
In the terminal stages in particular, the person with
dementia needs expert nursing care with a lot of attention
being paid to positioning in order to avoid pressure sores
and ulcers, along with moistening of the lips. When the per-
son is incontinent, regular washing and changing will be
important to protect the perineal area. A variety of environ-
mental measures, which are also psycho-social in nature,
including Snoezelen, music, warmth and pleasant aromas
may also help to keep the person calm.
At the very end of life more specialist palliative care may
be required. Often, if the person is dying solely from demen-
tia, death may be quite peaceful without the need for medical
intervention other than good nursing care. But sometimes
people with dementia are dying from other conditions, so
that relief of their symptoms is more complex and requires
specialist intervention. Syringe drivers, for instance, are not
always readily available in people’s homes or in care homes,
but specialists in palliative care may be able to provide both
the technology and know-how to enable the person to die
comfortably where they have lived rather than to require a
move to a hospital or hospice.
34.9 PSYCHOSOCIAL AND SPIRITUAL
SUPPORT
Emotional support is going to be of great importance
throughout the course of dementia, from the mildest stages
to the most severe. To be holistic, this must include emotional
support for the family and for the carers of the person with
dementia. Proper holistic support will include attention to
spiritual matters. There should be an assessment of the per-
son’s religious affiliations and involvement in order to seek
out the best means of providing spiritual support. Enlisting
End-of-life and palliative care in dementia 347
the help of faith leaders will often be of benefit not only to
the person with dementia, but also to his or her family and
close carers. It has often been observed that rituals and sym-
bols of great familiarity have helped to bring some comfort
to people with dementia who have held religious beliefs and
they might, too, prove helpful to close friends and family.
34.10 FAMILY CARE AND INVOLVEMENT
The holistic approach of palliative care always involves the
family and those close to the person concerned. Once again,
this is a way of recognizing the situated nature of the per-
son who is always embedded in a family as well as in a cul-
ture and particular social context (Hughes, 2011). Because
of these intimate bonds, families will often experience
caregiver burden. It is important to note that the support
required by families continues throughout the trajectory
of dementia. Addressing the specific needs of families dur-
ing these stages of dementia requires awareness, but also
resources. Families differ, of course, but some will wish to
stay very involved even when the person with dementia is
moved into long-term care. The family will often act as the
proxy decision maker for which they will require support.
Some of the carer burden may actually be ethical burden in
that close family carers may feel as if they are being required
to make quite difficult ethical decisions. Education and sup-
port, therefore, are vital.
It should not, however, be thought that all carers find
caring to be a burden, since some describe positive aspects
in terms of the insight and understanding that they acquire
through the journey of caring for someone they have loved.
Nevertheless, as the person fades, families will often suf-
fer symptoms of bereavement even before the person has
died and families should continue to receive support.
Complicated grief reactions are more likely in those carers
who have been heavily involved in care, or have high levels
of depressive symptoms prior to the death of the person for
whom they are caring, or where they have been caring for
somebody with more severe cognitive impairment.
34.11 EDUCATION OF THE
HEALTHCARE TEAM
If palliative care is to be provided effectively, it will require
a team effort. This means that training across all those
involved in palliative care for people with dementia will
be required on an ongoing basis. Palliative care specialists
will need to learn more about dementia and dementia care
specialists will need to know more about palliative care.
Meanwhile, those who work in institutional settings will
also require the skills to recognize when people are deterio-
rating and when they might be developing symptoms that
require palliative interventions.
348 Dementia
34.12 SOCIETAL AND ETHICAL ISSUES
Both palliative and dementia care specialists tend to be
attuned to ethical issues, which arise in the context of holis-
tic care (see Chapter 33).
One broader societal issue is that palliative care should
be available to people with dementia wherever they live,
whether in their community, in residential care or in an
acute hospital. Support should also be available for fami-
lies in all of these settings. The provision of palliative care
throughout the course of dementia and wherever the per-
son is residing will be facilitated when there is good col-
laboration between dementia health and care services and
specialist palliative care services. Close working between
teams will be beneficial for all concerned. But the commit-
ment to this must start early with specific training for both
physicians and for nurses at undergraduate and postgradu-
ate level to include palliative care for patients with illnesses
other than cancer. Given the challenging nature of this work
and the increase in the prevalence of dementia, there should
be systemic economic incentives to encourage excellence in
palliative and end-of-life care for people with dementia.
The issues that professionals and families face in connec-
tion with palliative care for people with dementia also need
to be given a higher profile in a way that will encourage the
general public to be more supportive of individuals and fami-
lies who live with dementia. This is in keeping with the notion
of solidarity, which was emphasized in the report Dementia:
Ethical Issues (Nuffield Council on Bioethics, 2009).
34.13 CONCLUSION
Palliative care for people with dementia is not optional. It
is essential. The needs of people with dementia, especially
in the moderate to severe stages of the disease, are about
as complex as any that face health and social care profes-
sionals. The issues of pain and distress in severe dementia,
where the person is unable to convey information about the
potential causes of his or her symptoms or signs, are them-
selves complex and require specialist help at times. This
help may come from dementia specialists, but may also
come from palliative care where the concerns are about
the possibility of pain and its management. Especially at
the end of life, when the person is finally dying, dementia
care and palliative care must in one way or another come
together.
The inspiration behind palliative care is, of course, the
work of Dame Cicely Saunders who established the first
modern hospice, St Christopher’s in London, which opened
in 1967. In the realm of dementia care we should be able
to say to people with dementia, as Dame Cicely Saunders
said: ‘You matter because you are you. You matter to the
last moment of your life, and we will do all we can to help
you not only to die peacefully, but also to live until you die’
(Saunders, 2006, p.137).
REFERENCES
Hughes, J.C. (2011). Thinking through Dementia. Oxford:
Oxford University Press.
Hughes, J.C., Lloyd-Williams, M. and Sachs, G.A. (eds.)
(2010). Supportive Care for the Person with Dementia.
Oxford: Oxford University Press.
Jordan, A., Regnard, C., O’Brien, J.T. and Hughes,
J.C. (2012). Pain and distress in advanced demen-
tia: Choosing the right tools for the job. Palliative
Medicine, 26: 873–878.
Kitwood, T. (1997). Dementia Reconsidered: The Person
Comes First. Buckingham: Open University Press.
Nuffield Council on Bioethics (2009). Dementia: Ethical
Issues. London: Nuffield Council on Bioethics.
Saunders, C. (2006). Cicely Saunders. Selected Writings
1958–2004. Oxford: Oxford University Press.
United Nations (2008). UN Convention on the Rights of
Persons with Disabilities. Accessed 30 November
2014. Available at http://www.un.org/disabilities/­
convention/conventionfull.shtml.
van der Steen, J.T. (2011). Prolonged life and increased
symptoms vs prolonged dying and increased comfort
after antibiotic treatment in patients with dementia
and pneumonia. Archives of Internal Medicine, 171:
93–94.
van der Steen, J.T., Radbruch, L., Hertogh, C.M.P.M. et al.,
on behalf of the European Association for Palliative
Care (EAPC) (2014). White paper defining optimal
palliative care in older people with dementia: A Delphi
study and recommendations from the European
Association for Palliative Care. Palliative Medicine,
28: 197–209.

Advanced dementia and care at the end of life
KIRSTEN MOORE AND ELIZABETH SAMPSON
35.1 INTRODUCTION
Dementia is now more commonly understood to be a
terminal condition and, as such, has been identified as one
where a palliative care approach may be beneficial (Connor
and Bermedo, 2014; van der Steen et al., 2014). A growing
number of deaths are attributable to dementia and it is now
the fourth highest cause of death in high income coun-
tries (World Health Organization, 2014). However, it is still
under-recognized as a cause of death on death certificates
(Wachterman et al., 2008). In addition, a review of dementia
strategies from 14 countries found that 8 did not refer to
palliative care (Nakanishi et al., 2015). While recognition
of the need for a palliative approach is growing, there is still
limited research evidence to this approach in dementia care.
This chapter begins with an overview of the com-
mon symptoms that occur during the advanced stages of
dementia followed by a discussion of the difficulties associ-
ated with identifying end of life in dementia and the chal-
lenges of planning for end-of-life care. The third section
will discuss comfort care and holistic care and how the
goals of care change during the advanced stage of disease.
The final section highlights the importance of working
with family members as those who have knowledge and
insights into the person with dementia but also as those
who may be experiencing a prolonged period of pre-death
grief as they witness the multiple losses of the family mem-
ber they have known before the onset of dementia.
35.2 WHAT IS ADVANCED DEMENTIA?
There are numerous validated questionnaires that have
been developed to assess the severity of dementia. The
Functional Assessment Staging (FAST) focuses on function
and requires a proxy to rate the level of disability on a scale
ranging from no difficulties through to loss of ability to
35
hold up head independently (Reisberg, 1988). The Global
Deterioration Scale (GDS) uses a similar approach to stages
of disease progression but incorporates both cognitive and
functional abilities (Reisberg et al., 1982). The Bedford
Alzheimer Nursing Scale – Severity Subscale (BANS-S)
assesses severity in dementia of the Alzheimer type by incor-
porating cognition, activities of daily living and appearance
of pathological symptoms (including sleep wake cycle dis-
turbance and contractures) (Volicer et al., 1994).
These are mainly research tools, however, and in day-to-day
care the advanced stages of dementia are defined by depen-
dence in all care, limited speech, extreme apathy, incontinence
and difficulties with chewing and swallowing and increased
occurrence of infections (Forstl and Kurz, 1999). Management
of other co-morbidities may become difficult as the person
may not be able to agree to various procedures or medications.
The reduced ability to communicate during advanced demen-
tia creates challenges to identifying physical and psychosocial
needs, such as pain, hunger, boredom or loneliness.
Table 35.1 shows the common symptoms for people with
dementia towards the end of life. Vandervoort et al. (2013)
considered symptoms associated with end of life according
to dementia severity. In their sample of nursing home resi-
dents who died, 54% had very severe/advanced dementia,
28% had severe dementia and 18% had mild or moderate
dementia. Occurrence of pneumonia and febrile episodes
in the last month did not differ between stages of dementia,
although choking, swallowing difficulties, incontinence and
dehydration during the last week were higher for those with
more advanced dementia.
35.3 IDENTIFYING AND PLANNING
FOR THE END OF LIFE
The experience of end of life at different stages of dementia
may be similar (Vandervoort et al., 2013) and only 41% of
long-term care residents who die with dementia have reached
349
350 Dementia
Table 35.1 Common end-of-life symptoms and needs in dementia
Study and method
Longitudinal prospective study of 323 U.S. nursing home
residents with advanced dementia. 55% died during the
18-month period of the study (Mitchell et al., 2009)
Retrospective study of 198 Belgium nursing home residents
with dementia at any stage (Vandervoort et al., 2013)
Systematic literature review (Potter et al., 2013)
the advanced stages of disease (van der Steen et al., 2013b).
During the advanced stages, however, quality of life is gener-
ally very low. At this point, the goals of care tend to shift from
active treatments to a palliative and comfort approach (van
der Steen et al., 2014). As dementia may progress very slowly,
it can be difficult to identify a point in time when someone
shifts from moderate-to-severe dementia. This may be pre-
cipitated by a sentinel event such as a fall or it may be a slow
gradual process over months or years. While it may be helpful
to inform families of when end of life is nearing, prognostic
tools have only shown modest results in predicting end of life
(Mitchell et al., 2010).
One of the difficulties of estimating survival is that
there may be multiple causes of death, and events that
can cause final death may also respond to treatment.
For example, while people with dementia are more than
twice as likely to die with pneumonia than those with-
out dementia (Foley et al., 2014), they may also respond
to treatment so that their health temporarily stabilizes.
However, as the underlying causes of the pneumonia,
such as dysphagia, are likely to remain, the risk of devel-
oping pneumonia again is high. The broader concept of
frailty is relevant here as the cumulative effect of declines
in multiple body systems may increase the likelihood of
death (Fried et al., 2004).
Common end-of-life symptoms and needs (%)
Last 3 months:
• Eating problems (90)
• Pneumonia (37)
• Febrile episodes (32)
• Dyspnoea, pain, pressure ulcers and aspiration all
increased towards the end of life
Last month:
• Most common symptoms: pain, fear, anxiety
• Pneumonia (32)
• Febrile episodes (43)
• Eating problems (66)
Last week:
• Urinary incontinence (89)
• Faecal incontinence (86)
• Dehydration (39)
• Decubitus (27)
• Requires assistance for daily tasks, self-care and
continence
• Eating and feeding difficulties
• Reduced mobility and posture
• Contractures
• Persistent agitation and withdrawal
• Recurrent infections
• Inability to recognize familiar people and things
One of the goals of comfort care is to avoid burdensome
interventions that may increase distress and pain yet may not
create any substantial increase in quality of life or life expec-
tancy. Burdensome interventions, however, are still common
in advanced stages of disease. Mitchell et al. (2009) identified
that 41% of nursing home residents with severe dementia had
a burdensome intervention in the last 3 months of life. These
most commonly included parenteral therapy (29%), being
hospitalized (12%) and being tube fed (7%).
Comfort care aims to minimize pain, agitation and dis-
tress with an overall goal of maximizing quality of life. In
advanced dementia and end-of-life care a holistic, interdis-
ciplinary approach with individualized care plans provide a
sound basis for assessing needs and planning and providing
care (Kovach et al., 1996; Hall et al., 2011). An integrated
approach involving a care coordinator who provides a sin-
gle point of contact for families and ensures that plans are
followed and kept relevant also appears to be critical for
improving end-of-life care (Elliott et al., 2014). A person-
centred approach to end-of-life care encourages meeting
the goals and wishes of the person with dementia; however,
identifying these goals during the advanced stages can be
difficult and reliance on proxy decision makers or prefer-
ences documented by the person when they still had capac-
ity may be required.

35.4 ADVANCE CARE PLANNING
Advance care planning (ACP) involves informal discus-
sions and may include formal documentation of decisions
about future and end-of-life care while the person still has
capacity. Making plans for the future may involve legally
appointing someone to act as a proxy decision maker for
when the person with dementia no longer has capacity.
Although the legal terms and roles differ across juris-
dictions, the role is often called an Enduring or Lasting
Power of Attorney. During the early stages of dementia,
people may still have capacity to record decisions about
their future care, such as whether or not and under what
circumstances they would want certain interventions such
as cardiopulmonary resuscitation (CPR), artificial feeding
or hydration and mechanical ventilation. ACP offers an
opportunity for people with the early stages of dementia to
express their values and preferences to the health profes-
sionals and family members who are likely to be making
future decisions on their behalf.
While ACPs appear a promising way of ensuring the
wishes of the person with dementia are followed, there are
many challenges to implementing ACP and evidence of
effectiveness is modest. A systematic review of ACP inter-
ventions only identified four studies, all of which were
conducted in nursing home settings where the majority of
residents lacked capacity to participate in ACP discussions
(Robinson et al., 2012). The review concluded that there was
limited evidence of benefits for residents, although there
appeared a reduction in inappropriate hospital admissions
(Robinson et al., 2012).
Families report numerous obstacles to discussing
future care with their relative during the early stages of
dementia such as not recognizing the importance of ACP
until it was too late, actively avoiding the discussion, feel-
ing that the personality of the person with dementia was a
barrier to the discussion or that the person with dementia
was in denial of their diagnosis (Hirschman et al., 2008).
Hirschman et al. (2008) also found that family carers
regretted not having had these discussions earlier and not
having had more specific discussions about topics such as
medications and tube feeding. They also found that law-
yers, accountants and health professionals played a key
role in initiating discussions about future plans and care
(Hirschman et al., 2008). Religious beliefs, education, feel-
ings of guilt, carer burden and negative assumptions about
quality of life can influence family carers’ decisions about
end of life and may prevent a family member being able to
make best interest decisions regarding their relative’s care
(Dening et al., 2011).
Professionals involved in working with people in pal-
liative and dementia care also describe numerous obstacles
to implementing advance care plans including when and
who was responsible for instigating discussions, planning
for all possible scenarios, concerns about the terminology
used and the applicability of various documents in different
Advanced dementia and care at the end of life 351
settings (Robinson et al., 2013). Health professionals and
patients tend to be hesitant to initiate end-of-life discussions
during consultations (Almack et al., 2012). Professionals
also queried the usefulness of ACPs given patient’s prefer-
ences were not always able to be fulfilled, such as wishing to
remain at home (Robinson et al., 2013).
Few studies have obtained the views from people with
early stages of dementia about future care preferences. Some
studies have looked at hypothetical scenarios to investigate
how older people might make decisions about their future
healthcare. Gjerdingen et al. (1999), found that most older
people would not want burdensome interventions such as
CPR, tube feeding, hospitalization or antibiotics during
advanced dementia. Low et al. (2003) interviewed nursing
home residents without dementia about interventions they
would want if they had advanced dementia and recurrent
pneumonia. The majority wanted antibiotic treatment and
hospitalization but only a quarter would agree to artificial
feeding. A study involving people with mild dementia who
had capacity to participate in a discussion on ACP found
that they had difficulty envisaging their future selves and
the possibility of being more dependent on others (Dening
et al., 2013). Even during the early stages, people with
dementia may struggle to think about and plan for possible
future situations.
Often ACPs include consideration of CPR. CPR in
people with advanced dementia is unlikely to be success-
ful (Cooper et al., 2006), is an undignified way to die and
is undertaken with a high risk of multiple rib and ster-
num fractures (Lederer et al., 2004). Studies investigat-
ing hypothetical scenarios of whether people would want
CPR or mechanical ventilation if they had dementia show
mixed responses (Westenhaver et al., 2010), although
video education and experience of having a relative with
dementia may increase the likelihood of people choosing
comfort care over life prolonging treatment (Volandes
et al., 2007).
35.5 PLACE OF END-OF-LIFE CARE
While most people with dementia tend to die in a residen-
tial care setting (see Table 35.2), there is very little known
about the preferences of people with dementia and their
family about preferred place of death (Badrakalimuthu and
Barclay, 2014). International comparisons also show large
differences across countries in location of death and this can
be partly explained by availability of long-term care beds
(Reyniers et al., 2014) but may also reflect varying cultural
practices and preferences. The high proportion of nursing
home deaths in the Netherlands may reflect the medical
specialty of elderly care physicians (Koopmans et al., 2010)
working within the nursing home setting and providing a
high level of medical support.
Transfer to hospital from care homes during the final
stages of life is often considered undesirable with minimal
352 Dementia

Table 35.2 Location of dementia-related deaths

Location of death (%)
Nursing home/­
Country long term care Home Hospital Other Reference
Belgium 2008 66.7 11.2 21.6 0.5 Reyniers et al. (2014)
Canada 2008 59.4 3.4 32.3 4.9 Reyniers et al. (2014)
Czech Republic 2008 61.5 10.6 27.5 0.4 Reyniers et al. (2014)
England 2001 57.9 4.4 37.5 0.3 Sleeman et al. (2014)
England 2006 48.8 NR 45.4 NR Sleeman et al. (2014)
England 2010 52.6 6.7 40.1 0.6 Sleeman et al. (2014)
France 2008 34.0 27.2 35.9 2.9 Reyniers et al. (2014)
Germany 2008 26.9 42.4 26.2 4.5 Escobar Pinzon et al. (2013)
Hungary 2008 NR NR 62.3 37.7 (Reyniers et al. (2014)
Italy 2008 19.5 42.2 32.1 6.2 Reyniers et al. (2014)
Mexico 2008 NR 69.3 26.2 4.5 Reyniers et al. (2014)
New Zealand 2008 76.6 4.5 14.3 4.7 Reyniers et al. (2014)
The Netherlands 2008 93.1 3.8 1.6 1.5 Reyniers et al. (2014)
Scotland 2003 60.8 5.0 33.9 0.4 Houttekier et al. (2010)
South Korea 2008 5.5 20.5 73.6 0.4 Reyniers et al. (2014)
Spain 2010 20.1 46.1 33.6 0.2 Reyniers et al. (2014)
United States 2007 62.6 15.3 13.2 8.9 Reyniers et al. (2014)
Wales 2008 48.9 4.2 43.1 3.8 Reyniers et al. (2014)
Abbreviation: NR, not reported.

benefits in terms of life expectancy or quality of death.

People with dementia have an increased risk of adverse
events in hospital (Watkin et al., 2012) and the ability to pro-
vide person-centred and comfort care in the hospital setting
is challenging. Transfers to hospital may also be more costly
to health and care systems (Lane et al., 1998).
Also included in Table 35.2 are dementia-related deaths
occurring in England between 2001 and 2010, which demon-
strates that from 2006 to 2010, the proportion of dementia-
related deaths in care homes increased and hospital deaths
decreased (Sleeman et al., 2014). This perhaps reflects recent
concerted efforts to provide end-of-life care in care homes
and avoid transfers to hospital at end of life.
Hospice care is associated with better emotional
support, higher levels of respectful treatment and satis-
faction with care when compared with nursing home and
hospital settings (Teno et al., 2004; Shega et al., 2008).
However, the specialized nature of these services and
their limited availability is unlikely to meet the grow-
ing number of people living and dying with dementia.
A more realistic approach is to improve end-of-life care
skills within nursing home and long-term care settings
to reduce the need for transfers to hospital for symp-
tom management. Bringing hospice expertise into the
care home setting may be a way of achieving this goal
(Stevenson and Bramson, 2009). Barriers to end-of-life
care in residential settings also need to be addressed,
such as variable engagement from medical practitioners,
access to out of hours support and availability of training
(Seymour et al., 2011).
35.6 COMFORT CARE
Meeting the needs of people with dementia at the end of
life requires consideration of their physical, psychological,
social, spiritual, environmental, supportive and individual
needs (Perrar et al., 2015). Psychosocial needs are impor-
tant and may not be adequately addressed, particularly in
settings based on a medical model where demands on staff
lead to a focus on physical tasks over positive social engage-
ment. Kitwood (1997) argued that the medicalization of
dementia has led to an overemphasis on the losses associ-
ated with dementia with a failure to acknowledge the needs
associated with maintaining personhood including the
need for attachment, comfort, inclusion, identity and occu-
pation. Holistic person-centred approaches are now widely
espoused and have been shown to be effective in reducing
agitation in nursing home settings (Chenoweth et al., 2009;
Livingston et al., 2014).
People with advanced dementia may not be able to ver-
bally communicate needs and signs of distress, and with-
drawal and agitation can indicate unmet need. Trials for
reducing distress and behavioural and psychological symp-
toms to dementia (BPSD) often have mixed results and tend
to highlight the limitation of research approaches that rely
on a single intervention to address an issue. Approaches that
are multifaceted and incorporate individual and holistic
assessment are more likely to be effective in reducing symp-
toms. For example, the Serial Trial Intervention has been
shown to effectively increase nurses’ level of assessment of

symptoms and persistence in intervening combined with
reduced distress among residents (Kovach et al., 2006a). The
intervention consists of behaviour change identification fol-
lowed by serial assessment and intervention (Kovach et al.,
2006b). The approach has five steps and if any step is ineffec-
tive in improving the symptom the next step is trialed. The
steps include the following:
1. Physical assessment and treatment
2. Assessment of affect (environmental stressors, balance
of stimulation and rest and at least 10–20 minutes of
positive social engagement twice daily) and addressing
any gaps identified
3. Trialling non-pharmacological approaches
4. Introducing or increasing analgesics
5. Consultation with experts in mental health and ageing
and possibly the use of psychotropic medication
Fewer studies have examined strategies for reducing
distress for people living with dementia at home, although
there is some evidence that family carers of people who have
high levels of BPSD tend to have limited understanding
and repertoire of strategies to reduce these symptoms
(Moore et al., 2013).
Kovach et al.’s (2006a) study highlighted the importance
of addressing pain with 46% of residents in the interven-
tion group, compared with only 3% of the control group
residents being prescribed an analgesic. Pain management
in advanced dementia is particularly challenging given the
subjective nature of pain and importance of self-report.
A number of measures have been developed that rely on
observing possible signs of pain such as facial grimaces and
negative vocalizations. Psychometrically, the most prom-
ising tools include the Abbey Pain Scale, DOLOPLUS2,
Pain Assessment in Advanced Dementia and the Pain
Assessment Checklist for Seniors with Limited Ability to
Communicate (Hadjistavropoulos et al., 2014). The extent to
which these measures are identifying physical pain or emo-
tional distress is difficult to ascertain (Jordan et al., 2012)
and therefore identifying the source and potential remedy
can be difficult and may require a trial and error approach.
Namaste care is another approach underpinned by a
person-centred approach and which engages people through
sensory input, comfort and pleasure. It aims to enhance
social interaction and shared activity as well as support
family through the progression of dementia in a positive
context by seeking to improve quality of life. It has been
demonstrated to reduce neuropsychiatric symptoms among
nursing home residents with advanced dementia without
requiring an increase in care staff (Stacpoole et al., 2014).
The authors of this study also acknowledged that the suc-
cess of the programme relied on good support from medical
staff to ensure effective clinical care and pain management
(Stacpoole et al., 2014).
Maintaining nutrition and hydration in advanced demen-
tia is challenging as people may lose interest in eating and
develop difficulties with swallowing. The use of percutaneous
Advanced dementia and care at the end of life 353
endoscopic gastrostomy (PEG) and nasogastric tubes for
providing nutrition during advanced dementia is still
common in some countries (Bentur et al., 2014; Wada et al.,
2014); however, there is a lack of evidence for its efficacy
in improving life expectancy or reducing pneumonia risk
(Sampson et al., 2009; Goldberg and Altman, 2014). Studies
investigating artificial feeding have also failed to consider
issues of quality of life and comfort (Sampson et al., 2009).
Artificial feeding also raises ethical issues related to euthana-
sia and prolonging suffering. Less invasive approaches may be
preferable, such as postural adjustments and use of modified
textured diets and thickened fluids. While these approaches
are commonly used in nursing homes and hospitals, the
overall benefit of modified diets is questionable given their
reduced acceptability and potential risk of malnutrition and
dehydration (Sura et al., 2012). Referral to a dietitian for those
who are nutritionally at risk or a speech therapist for those
with swallowing difficulties is recommended.
A multidisciplinary approach involving physiotherapists
and occupational therapists for problems with mobility
and contractures, and nurse specialists for pressure ulcer
care, can be useful where routine management such as
regular movement and pressure relieving devices are inef-
fective. Breathing difficulties during the last days of life are
another symptom that may be distressing for families (Wee
et al., 2006), yet there is little consensus about treatment.
Researchers who recently developed practice guidelines for
managing pneumonia among nursing home residents with
dementia found that there was a lack of research evidence
and so relied on a Delphi process to gain consensus among
experts regarding preferred treatment options (van der
Maaden et al., 2014). The process identified that while palli-
ative care in dementia required a unique approach, existing
palliative care guidelines were still relevant for treatment of
symptoms. However, the experts did not agree on a number
of interventions such as the use of oxygen for dyspnea and
anti-cholinergics for rattling breath with the latter treat-
ment being considered a strategy for relieving the distress
of relatives more than for the well-being of the dying patient
(van der Maaden et al., 2014).
35.7 WORKING WITH FAMILY
Family carers across the globe have a vital role as they pro-
vide the bulk of care to people with dementia (Alzheimer’s
Disease International, 2009) and in the advanced stages
they are usually relied on as proxy decision makers regard-
ing end-of-life care and treatment. Family members can
provide vital information to assist service providers and
health professionals in the provision of care. While they
may not always know what the person with dementia would
have wanted in terms of treatment, they are best placed to
inform a holistic approach to care and to have insight into
the goals, values and preferences of the person with demen-
tia both during and prior to developing dementia.
354 Dementia
Involving family members in discussions about end-
of-life care is also important. For example, a U.S. study of
nursing home residents with advanced dementia found
that when family members believed their relatives had less
than 6 months to live and understood likely clinical com-
plications, the person with dementia was significantly less
likely to receive a burdensome intervention during their
last 3 months of life (Mitchell et al., 2009). Another study
in Dutch long-term care facilities found that while only
43% of family members reported dementia as a disease you
can die from (prior to the resident’s death), agreement with
this statement was associated with higher resident comfort
at end of life as assessed by the physician (van der Steen
et al., 2013b). In this study, however, family members’ level
of understanding of dementia prognosis and complications
did not impact on the resident’s comfort at end of life.
Both of these studies found that family carers were rarely
counselled on how long the person with dementia was likely
to live (18%–21%) or clinical complications associated with
advanced dementia (33%–39%) (Mitchell et al., 2009; van der
Steen et al., 2013b). These figures appear exceptionally low
when the participants with dementia were living in long-term
care facilities and most had advanced dementia. As described
above, there are many obstacles to end-of-life discussions and
if family carers are unaware that dementia is a terminal dis-
ease, it is understandable they would not initiate these discus-
sions. The onus lies on health professionals to raise end-of-life
discussions particularly since studies have shown that discus-
sions about end-of-life care with family members increases
satisfaction with care (Reinhardt et al., 2014) and end-of-life
care (Engel et al., 2006) and can help carers in making treat-
ment decisions (Caplan et al., 2006).
Communicating with family carers about advanced
dementia requires patience and sensitivity. Family car-
ers may not be prepared to commit to documented care
decisions, possibly as they attach more importance to
advance directives than health professionals (Rurup et al.,
2006). However, despite reluctance to formalize plans,
they do appear to appreciate and benefit from the discus-
sion (Sampson et al., 2011). Caplan et al. (2006) ‘found that
most families said that previously no one had explained to
them what the natural history of dementia was or that their
relative in a [nursing home] was actually dying. They were
relieved to have this information, which allowed them to
think more clearly about what treatment would be helpful
and what would not’ (p. 584).
Booklets on end-of-life care and advanced dementia
have been shown to be helpful for family carers and health
professionals and could be used to promote end-of-life
discussions. Booklets have been developed and evaluated
in Australia (Chang et al., 2010) and Canada (Arcand and
Caron, 2005) and the Canadian booklet has been modified
for use in the Netherlands, Italy and Japan (van der Steen
et al., 2013a). A study of the Australian booklet found that
two-thirds of carers preferred receiving the booklet at a
specific stage of dementia and of these, 72% indicated that
they would have liked the booklet at onset of symptoms or
just after diagnosis (Chang et al., 2010). Health professionals
reported that having a booklet was useful for aiding discus-
sions with family and that these booklets should be widely
available and do not always need to be provided by a health
professional (Chang et al., 2010; van der Steen et al., 2011).
The timing and sensitive delivery of information is impor-
tant as some carers may find it distressing to hear about
advanced symptoms of dementia, particularly during the
early stages when many symptoms may not be evident and
the focus is on ‘living well’ with dementia.
The needs of family carers are also critical as they are at
high risk of experiencing burden and depression (Pinquart
and Sorensen, 2003; Etters et al., 2008). While much research
has focused on this, the importance of grief should not be
underestimated. Pre-death grief in dementia highlights the
importance of grief throughout various losses associated
with dementia including communication, personhood and
capacity to recognize family members. Pre-death grief dif-
fers from anticipatory grief that has often been described in
the context of cancer where the person who has cancer can
communicate with family to resolve old conflicts and help
them adjust to the impending loss (Lindauer and Harvath,
2014). Discussions can have a therapeutic effect by assisting
family members to emotionally prepare, but the actual loss
of the person has not yet occurred and can only be antici-
pated. In dementia, family carers will experience losses
while the person with dementia is alive and so the grief
process may be expanded over many years in a protracted
period of loss.
Another important loss can be when the person with
dementia moves into residential care. This transition can
cause significant grief and guilt for family carers (Afram
et al., 2014). It can indicate the end of a long period of
cohabitation and for spousal carers this can be a large defin-
ing element of their marriage (Moore and Dow, 2014). It
is unclear to what extent pre-death grief may help family
carers adjust or complicate grieving when the person with
dementia dies. A study by Schulz et al. (2003) found that
72% of family carers described their relative’s death as a
relief and while depressive symptoms increased towards
death, they dropped in the 15 weeks post-death. This was
in contrast to the slight increase in depressive symptoms
reported by carers after placing their relative in residential
care. Only 21% of carers in this study accessed bereavement
services after their relative died. These findings suggest that
counselling and bereavement support for family carers may
be needed while the person with dementia is alive.
35.8 CONCLUSIONS
Dementia is a terminal condition requiring a pallia-
tive approach, particularly during the advanced stages
where the goals of care may shift towards providing com-
fort and allowing a natural death. The advanced stage of
dementia is characterized by high levels of dependence

and low quality of life. Palliative care requires a holis-
tic and coordinated approach that involves the person
with dementia and their family members as far as pos-
sible. Communicating with the person becomes difficult
as dementia advances and therefore addressing their
needs becomes challenging. Agitation and distress can
be signs of unmet needs such as physical pain or lack of
social engagement. Education of both the person with
dementia and their family appears important for improv-
ing outcomes such as satisfaction with care and reducing
burdensome interventions; however, the timing of infor-
mation provision is difficult to assess and is often delayed
and avoided. While people with dementia may be able to
have input into decisions about future care in the early
stages of dementia, there is evidence to suggest that they
have difficulty imagining themselves in the future when
they may be more dependent on others. Family carers can
also be influenced by their own experiences of burden
and pre-death grief and may not always be in a position
to make decisions that reflect the wishes of the person
with dementia. More research is needed to better under-
stand management strategies for numerous symptoms
associated with advanced dementia, however, there are
promising findings for multifaceted and person-centred
interventions, which reduce pain and agitation. Person-
centred approaches also require healthcare profession-
als to develop positive relationships with family carers
to support joint decision making and to develop a better
understanding of the needs and preferences of the person
with dementia.
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Alzheimer’s associations and societies
HENRY BRODATY, NICOLE PESA AND GLENN REES
36.1 INTRODUCTION
Alzheimer’s disease (AD) associations are voluntary orga-
nizations that advocate on behalf of people with dementia
(PWD) and their carers. The growth in these associations
has been brought about by a quantum leap of public aware-
ness about AD and related disorders, particularly in devel-
oped countries. The rise in public awareness has occurred as
a result of a number of converging factors.
The ‘greying’ of the world’s population or ageing is the
major risk factor for dementia. Average life expectancy in
developed countries is currently greater than 75 years for
males and 80 years for women. Approximately 8% of the
world’s population is aged 65 years and older, and in the
United Kingdom people aged 65 years and over comprise
17% of the population (United Nations, 2013). There is esti-
mated to be over 44 million PWD worldwide, and the num-
ber of people affected is expected to surpass 136 million by
2050 (Alzheimer’s Disease International, 2014). Moreover,
there is a common misconception that dementia only occurs
in developed nations. The majority of PWD (approximately
30 million or 60% of the world’s population) live in lower
income countries with this number set to triple to nearly 90
million or 70% of the world’s population by 2050.
Second, there has been increasing public awareness of
dementia and AD and resultant interest and fear of the dis-
ease. A recent poll in the United Kingdom shows that sig-
nificantly more people over 50 are more scared of getting
dementia than they are of getting cancer. The poll (www.
saga.co.uk) showed that while 1 in 10 people surveyed were
frightened of getting cancer, almost 70% were fearful of
developing dementia. This has been fuelled by publicized
cases of prominent people who have developed demen-
tia (such as Ronald Reagan, Margaret Thatcher, Charles
Bronson and Charlton Heston) and medical breakthroughs,
including discovery of contributing factors and trials of new
treatments.
36
Research activity is the third factor, aimed at improving
diagnosis and assessment, discovering preventative factors
and treatments for dementia and determining the impact
on carers and ways to reduce their burden and stress lev-
els. The importance of preventative factors and consequent
need for prevention studies was highlighted by the World
Alzheimer’s Report (Alzheimer’s Disease International,
2014) and research activity has been gaining momentum
in this area (Gillette-Guyonnet et al., 2009; Richard et al.,
2009; Kivipelto et al., 2013; Ngandu et al., 2014).
The final factor is the breakdown of traditional family
structures with the changing roles of women and adult chil-
dren and changing values that have reduced the moral obli-
gation to care for older members of the community. This
has increased pressure on governments and healthcare sys-
tems to support the needs of people with dementia and their
carers.
Being a carer of a person with dementia is very stressful,
and it is known that carers experience higher levels of psy-
chological distress and lower levels of self-efficacy and sub-
jective well-being than both non-carers and carers of people
with other types of diseases and disabilities (Pinquart and
Sorensen, 2003). Carers seek each other out for support and
company, and as a result Alzheimer’s associations around
the world have grown. In developed countries such as the
United Kingdom, United States and Australia, Alzheimer’s
associations have been a powerful voice for promoting car-
ers’ and care recipients’ needs.
The role played by Alzheimer’s organizations worldwide
has changed dramatically over the past 10 years. On both
the international and the national levels, these organiza-
tions have transformed to become the agents of change in
advocating for national plans to make dementia a health
priority. Their common objectives are to improve the qual-
ity of life of PWD through awareness, reducing the stigma
that results from a diagnosis of dementia, improving access
to dementia services, promoting community understand-
ing that the risk of dementia may be reduced and increasing
359
360 Dementia
investment in research to better identify those at risk and
delay progression of the disease.
36.2 ALZHEIMER’S DISEASE
INTERNATIONAL
National organizations are brought together under Alzheimer’s
Disease International (ADI), a global federation of 86
Alzheimer’s associations (as of 2016) (see Figure 36.1). ADI
focuses on a unique combination of global solutions to raise
awareness of dementia around the world and local knowledge
to empower, support and care for PWD locally in each c­ ountry.
Founded in 1984, ADI is governed by a ­council of ­representatives
from each member association that meets annually and elects
a board and an executive team, led by the chairman. Funding
comes from membership fees, conference fees, ­donations and
investments. Ibero-Latin America and Asia-Pacific regional
groupings hold their own annual c­onferences and produce
publications relevant to their zone and ADI has established
an Asia-Pacific regional office in Singapore. Europe has an
independent organization, Alzheimer Europe (http://www.
alzheimer-europe.org/), which collaborates closely with ADI.
ADI has close associations with the World Health
Organization (WHO), the International Psychogeriatric
Association, World Psychiatric Association and the World
Federation of Neurology. The pharmaceutical ­ industry
seeks ADI’s advice about dementia treatment and ­consumer
needs. ADI and WHO collaborated to produce a caregiver
publication, the WHO provides speakers for ADI confer-
ences and the organizations work together to achieve fund-
ing for projects. WHO supported the launch of ADI’s World
Alzheimer’s Day in 1994. Held annually on 21 September,
associations around the world mark World Alzheimer’s
Day by holding ‘memory walks’, open days, lectures, train-
ing courses and entertainment designed to raise awareness
about dementia. ADI supplies its ­members with a bulletin
that has a special focus each year and materials to which
they can add their own information, download, print and
Figure 36.1 Map of the world with those countries
belonging to Alzheimer’s Disease International shown
in dark grey. (From Alzheimer’s Disease International,
World Alzheimer Report 2009: The Global Prevalence of
Dementia, Alzheimer’s Disease International, London,
United Kingdom, 2009.)
distribute. ADI provides its member countries with materi-
als they can adapt to their culture and language.
ADI’s main aims are to build and strengthen member
associations by facilitating the sharing of expertise and
resources and encourage the formation of associations in
countries where they do not exist. To address these aims,
ADI developed the 3-day annual Alzheimer University
training program in 1998, a series of workshops that aim to
strengthen associations by focusing on issues fundamental
to running an organization (e.g. organizational structure).
For new and emerging associations, workshops are designed
to help them develop the skills to establish an association,
including identifying aims, fundraising, recruiting volun-
teers, running support groups, raising awareness, influenc-
ing public policy, governance and providing and distributing
information (Alzheimer’s Disease International, 2005). ADI
financially supports participants to attend.
ADI disseminates information and its annual World
Alzheimer Reports have been hugely influential g­ uiding both
health research and policy. They have published reports on the
global prevalence (Alzheimer’s Disease International, 2009)
and economic impact (Alzheimer’s Disease International,
2010) of dementia, the benefits of early diagnosis and
intervention (Alzheimer’s Disease International, 2011),
­
­overcoming stigma (Alzheimer’s Disease International, 2012)
and long-term care (Alzheimer’s Disease International, 2013).
The most recent report examined the evidence for risk reduc-
tion and prevention (Alzheimer’s Disease International,
2014). ADI issues a regular newsletter, fact sheets and
­publications on a number of issues relevant to PWD and their
carers and Alzheimer’s associations. Publications are avail-
able on the website www.alz.co.uk, and most are ­available in
English and Spanish. Links to websites that provide dementia
information in other languages are also provided.
Globally, ADI campaigns for policy change from gov-
ernments and the WHO and for recognition of dementia
as a public health priority. In March 2015, the First WHO
Ministerial Conference on Dementia was held involv-
ing 85 countries. There is the prospect of a Resolution at
the World Health Assembly on Dementia in May 2017.
Twenty-five national dementia plans are in place (2016).
An important part of ADI advocacy is the partnership
with Dementia Alliance International, an organization
of people with dementia. An annual international confer-
ence brings together PWD, their families, clinicians, care
professionals and researchers to share and exchange infor-
mation, resources and knowledge. From its 1985 inception
in Brussels, the conference has developed into a significant
international stage to raise awareness about AD and show-
case the growing unified effort and support for progress in
dementia policy and research.
Locally, ADI supports national Alzheimer’s associations
to effectively advocate for PWD and their caregivers by
equipping them with the skills and know-how to provide
high quality services.
The Twinning Programme launched in 2005 is another
ADI initiative that embraces peer-to-peer sharing of

knowledge, skills and experience between Alzheimer’s
associations from different countries. The vision for the
programme is that the partnerships created will strengthen
both associations by tackling issues together.
ADI facilitates a research network, the 10/66 Dementia
Research Group that carries out population-based research
on dementia and its risk factors in lower- and middle-
income countries, including China, India, Russia, Nigeria,
South Africa, Mexico and other countries, especially in
Latin America (www.alz.co.uk/1066). The group, estab-
lished in 1998, has published over 100 scientific papers in
peer-reviewed journals.
The 10/66 name derives from the fact that less than 10%
of all population-based research into dementia is directed
towards the 66% of all PWD who live in developing countries
and was formed to redress the balance. Funding comes partly
from ADI and mostly from grants; it has endorsement from
WHO. 10/66 has published results of studies from 28 centres
in India, China, southeast Asia, Latin America, Nigeria and
Russia and randomized controlled trials (RCTs) of caregiver
interventions in Russia, India, Venezuela, Peru, Dominican
Republic and China, Mexico, Chile and Argentina.
Interventions were designed to provide basic education
about dementia and specific training on managing prob-
lem behaviours. Three simple modules were delivered over
5 half-hour sessions, targeted at the main carer and also
involving other family members (Dias et al., 2008; Gavrilova
et al., 2008; Guerra et al., 2010).
Epidemiological studies involve surveys of residents
aged 65 years and older with sample sizes of at least 2,000
in each Latin American country, with an ultimate total
sample of 25,000 (10/66 Dementia Research Group, 2008).
The 10/66 group developed and validated a one-phase edu-
cation- and culture-fair dementia diagnostic algorithm to
be used in older populations with little formal education
(Prince et al., 2003, 2008) and to obtain information about
care arrangements for PWD (Prince, 2004), the impact
of caring on their carers and common behavioural prob-
lems (10/66 Dementia Research Group, 2004) and associa-
tions with subjective memory complaints (10/66 Dementia
Research Group, 2009). Qualitative research studies have
demonstrated a lack of awareness in these countries that
dementia is an organic brain disease and a belief that
symptoms were a normal part of aging (Shaji et al., 2003).
Member associations actively support medical research
in their countries and ADI’s Medical and Scientific
Advisory Panel provides expert advice and acts as interna-
tional ambassadors for ADI.
36.3 NATIONAL ORGANIZATIONS
The main aim of all Alzheimer’s associations is to improve
the quality of life for PWD and their families (http://www.
alz.co.uk/adi/). Many of these associations changed their
names from ‘Alzheimer Disease and Related Disorders
Alzheimer’s associations and societies 361
Associations’ (or similar) to Alzheimer’s associations even
though other dementias are covered.
Core functions that Alzheimer’s associations across the
world aspire to deliver include the following:
●● Raising public awareness to promote an understanding
of dementia and reduce the stigma associated with the
condition
●● Providing support services, education and information
educating carers and health professionals
●● Circulating publications and resources
●● Advocating to governments for improved health
systems that recognize the need for timely diagnosis,
improved care in hospitals, access to palliative care
●● Advocating for more investment into research
The capacity of individual Alzheimer’s associations to
undertake these roles varies enormously between developed
and developing countries. Some associations in many devel-
oping countries have no association or if they do have only
a few volunteers to provide information and assistance. At
the other extreme are organizations in developed countries
with sophisticated awareness activities, leading edge ser-
vices and capacity to invest in dementia research.
The evolution of Alzheimer’s associations across the world
has followed a similar pattern from an initial focus on family
carers to being inclusive of PWD of all ages; from a priority
for awareness and information to the provision of services and
training and education; from consumer resources to sophis-
ticated publications on dementia; from media to developing
policy and working with governments on dementia national
plans. This evolution has gathered pace in recent years and has
put great strain on the resources of the associations.
Many countries now have national plans with the
aim of making dementia a health priority including
Australia, South Korea, France, United Kingdom, Norway,
United States, Netherlands, Finland, Denmark, Belgium,
Luxembourg, Switzerland, Israel, Taiwan, Japan, Mexico,
Costa Rica and Cuba. The elements of these plans vary but
often include awareness and information, timely diagnosis,
access to ­community and residential services, improved care
in ­hospitals and training and education.
These plans are important not only in achieving need for
action on dementia but promoting partnerships between
Alzheimer’s organizations, health and aged care sectors and
the research community.
Important to the operation of many Alzheimer’s organi-
zations are consumer networks to empower PWD and their
carers to advocate for themselves. Advocacy and empower-
ment through person-centred and consumer-directed care
is a necessary shift in care culture, and the recognition that
PWD should be consulted and have choices about the care
they receive is a requisite for good dementia care. The philos-
ophy of person-centred care is based on the idea that instead
of providing the same care to every person, care should
be tailored to the needs and preferences of the individual.
Consumer-directed care takes this concept further and
362 Dementia
recognizes that the consumer, to the extent they are capable,
should make choices about the types of care services they
access and the delivery of those services. These care philoso-
phies are important across all care services including respite
care, a major care service in Western countries. While con-
sumer choice is gaining momentum globally, there are still
concerns about issues in care such as physical and medical
restraint. Together, ADI and individual national Alzheimer’s
associations reinforce an international dedication to improv-
ing the lives of people living with dementia, finding a cure for
the disease and continuing the fight against dementia.
Associations vary in their governance and ­ service
­provision. Associations may be centralized with a national
body and branches through the country (e.g. United Kingdom)
or may have a federated structure, with a­ utonomous organi-
zation in each state or province, which join together to form
a national body (e.g. Canada, Australia). While membership
is open to anyone with an interest in dementia, associations
mainly cater for c­ arers and PWD. Many people working in
the dementia area also join as do those who wish to lend their
support. Most ­associations strive to have a broad cross section
of the ‘dementia community’ on their boards – consumers
i.e. carers and (increasingly) PWD, service providers, ­doctors
and people with influence who are interested from the g­ eneral
community. It is generally considered desirable that consum-
ers constitute at least half of the board.
Standard services provided by Alzheimer’s associations
are support groups, free telephone help lines, telephone
counselling, information via the web, education, training,
public awareness, media campaigns and public advocacy.
Additionally, associations may provide in-person counsel-
ling, drop-in centres, speaker panels, opportunities for vol-
unteers and funding for research.
36.4 INFORMATION
Provision of information is one of the most important aims of
Alzheimer’s associations. They assist PWD, families, carers,
health professionals, governments and members of the public
to obtain information about the disease, how to manage legal
issues and problem behaviours and how to access community
and health services. Sources of information include websites,
factsheets, access to research publications, newsletters, infor-
mation sessions, support group meetings and telephone ‘hot-
lines’. To be able to offer these services, associations require
an office, access to appropriate technology and staff or volun-
teers. Collaboration between physicians and associations can
improve the quality and amount of information provided to
PWD and their carers (Fortinsky et al., 2002).
36.5 TRAINING
Alzheimer’s associations coordinate and run training and
education programmes for PWD, their carers and health
professionals. Often people who manage and care for PWD
both at home and in healthcare settings are untrained
or undertrained and rely on programmes developed by
Alzheimer’s associations. Even though education alone
has limited benefits (Brodaty, 1994; Brodaty et al., 1994;
Marriott et al., 2000), it is an integral part of any interven-
tion and combined with counselling has been found to
improve carer depression, burden, social support and self-
efficacy (see Chapter 14 and particularly: [Belle et al., 2006;
Mittelman et al., 2006]).
In 2012/2013, the UK Alzheimer’s Society piloted an
intergenerational exchange initiative in an effort to foster
dementia-friendly generations and communities. Schools
and colleges participated in the programme, which aimed
to educate children and young people, remove stigma and
provide opportunities for interaction with PWD. An evalu-
ation of 13 of the 22 participating schools found key ben-
efits including increased awareness of dementia and how to
assist PWD to live well, reduced stigma and fear, recogni-
tion of the importance of dementia education in schools,
and knowledge of carer support (Atkinson and Bray, 2013).
The impact of the programme spread beyond that of demen-
tia awareness, spilling into areas such as personal develop-
ment and extended beyond the school community and have
since been compiled into a Dementia Resource Suite. Over
140 schools delivered a dementia awareness program in
2013/2014 and the initiative is set to grow.
The UK Alzheimer’s Society runs a number of other
training programmes designed for PWD, informal and
professional carers that cover topics including introduction
to dementia care, ideas for activities for PWD, nutrition,
improving communication, facilitating the move to residen-
tial care and dealing with grief and other emotions, as well
as train-the-trainer programmes. They are run at various
locations and can be tailored for individual workplaces and
run in-house (such as nursing homes). The society also pub-
lishes the training materials (Alzheimer’s Society, 2009b).
Alzheimer’s Australia developed national Dementia and
Memory Community that provides information services
about dementia and preventative strategies, carer educa-
tion courses, conferences for families and professionals
and awareness raising activities. In 2012, the Australian
Department of Health and Ageing funded the National
Younger Onset Dementia Key Worker Program. The pro-
gramme provides individually tailored education and sup-
port to both individuals and service providers by providing
them with a direct point of contact through a key worker. The
Living with Memory Loss programme for carers and PWD
involves dementia education, information about treatment
options and services, strategies and emotional support, con-
ducted over 7 weekly 2-hour sessions. In an uncontrolled
evaluation of the programme of 339 carers and 231 PWD
participating in 41 groups, significant improvements in
general mental health scores, more positive perceptions of
caregiving, reduced depression scores and decreased stress
from problem behaviours were evident for carers either
immediately or 3 months following the programme and for

depression scores for PWD at the end of the programme
and at follow-ups (Bird et al., 2005).
The U.S. Alzheimer’s Association offers a number of
professional training programmes and workshops for for-
mal and informal carers such as ‘Foundations of Dementia
Care’ and ‘Activity Based Dementia Care’. Available
­programmes vary by state. In Cleveland, OH, primary care
physicians collaborated with the Cleveland chapter of the
association to provide individualized ­education to family
caregivers and capable care recipients r­egarding d ­ ementia
care and available services in the community. In an
­evaluation study involving 44 participants who completed
the full ­intervention, the programme led to enhanced self-
efficacy for ­managing dementia ­symptoms and ­accessing
community ­
­ services and high levels of ­ satisfaction
(Fortinsky et al., 2002). The Alzheimer’s ­association has
also developed online ­professional ­training programmes
and e-workshops. These include essentiALZ, an individual
training ­programme offered to both family and ­professional
carers that provide ­certification in quality dementia care.
There are two ­certification options: Dementia Advanced
Care and Dementia-Related Behaviour. The first c­overs
basic dementia and person-centred care, ­communication,
diet, recognizing pain and minimization of falls. The s­ econd
covers approaches and key responses to ­dementia-related
behaviours. Both courses involve prerequisite ­completion
of 8–10 hours of various CARES® programmes offered by
the ­association and recertification is required every 2 years.
Another ­programme offered under the CARES® umbrella is
CARES: A Dementia Caregiving Approach for Direct Care
Workers and Dementia Care Training for Team Leaders. Ten
1-hour modules, using an online interactive tool, have been
designed for nurses, social workers and other ­professionals
who work with PWD. It covers issues relating to caring
for, communicating with and engaging PWD in mean-
ingful activity. Dementia Care Training for Team Leaders
­provides guidance for those who supervise people who care
for dementia patients, such as nursing home administra-
tors and unit coordinators but not basic care issues. These
resources can be purchased through the U.S. Alzheimer’s
Association website (Alzheimer’s Association, 2009b).
Many other associations run programmes such as the
Singapore’s Alzheimer Disease Association’s (http://www.
alz.org.sg/) training programme for family caregivers. The
16-hour programme contains four core modules including
understanding person-centred care, behaviour of PWD, com-
munication, community resources and self-care for caregivers.
Alzheimer’s associations in low- and middle-income coun-
tries are increasingly developing training programmes to raise
awareness and educate carers and healthcare workers about
dementia. The Alzheimer’s and Related Disorders Society of
India launched a Comprehensive Dementia Care Program in
Cochin in 2004. The 10-month training programme includes
nursing, community health and welfare and the challenges
of geriatric nursing in dementia (Alzheimer’s and Related
Disorders Society of India, 2009). They have expanded their
training programmes to include 6- and 12-month courses in
Alzheimer’s associations and societies 363
geriatric care and orientation to dementia care for staff at aged
care facilities. The Lanka Alzheimer’s Foundation in Sri Lanka
runs periodic workshops and in-house training programmes
for formal and informal carers on a ­one-to-one basis (Lanka
Alzheimer’s Foundation, 2009). In 2013, Alzheimer’s Pakistan
Rawalpindi Chapter introduced a 2-day course on caregiving
containing information on ­general care, respite care, current
treatments and genetic aetiology. Participants received a cer-
tificate upon completion.
36.6 SERVICES
Services used by carers include home care, day care, in-home
(sitting), residential respite and permanent care. Carers
have different needs and finding the right solution can help
reduce carer stress and depression and delay or make insti-
tutionalization of the care recipient less likely (Callahan
et al., 2006; Mittelman et al., 2006). Meeting the service
needs of carers is difficult because of limited resources.
Despite the demands on dementia carers and their high
levels of stress and burden, even when services are available,
their use is low (Brodaty et al., 2005). Impediments to using
services were perceived lack of need, resistance to accept-
ing help, not having enquired, lack of knowledge, lack of
availability, previous bad experiences, ineligibility and cost.
Many carers who denied needing services displayed other
indications of need, such as low levels of life satisfaction and
satisfaction with their role and high levels of resentment
and overload (Brodaty et al., 2005). Alzheimer’s associa-
tions have an important role in providing, enhancing and
facilitating use of services for PWD and their families. They
can also inform governments how to deliver and monitor
services with reasonable standards of care at economic cost.
For example, the Alzheimer Society of Finland examines
these issues through a survey of the social and healthcare
sectors every 5 years in their national memory barometer.
The survey elicits information on the standard of services
provided to PWD and their families (Sirpa et al., 2011).
36.7 RESEARCH
Research in AD and other dementias is critical, but glob-
ally is underfunded in relation to disease burden or in many
countries funding is completely lacking. In Australia, for
every seven research projects funded in cancer, only one is
funded in dementia (Anstey and Kiely, 2012). In the United
Kingdom, the government invests eight times more in can-
cer than dementia research (Alzheimer’s Society, 2009a). The
World Alzheimer Report (Alzheimer’s Disease International,
2009) ­ highlighted that worldwide research funding is
skewed to disease with high levels of mortality such as can-
cer and heart disease while those with high levels of disease
burden are under-resourced. Alzheimer’s associations act
364 Dementia
as advocacy groups to pressure funding bodies and govern-
ments to make funding available for research. Additionally,
they facilitate researchers’ access to PWD and their families
and give advice on research projects, particularly about the
carer p ­ erspective. The UK Alzheimer’s Society has a large
­public ­involvement in dementia research, ­investing over £6
million ­annually, funding over 100 projects at ­universities
and other ­institutions and w ­ orking in ­partnership with the
­scientific community and people affected by dementia. The
Quality Research in Dementia network of 80 ­community
­volunteers works with s­ cientists to set the research agenda
and award grants to ensure the best projects, which
are likely to have the ­ biggest impact, receive funding
(Alzheimer’s Society, 2015). The Alzheimer’s association
in the United States facilitates dementia research by offer-
ing grants, p ­ ublishing several peer-reviewed journals, the
flagship being the monthly Alzheimer’s & Dementia: The
Journal of the Alzheimer’s Association, hosting the annual
Alzheimer’s Association International Conference and con-
vening a Research Roundtable, a consortium of Alzheimer’s
association staff, advisors, scientists, academics and gov-
ernment a­ gencies. The roundtable facilitates the develop-
ment and ­implementation of new dementia treatments and
sponsors the association grants (Alzheimer’s Association,
2009c). Researchers help Alzheimer’s associations by advis-
ing, contributing to publications, submitting research ideas
for funding consideration and delivering presentations.
36.8 PUBLIC AWARENESS
Alzheimer’s associations help raise awareness about demen-
tia, which increases public interest and coverage in the
media and fosters recognition of dementia as a priority area
of concern. This is achieved through publications, courses,
training materials, funding and contributing to research
and conferences and posting information on websites. Some
associations are involved in lobbying politicians, form-
ing links with professional associations, or engaging high-
profile personalities who hugely raise public awareness,
help destigmatize dementia and increase research funding.
For example, in the United States, former President Ronald
Regan publicly announced his diagnosis of AD, in New
Zealand a well-recognized former football captain received
much media attention and in Australia, a famous media
personality became president of Alzheimer’s Australia and
then Australian of the year. In response to a movement run
by Alzheimer Europe and its member organizations, on 16
December 2008 the Council of the European Union recog-
nized that AD constitutes a ‘priority for action’ (Council of
the European Union, 2008; Alzheimer Europe, 2009); and
in 2011, the United Nations Summit on Non-Communicable
Diseases (NCD) declared AD a major disease area (United
Nations, 2011). In 2013, the G8 made dementia a priority and
subsequently appointed a World Dementia Council and a
World Dementia Envoy. The United Kingdom and European
Union have substantially increased their research funding.
36.9 SUPPORT
Emotional and practical supports are offered through
carer groups or individually through in-person or tele-
phone counselling. Support groups are the backbone of
Alzheimer’s associations (and may be offered by residential
facilities and other organizations).
Support groups, also called self-help groups, are gather-
ings of people who come together with a common problem
or goal to provide support to members, share their expe-
riences, problems, ideas and strategies, learn and gather
information about a topic and encourage each other to
take care of their own health and well-being (Alzheimer’s
Disease International, 2000). They are available for most
chronic conditions and clinicians should be aware and able
to provide relevant information about them.
The advantages of support groups are as follows:
●● Support, both emotional and practical
●● Education
●● Universalization – a sense of belonging and not being
alone
●● Identity and a sense of purpose
However, they are not appropriate for everyone – some
people may feel uncomfortable sharing their feelings in a
group setting. Support groups are not clinical and are dis-
tinct from group psychotherapy sessions, as members are
not viewed as patients. They are usually led by a profes-
sional such as a psychologist and/or someone who is a carer.
Professional leaders of groups have relevant qualifications
and training, whereas peer group leaders tend to rely more
on experience. Regardless, a group leader needs appropriate
skills, including public speaking, encouraging participa-
tion, listening without judging, ensuring respect of group
rules and identifying individuals requiring more support
(Alzheimer’s Disease International, 2000). Particularly for
peer-led groups, it may be appropriate to have two leaders
so that if a member requires individual support during a
session, or if the leader becomes unavailable e.g. if caring
responsibilities need attention, the group does not become
leaderless (Alzheimer’s Disease International, 2000).
Alzheimer support groups are usually provided for car-
ers and increasingly for people with (early stage) dementia,
or for both PWD and carers. The timing, structure and con-
tent vary between groups that often meet monthly for 1–2
hours, sometimes highly structured with set discussion top-
ics, videos and guest speakers or unstructured to allow for
more informal interaction. Some groups are located next to
day centres that have activities for patients while carers attend
the support group. Anecdotally, some carers benefit greatly
from support groups and attend regularly for months or years

(Ebenstein, 2004). Others find they are unsuitable and others
may attend irregularly, during a particularly stressful time
or only when invited. Carers who never attend may feel that
they have sufficient support (e.g. social, counselling) or may
be unaware of the existence of groups or how to access them.
Emerging technology has allowed support to be pro-
vided in ways other than face-to-face, such as by telephone
or online. This is important for reaching isolated carers par-
ticularly in rural areas (O’Connell et al., 2014), and to allow
for carers to access support at any time and from any loca-
tion. Interventions include conference calling among family
members, telephone support systems with automated mes-
sages, stress monitoring and advice, respite calls for care
recipients, online discussion groups, electronic reminder
services, computer-based forums and question and answer
sessions (Internet and non-Internet-based networks), email,
electronic encyclopaedias and libraries, online virtual envi-
ronments using avatars and computer-based decision sup-
port modules (McClure and Sanders, 2008; Powell et al.,
2008; Martindale-Adams et al., 2013; O’Connor et al., 2014).
Like carers, PWD may need support and people to talk to
who are going through the same experiences, especially in
the early stages of the illness. The presumption that PWD are
unable to benefit from support groups due to lack of aware-
ness of their disease and its implications is erroneous. A small
number of studies have examined the effectiveness of support
groups for PWD and a recent systematic review found that
they may reduce depression and improve quality of life and
self-esteem (Leung et al., 2014). These groups require careful
planning and should be led by trained facilitators (Alzheimer’s
Disease International, 2003; Beattie et al., 2007). Examples
include the online ‘virtual’ group The Dementia Alliance
International (www.dementiaallianceinternational.org) and
the ‘Memory club’ a support group for people with early-
stage dementia and their carers (Zarit et al., 2004). Following
the Netherlands, Alzheimer’s associations in the United
Kingdom, Ireland and Australia have developed ‘Alzheimer
cafes’ for people with early-stage dementia and their families.
Their purpose is to provide social and emotional support, and
a forum for informal advice and consultations with staff from
the associations (Bailey and Moriarty, 2006; Mather, 2006).
People with early-stage dementia have been able to be suc-
cessfully integrated into these programmes and anecdotal
evidence indicates that they enjoy the sessions and find them
beneficial (Mather, 2006).
36.10 THE EFFICACY OF SUPPORT
GROUPS
Participation in support groups has been found to have
a positive impact on the well-being of carers (Chien
et al., 2011). Specifically, it has been found to be associ-
ated with lower levels of carer burden (Parker et al., 2008;
Chien et al., 2011) and depression (Chien et al., 2011;
Alzheimer’s associations and societies 365
Chu et al., 2011), higher subjective well-being (Pinquart
and Sorensen, 2006), better self-reported general health
(Javadpour et al., 2008), higher morale (Gonyea, 1990),
enhanced competence and empowerment (Chan and
O’Connor, 2008) and increased use of formal support ser-
vices (Ebenstein, 2004).
The efficacy of support groups is equivocal. In Pinquart
and Sorenson’s (2006) systematic review, only one of the
support group interventions (number of support interven-
tions reviewed not specified) resulted in a significant posi-
tive effect on one outcome measure, subjective well-being.
Parker et al.’s (2008) systematic review of carer interven-
tions included three support group interventions. A support
group led by a nurse over 12 weeks, which included psycho-
logical support, education and problem solving reported
significant reductions in distress and improvements in
quality of life for participants (Fung and Chein, 2002). In
the other two studies support group participation had no
significant effect on participants’ depression or self-esteem
scores (Pillemer and Suitor, 2002) or on neuropsychiatric
symptoms of the participants’ care recipients (Senanarong
et al., 2004). Telephone and Internet-based support inter-
ventions were found to enhance carers’ and care recipients’
quality of life and independent living skills (Eisdorfer et al.,
2003; Topo, 2009). Support groups are most likely to have
positive effects if they include a counselling component and
individualized strategies rather than only providing edu-
cation and general training (Selwood et al., 2007). Groups
led by professionals tend to produce greater improvement
in participants’ psychological functioning, while peer-led
groups increase informal support networks and feelings
of self-efficacy (Toseland et al., 1989). Carer variables are
also important. Longitudinal evidence suggests that sup-
port group attendance is predicted by caregiver perceptions
of similarity between themselves and group members and
the amount of social support offered (Steffen and Mangum,
2012). Participation is likely to be more beneficial for carers
whose social networks do not include people who under-
stand their experiences, and carers who are more stressed,
are dissatisfied with their caregiving role, are employed or
have care recipients who are more apathetic or in nursing
homes (Cuijpers et al., 1996; Pillemer and Suitor, 2002).
A major barrier to carer attendance at support groups,
reported by 80% of carers, is that they had not received advice
encouraging them to attend (Molinari et al., 1994). The main
ways support groups build and maintain membership are
through general public awareness and outreach to individuals
who share the group’s concern but are not currently attend-
ing (Wituk et al., 2002). Groups tend to be more successful
when they have specific strategies to target and recruit poten-
tial members (Wituk et al., 2002). It is also the responsibility
of health professionals such as general practitioners (GPs) to
provide carers with information about support groups; and
communication problems (including use of jargon, lack of
face-to-face contact) between the carer and health professional
can impede such referrals (Bruce et al., 2002; Carpentier et al.,
2008). Recommendations by GPs about joining supportive
366 Dementia
organizations (Donath et al., 2010) improved communication
between health professionals and carers, and active outreach
by support groups may facilitate their use.
36.11 THE IMPACT OF CULTURAL
FACTORS
In Western countries such as the United States, Australia
and the United Kingdom, ethnic minority groups are
under-represented in the use of community services such
as support groups (Henderson et al., 1993; Chan and
O’Connor, 2008; Low et al., 2009). While it is unclear
why carers from minority groups are less likely to attend
support groups, a number of contributing factors may be
the diverse interpretations of dementia and the stigma
attached to the disease in some cultures, programmes may
be culturally insensitive or noninclusive in their approach,
and minority group experiences and expectations may
differ from the other ‘mainstream’ participants (Chan and
O’Connor, 2008). Cultural differences occur at multiple
levels (e.g. intrapersonal, interpersonal and environmen-
tal) and in multiple domains (e.g. psychosocial health, life
satisfaction, caregiving appraisals, spirituality, coping,
self-efficacy, physical functioning, social support, filial
responsibility, familism, views towards elders and use of
formal services and healthcare) (Napoles et al., 2010). For
instance, ethnic minority groups may find it difficult to
relate to mainstream support group practice norms such
as questioning authority and discussing conflict and feel-
ings towards caregiving (Diaz, 2002).
In Australia, dementia is five times more prevalent in
aboriginal Australians than non-aboriginal Australians,
yet there is a severe lack of services available for Aboriginal
PWD and their families including caregiver support (Smith
et al., 2011). Smith et al. (2011) identified a number of factors
that would facilitate access to care, including implemen-
tation of community-based and culturally safe services,
increased Aboriginal workforce within services, cultural
training for staff external to the community and increased
education and awareness of dementia.
Despite these limitations, there is evidence that diverse
cultural groups can benefit from participating in sup-
port groups. A U.S. study reported positive psychological
benefits for a culturally tailored support group for Latino
caregivers, who are heavily under-represented in the
healthcare system (Gonyea et al., 2014). Chinese people,
who have culturally defined caregiving roles based on the
notion of filial piety and are traditionally known to be
uncomfortable discussing personal problems, were able
to openly express their feelings and difficulties in a sup-
port group environment with other carers who had simi-
lar experiences and experienced significant reductions
in distress levels compared to controls (Fung and Chein,
2002; Leung et al., 2014). Further research is required to
determine whether similarly positive outcomes would be
found for other minority group participants in a culturally
diverse group.
Support groups can be made more appropriate and
attractive to a range of cultures through the following:
●● Active outreach by groups to culturally diverse
communities
●● Group leaders addressing from the outset the reluctance
of some cultures to ‘speak out’ about negative feelings
about the caregiving role, normalizing feelings of guilt
and reframing traditional beliefs about speaking out
(Chan and O’Connor, 2008)
●● Recruiting and training ethnic support group leaders
●● Finding a culturally neutral site for the group to meet
●● Letting participants decide the form of the group
(Henderson, 1992; Henderson et al., 1993)
A number of studies have trialled supportive interven-
tions for family carers in low- and middle-income coun-
tries. A 12-week support group for dementia caregivers
in Taiwan was found to reduce depression levels after the
intervention and at 1-month follow-up (Chu et al., 2011).
A Thai intervention including support group participa-
tion (Senanarong et al., 2004) helped to decrease neuro-
psychiatric symptoms of care recipients and had a small
effect on reducing carer distress (see Chapter 14). In Iran,
29 female carers attended 8 weekly sessions in a support
group conducted by a trained senior psychiatry resident
involving education and interactive group activities based
on the Alzheimer’s Association Guidelines for Carers. Post-
intervention scores showed highly significant reductions in
perceived stress and general health of carers and the neu-
ropsychiatric symptoms of their care recipients (Javadpour
et al., 2008). There was no longitudinal follow-up and addi-
tional research would help to consolidate these findings.
36.12 SPECIAL SUPPORT GROUPS
People with younger-onset dementia or uncommon forms
of dementia, gay couples affected by dementia, people in
second (or later marriages) or people who are very promi-
nent in their community and their families may find that
mainstream support groups are unsuitable (Moore, 2002;
Chaston et al., 2004; Arai et al., 2007). Some Alzheimer’s
associations (e.g. Alzheimer’s Australia) have developed
support groups tailored specifically for groups such as those
with younger-onset dementia, those in the early stages of
dementia and their families, multicultural carers, male car-
ers, adult children of PWD and people with frontotemporal
lobe dementia and Pick’s disease (Alzheimer’s Australia,
2005, 2009). The U.S. Alzheimer’s Association has online
support groups for Spanish-speaking carers and carers
who have lost their care recipient (Alzheimer’s Association,
2009a).

36.13 CONCLUSIONS
Alzheimer’s associations are a major support for PWD and
their families and have shaped policy internationally and
nationally, and raised awareness among policy makers, cli-
nicians and the general public. They are a key part of the
awareness, political and societal processes to destigmatize
dementia, to assure adequate services and to improve the
quality of life of those living with dementia. The outcomes
of the activities of these associations can be seen in the
implementation of national plans, and most recently, in the
commitment of the G7 Dementia Summit to develop an
international dementia research action plan. While recog-
nizing their substantial achievements, there is still difficulty
in attracting necessary funding and establishing well-inte-
grated care.
Alzheimer’s associations are an important therapeutic
intervention in their own right and should be part of the
armamentarium of clinicians helping those who live with
dementia. It may be helpful for clinicians to ‘prescribe’ con-
tact with an Alzheimer’s association as part of a manage-
ment package. The rise and development of associations
around the world is testimony to their value.
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Health economic aspects of dementia
ANDERS A. WIMO, LINUS JÖNSSON AND BENGT WINBLAD
37.1 INTRODUCTION
A highly prevalent and debilitating condition, such as demen-
tia, presents a challenge for any healthcare and social sup-
port system. Care of people with dementia is extremely costly
(Wimo et al., 2013a), and there is an important contribution
by informal carers (Wimo and Prince, 2010). In high-income
countries, it has been debated how healthcare and social sup-
port systems will be able to manage the increasing number
of elderly people in general (The Organisation for Economic
Co-operation and Development [OECD], 2013), and people
with dementia in particular (Lovestone, 2002; Banerjee, 2012;
OECD, 2015). In low- and middle-income countries, the chal-
lenge is rather to establish a care infrastructure for long-term
care (ADI, 2013). Although the global economic impact of
dementia is enormous, the scientific base in terms of health
economic studies in dementia care is comparatively small. The
first (and so far only) basic textbook in this field (Wimo et al.,
1998a) was published in 1998 and reviewers have stressed the
need for further studies (Jönsson et al., 2000; Shukla et al.,
2000; Lamb and Goa, 2001; Morris, 2001; NICE, 2001; Gray,
2002; Grutzendler and Clegg et al., 2002; Lyseng-Williamson
and Plosker, 2002; Wolfson et al., 2002; Birks and Harvey,
2003; Jönsson, 2003a; Leung et al., 2003; Lyseng-Williamson
and Plosker, 2003; Olin and Schneider, 2003; SBU, 2008;
NICE, 2009; Jönsson and Wimo, 2009; Pouryamout et al.,
2012; Costa et al., 2013; Knapp et al., 2013).
37.2 COSTING
37.2.1 DIRECT AND INDIRECT COSTS
The opportunity cost is the value of a resource in its best
alternative use. This is the value that should theoretically
be assigned to a resource within the context of a cost-of-
illness (COI) study or economic evaluation. Costs are often
37
categorized as direct costs (of resources used) and indirect
costs (of resources lost due to e.g. mortality, morbidity and
production losses). Direct costs are often presented in two
ways: direct medical costs (e.g. hospital care, clinic visits,
drugs etc.) and direct non-medical costs (e.g. social/home
services, nursing home care). Informal care (see below) is
often regarded as an indirect cost although this is not always
obvious since many carers are retired and sometimes also
paid for parts of their care.
37.2.2 PERSPECTIVE
An important purpose of economic evaluation is that it should
serve as a tool for decision making regarding allocation of
scarce resources (Drummond et al., 2004). There are many
different stakeholders involved in delivery and financing of
dementia care. Therefore it is essential to define the perspec-
tive of any pharmacoeconomic analysis, i.e. from whose view-
point costs and benefits are calculated. The viewpoint may be
a county council, a municipality, the public sector in general,
an insurance company, a family member or a patient. The
main cost components are costs of living (in its wide context,
including also care in nursing homes) and informal caring
(Wimo et al., 2003b; Schaller et al., 2015). There is a complex
interaction between those who finance the care and those
who may benefit from the results of interventions. Therefore,
the detection of suboptimal incentives is an essential part of
the economic analysis. Limiting the economic analysis only
to the healthcare sector or the public sector excludes substan-
tial components. Thus, a societal perspective where all rele-
vant costs are identified and included regardless of where they
occur and of who pays is often to be preferred.
37.2.3 INFORMAL CARE
Informal carers (mostly spouses or children) are of great
importance in dementia care. An informal carer is often
part of a ‘dementia family’. In that sense, their situation
can be analysed in terms of burden, quality of life, coping,
371
372 Dementia
stress, social network and morbidity (Max et al., 1995;
Jansson et al., 1998; Schulz and Beach, 1999; Wimo et al.,
1999b; Almberg et al., 2000; Etters et al., 2008; Raccichini
et al., 2009; Muangpaisan et al., 2010).
They are also often providers of an extensive amount of
unpaid informal care (Rice et al., 1993; Stommel et al., 1994;
Langa et al., 2001; Moore et al., 2001; Wimo et al., 2002;
Nordberg et al., 2005; Knapp and Prince, 2007; Mesterton
et al., 2010; Hurd et al., 2013; Wimo et al., 2013a, 2013b),
which constitute a great part of the societal costs.
Measuring caregiver time is problematic. Support in
personal activities of daily living (ADLs) and instrumen-
tal ADLs (IADLs) are well-defined activities. However, a
substantial part of care activities is linked to supervision
to manage behavioural symptoms or to prevent dangerous
events (Wimo et al., 2002). The assessments of supervision
and surveillance in terms of minutes and hours may be
difficult.
Two other important factors to consider are care pro-
ductivity and joint production. A formal and professional
carer is probably more efficient and takes less time to sup-
port ADL tasks than an informal carer. This must be con-
sidered if a replacement approach is used (see below). Joint
production means that one activity can result in different
outcomes, or the patient and the carer are doing things
together (e.g. shopping).
Costing informal care is also a complicated and contro-
versial issue (Koopmanschap, 1998; Jönsson et al., 2000; van
den Berg et al., 2006). There are two frequently used meth-
ods, the opportunity cost approach and the replacement
cost approach.
Whether the carer is paid or not is not of interest for the
economic valuation. Payment has an impact on the distri-
bution of the economic burden, but not on the total societal
cost. The relevant cost is the opportunity cost and thus, the
question is to identify the alternative use of the carer’s time.
If the alternative is working in the labour market, the cost
for informal care should be valued to the production loss
due to absence from work.
However, more problematic is the costing of leisure
time and care time during retirement. There is no consen-
sus on how this should be performed. The cost for the car-
er’s time may include the value of the time used as leisure
time (Karlsson et al., 1998). However, there is no such mar-
ket price available. Willingness-to-pay approaches – for
example the contingent valuation method (Johannesson
et al., 1992) are options to get prices and studies with these
approaches have been published in the field of demen-
tia (Konig and Wettstein, 2002; Gustavsson et al., 2010;
Jutkowitz et al., 2010).
With the replacement cost approach it is assumed that the
informal carer should be replaced with a professional carer
in a 1:1 ratio. The informal carer’s time and the professional
carer’s time are regarded as perfect substitutes. However, we
do not know if there will actually be a complete replacement
with a professional carer (in practice, most likely to a lower
replacement level).
37.2.4 GEOGRAPHIC TRANSFERABILITY
The way the care is financed and organized as well as the
relative supply of different forms of care, the general taxa-
tion level and the economic strength of countries are factors
that make cost comparisons between countries difficult.
Comparing currencies presents problems. Usual cur-
rency exchange rates reflect trade between countries rather
than purchasing power. Purchase power parities (PPPs)
(OECD PPP, 2003), are probably better to use than exchange
rates. Comparisons over time both within and between
countries are also linked to uncertainty. Consumer price
indices are often used, but an index that reflects changes in
the healthcare sector is better. The Statistical Office of the
European Communities (Eurostat) presents Harmonized
Indices of Consumer Prices (HICPs) for different sectors,
including healthcare.
In multinational studies, the results can be aggregated in
terms of resource use (and not in monetary terms) from every
country. The cost calculations can then be presented in one
currency, based on aggregated resource use. However, if there
are great differences in care organization between coun-
tries, aggregation of resource utilization results may also be
problematic. For example, the concept of ‘nursing home’ can
include a wide range of resources in terms of number of staff
and their competence, physical environment and technical
equipment, resulting in a great variation in costs. There are
also care concepts that are used just in one or few countries
such as DOMUS care in the United Kingdom. (Beecham
et al., 1993), Group Living in Sweden (Wimo et al., 1995) and
Special Care Units (SCUs) in the United States. (Maas et al.,
1998). Home care may denote social services with poorly
qualified staff, but also specific teams focused on demen-
tia. Even if a care organization can be divided roughly into
levels (such as nursing home care, intermediate care alter-
natives, home care), such a simplistic division questions the
validity of multinational intervention studies. Thus, another
option could be to aggregate costs based on a classification
of countries in terms of health and social care systems. Such
a classification could be based on how care is organized and
financed, economic strength and major differences in care
culture (such as the role of informal care).
37.3 OUTCOME MEASURES
Cognition is considered as a mandatory primary efficacy
outcome in most dementia trials. For the patient, the cog-
nitive capacity is indeed a relevant outcome since it affects
intellectual capacity and thinking. However, other out-
comes probably are more important for the informal carers
such as ADL capacity, mood-depression and behavioural
and psychological symptoms of dementia (BPSD). For both
patients and carers, aspects of quality of life are significant
outcomes. For staff ADL capacity and BPSD, and in a wider
context, care planning, are essential.

Surrogate end points are, in principle, regarded as inap-
propriate to use in cost-effectiveness analysis (Johannesson
et al., 1996).The Mini-Mental State Examination (MMSE)
(Folstein et al., 1975) is often used in dementia studies as
well as other measures of cognitive capacity such as the
Alzheimer’s Disease Assessment Scale – cognitive subscale
(ADAS-cog) (Rosen et al., 1984). However, in our view they
should be regarded as surrogate end points. Since the MMSE
is highly correlated with costs (Ernst et al., 1997; Hux et al.,
1998; Wimo et al., 1998c; Jönsson et al., 1999a), and also to
other, more relevant outcomes, such as ADL capacity, posi-
tion in care organization and severity of dementia, it has
nevertheless frequently been used in economic evaluations
of dementia. The MMSE is also used in most longitudinal
population-based studies and thus it may be useful as a link
between clinical studies and population studies in the dis-
cussions of efficacy versus clinical effectiveness. However,
when both MMSE and ADL are included in the same data
sets, ADL has a stronger correlation to resource use and
costs than cognition in terms of MMSE (Gustavsson et al.,
2011; Lindholm et al., 2013). Delay in progression in terms
of severity presents a broader outcome than cognition and
severity scales such as the Clinical Dementia Rating (CDR)
(Berg, 1988) and the Global Deterioration Scale (GDS)
(Reisberg et al., 1988) or multidimensional instruments
such as the Gottfries–Bråne–Steen scale (GBS) (Brane
et al., 2001) are thus suggested as more relevant for use than
cognition.
Postponing or preventing nursing home entry has also
been suggested. A study by Knopman et al. (1996) indicated
that nursing home care can be postponed about 1 year with
tacrine treatment. In a Swedish study (Wallin et al., 2004) of
tacrine, the findings were similar. Sano et al. (1997) found
that Vitamin E/selegiline treatment postponed nursing
home placement. A study on donepezil indicated an even
longer postponement of institutionalization (Geldmacher
et al., 2003). However, the situation is more complex regard-
ing carers. It may be an advantage that spouses can go on
living together, but a prolonged period at home may be more
stressful for the informal carer (Max, 1996). This poten-
tial risk was, however, not confirmed in the two published
randomized controlled trials (RCTs) where the amount of
informal care was measured (Wimo et al., 2003a, 2003b).
Quality of life (QoL) of both patients and carers is a rel-
evant outcome. Health-related QoL includes several dimen-
sions, such as ADLs, social interaction, perception, pain,
anxiety and economic status. One potential problem in QoL
assessments is the patient’s difficulty to value his/her own
health condition (Stewart and Brod, 1996). Thus, proxies
(mostly carers) are often used. Proxies are not necessarily a
problem. The U.S. panel for cost-effectiveness recommends
that the general public should value health states and in that
sense, an indirect measurement is not disqualified (Siegel
et al., 1997). However, if the proxy is a family member, the
answers may reflect, in part, the situation and interests of
the proxy, which must be considered. Some attributes may
be difficult for proxies, such as ‘pain’, whereas others, such
Health economic aspects of dementia 373
as ‘mobility’ are less problematic. In a project where proxy-
rated and self-rated QoL were used simultaneously, great
differences between the two approaches occurred (Jönsson,
2003b; Jönsson et al., 2006a).
In principle, two kinds of QoL instruments can be used:
diagnosis-specific or generic instruments (Bowling, 1995;
Spilker, 1996; Salek et al., 1998; Walker et al., 1998).
More or less dementia-specific instruments such as the
dementia quality of life instrument (DQoL) (Brod et al.,
1999), Quality of Life in Alzheimer’s disease (QOL-AD)
(Selai et al., 2001; Logsdon et al., 2002) and Quality of Life
Assessment Schedule (QOLAS) (Selai et al., 2000; Elstner
et al., 2001) may be useful in trials with a cost consequence
design, but are inappropriate for complete economic
evaluations since these instruments not are preference
based (Torrance et al., 1996; Siegel et al., 1997). However,
Dementia–Quaity of life (DEMQOL) is a dementia-specific
instrument (Smith et al., 2007), where there also is a pref-
erence-based version, Dementia–Quaity of life–Utilities
(DEMQOL-U) (Mulhern et al., 2013).
There is a great number of generic QoL scales, such as
the Sickness Impact Profile (SIP) (Bergner et al., 1981), the
Short Form series (SF) (for example, SF-36 and the utility
instrument SF-6D) (Ware and Sherbourne, 1992; Walters
and Brazier, 2003), the QLA-scale (Blau, 1977), the Health
Utilities Index (HUI) (Torrance et al., 1996; Neumann
et al., 2000), the EuroQoL/EQ-5D (Coucill et al., 2001),
15-D (Sintonen, 2001) and the Quality of Well-Being Scale
(QWBS) (Kerner et al., 1998).
HUI, EQ-5D, QWBS, SF-6D and the caregiver quality of
life index (CQLI) (Mohide et al., 1988) can be used to cal-
culate quality-adjusted life years (QALYs) (Torrance, 1997).
QALYs are used in cost–utility analysis (CUA) and reflect
both quantity and quality of life (Torrance, 1996; Torrance et
al., 1996) and give opportunities for comparisons with other
diseases. Utilities are expressed as a figure between 0 (death)
and 1 (perfect health). Disease-related utilities have also
been developed, e.g. in Alzheimer’s disease (AD) by Ekman
et al. (2007) and DEMQOL-U as mentioned above (Mulhern
et al., 2013). QALYs are not uncontroversial (Tsuchiya et al.,
2003). Chronic incurable progressive disorders may be mis-
favoured when compared with surgical treatments, such as
cataract surgery or hip replacement surgery.
There are also other approaches, such as disability-
adjusted life years (DALYs) (Allotey et al., 2003) and healthy-
years equivalents (HYE) (Dolan, 2000). However, DALYs
(often used by the World Health Organization [WHO]) focus
on productivity and disability rather than QoL, and HYEs
require a great number of health scenarios (Torrance, 1996).
Burden scales, such as the Burden Interview (BI) (Zarit
et al., 1980) can to some extent be used as indicators of carer
QoL, but the interplay between patient status, carer QoL
and burden is complex (Deeken et al., 2003).
The choice of outcome measure in economic evaluation
in dementia is not an obvious one. As different outcome
measures give different pieces of information, several out-
come measures can be used.
374 Dementia
37.4 STUDY DESIGN AND DATA
COLLECTION
37.4.1 MEASURING RESOURCE USE
The costing process usually consists of two phases; first,
resource utilization is expressed in terms of physical units
(such as nursing home days) and second, the resource uti-
lization figures are calculated into costs by the use of unit
costs for each resource. Resource Utilization in Dementia
(RUD) (Wimo et al., 1998b) is an example of a framework
assessing the use of formal and informal resources, aiming
at calculating costs from a societal perspective (Box 37.1).
RUD has been used in several studies (Wimo et al., 1999a;
Wimo et al., 2000; Wimo et al., 2003a; Wimo et al., 2003b).
A comprehensive battery can be time-demanding and
thus, a short version, the RUD Lite (Wimo and Winblad,
2003b) was developed. It was possible to limit the number
of variables in the RUD considerably without losing the
societal perspective in the analysis; RUD Lite covers about
95% of the costs resulting from the complete RUD (Wimo
and Winblad, 2003b). One part of the RUD is the caregiver
time subscale. The Client Service Receipt Inventory (CSRI)
(Beecham and Knapp, 2001) and the Resource Use Inventory
(RUI) (Sano et al., 2006) are other instruments aiming at
a broad assessment of resource use while the Caregiver
Activities Time Survey (CATS) (Clipp and Moore, 1995)
and the Caregiver Activity Survey (CAS) (Davis et al., 1997)
focus on caregiver time.
Since the organization of dementia care varies between
countries, any resource use battery must be adapted to the
specific situation in a country.
BOX 37.1: Components of a resource
utilization battery, Resource Utilization
in Dementia
Patient Carer
Accomodation/ Informal care time
long-term care (for patient)
(Work status) Work status
Respite care (Respite care)
Hospital care Hospital care
Out clinic visits Out clinic visits
Social service Social service
Home nursing care Home nursing care
Day care Day care
Drug use Drug use
Source: Wimo, A. et al., Evaluation of the resource utilization
and caregiver time in anti-dementia drug trials – A
quantitative battery, In Wimo, A. et al. (eds.), The
Health Economis of Dementia, London, United
Kingdom, John Wiley & Sons, 1998b.
37.4.2 STUDY DESIGNS
There are two basic types of health economic studies (Box
37.2): descriptive studies and normative studies (economic
evaluations). Here we refer more or less to the classification
suggested by Drummond et al. (2004).
37.4.2.1 Descriptive studies
Cost description (CD) describes only the costs (no outcome)
of a single treatment/care, without making any comparison
between alternative treatments. Thus, CD cannot give any
support in priority discussions, but presents a framework
for how costs are calculated.
COI studies are also descriptive. The COI is equal to what
these resources would have been used for if there had been
no case of illness (the opportunity cost). Two approaches can
be used: an incidence approach or a prevalence approach.
With the incidence approach the costs for new cases are
estimated where both the annual costs and future (dis-
counted) costs are included. In the prevalence approach the
costs for all cases during, e.g. a year, are estimated – both for
those who have dementia already and for new cases occur-
ring during the year in question (Lindgren, 1981; Rice et al.,
1985). Only exceptionally have both approaches shown the
same results. The choice of approach depends on the pur-
pose of the study; if the aim is to obtain information for
analysis of the economic consequences of interventions, the
incidence approach is preferable. If the idea is to estimate
the economic burden during a defined year, the prevalence
approach is the best option.
Another issue is whether to use a top-down or a bottom-
up approach. In the ‘top-down’ approach, the total national
cost for a specific resource is distributed on different diseases.
Different types of registry data are often used in ‘top-down’
analyses. The ‘bottom-up’ method starts from a defined sub-
group with e.g. dementia, and registers all COI related to it,
followed by an extrapolation to the total dementia popula-
tion. In any COI study, it is problematic to compensate for
BOX 37.2: Different kinds of health
economic studies
Descriptive studies
CD Cost description
COI Cost of illness
Evaluation studies
CA Cost analysis (incomplete evaluation)
CMA Cost–minimization analysis
CEA Cost-effectiveness analysis
CBA Cost–benefit analysis
CUA Cost–utility analysis
CCA Cost–consequence analysis
 Health economic aspects of dementia 375

comorbidity and to identify the costs related to a single condi-
tion (such as dementia), ‘net costs’, may be difficult to estimate.
In a Swedish COI study (Wimo et al., 2014b) the proportion of
net costs (costs assumed to only due to dementia) and gross
costs (costs including comorbidities) was about 75%.
It is also important to specify the included cost categories
(Is e.g. cost of informal care included?). It is obvious that
dementia care is costly, but the great range in cost figures in
Table 37.1 illustrates that the costing approaches may vary
in studies (Wimo, 2009).
In an estimate of the worldwide societal costs of demen-
tia, resulting in a total cost of $604 billion (US) in 2010, we
included direct costs ($353 billion [US]) and costs of infor-
mal care ($252 billion [US]) (Wimo et al., 2013a) (Table
37.2), but the variability in the sensitivity analysis (Table
37.3) illustrates the importance of transparency, otherwise
it is difficult to know whether presented cost differences
depend on costing methods or true differences in costs.
Issues that should be considered are for example, which cost
categories are included, whether the sample is population-
based or convenience samples.
37.4.2.2 Normative studies
(economic evaluations)
Economic evaluations are aimed at being a support in deci-
sion making. In a cost analysis (CA), only the costs of dif-
ferent therapies are compared (not outcomes). Thus, a CA is
an incomplete economic evaluation. A complete economic
evaluation includes the incremental costs ([C] and out-
comes [E]) and comparisons between different treatment
alternatives. It is often expressed as the incremental cost-
effectiveness ratio (ICER): (C/(E, although net benefit con-
cepts also can be used.
In a cost–minimization analysis (CMA) the effects of
different treatments are assumed to be equivalent and the
analysis is focused on to identify the cheapest therapy.
The value of CMA is questioned, since the assumption
of similar treatment effects is problematic (Briggs and
O’Brien, 2001).
In a cost-effectiveness analysis (CEA), the effect is
expressed as a non-monetary quantified unit. It may be the
costs for ‘a saved year of living’ or in dementia ‘the cost per
nursing home admission averted’. A cost–benefit analysis
(CBA) expresses all costs and outcomes in monetary units.
Few attempts have been made to apply CBA to dementia.
It has, however, been argued that CBA approaches such as
‘willingness-to-pay’ could be of value (Wimo et al., 2002;
Gustavsson et al., 2010). In a CUA, the effect is expressed as
utilities, such as QALYs (Torrance, 1997).
In a cost–consequence analysis (CCA), cost and out-
comes are listed and presented separately. The value of CCA
is debatable (Winblad et al., 1997), since results may be
difficult to interpret and the selection of outcomes may be
biased. However, in a situation where it is difficult to iden-
tify the most relevant and single outcome measure, it may
be of more interest to capture as much information as fea-
sible (Mauskopf et al., 1998).
37.4.3 ECONOMIC MODELS
An intervention in dementia may influence the lifelong
course of the disease. Therefore, an economic evaluation
should try to take into account impacts on costs and out-
comes during the remaining whole lifespan. Most clinical
studies last for 6–18 months. Due to practical and ethical
issues, single studies covering the whole disease period
will probably never be undertaken. One option to deter-
mine long-term effects is to extend ongoing studies. In

Table 37.1 Cost-of-illness studies expressed as $US (inflated to 2014)

Cost per person with
dementia Cost categories
Country/region $US 2014 included Source
World 20,549 D, IC Wimo et al. (2013a)
EU27 28,452 D, IC Wimo et al. (2008)
Europe 24,048 D, IC Gustavsson et al. (2013)
United States 45,413 D, IC Hurd et al. (2013)
Canada 31,952 D, IC Alzheimer Society (2010)
United Kingdom 51,236 D, IC Prince et al. (2014)
France 30,317 D, IC Rigaud et al. (2003)
Germany 75,572 D, IC community Schwarzkopf et al. (2011)
Ireland 56,089 D, IC Connolly et al. (2014)
Nordic 18,385 D, IC Jönsson et al. (2006b)
Italy 69,195 D, IC Cavallo and Fattore (1997)
Spain 40,304 D Atance Martinez et al. (2004)
Sweden 58,804 D, IC Wimo et al. (2014b)
Abbreviations: D, direct costs; IC, informal care.
376 Dementia

Table 37.2 Costs per person with dementia ($US) and aggregated costs (bns US$) by World Bank income
classification in 2010
Aggregated costs (US$ bn)
Number of
Per capita people with Total Informal care Direct Direct social
costs ($US) dementia costs (all ADLs) medical costs costs
Low income 868 5,036,979 4.37 2.52 1.23 0.62
Lower middle income 3,109 9,395,204 29.21 18.90 6.74 3.57
Upper middle income 6,827 4,759,025    32.49 13.70 10.44 8.35
High income 32,865 16,367,508 537.91 216.77 78.00 243.14
All 16,986 35,558,717 603.99 251.89 96.41 255.69
Source: Wimo, A. et al., Alzheimer’s Dementia, 9, 1–11, 2013a.
Abbreviation: ADL, activities of daily living.

Table 37.3 Sensitivity analysis of the global costs Wimo et al., 2014a). The basic idea is that, results from a
(bns US$) of dementia short core period are extrapolated to a longer period. Inputs
from several sources, e.g. efficacy, costing and progression,
Costs are used. Markov models are frequently used for this pur-
Base case 603.99 pose (Sonnenberg and Leventhal, 1998). Other approaches,
Basic ADLs only for 469.60 such as decision tree models (Weinstein and Fineberg,
informal care 1980), survival models (Fenn and Gray, 1999) and discrete
All ADL + supervision 783.29 events simulation (Caro, 2005) have been used. In a review,
for informal care 13 types of models regarding Alzheimer’s disease (AD)
Regression model 601.63 were identified (Cohen and Neumann, 2008). Discounting
of costs (and perhaps outcomes) is recommended. The dis-
Spouse caregiving 548.29
count rate is often 3%–5% (Siegel et al., 1997), but it can be
valued at 50% of
varied in a sensitivity analysis.
average wage
The use of models is often under discussion. The use
Spouse caregiving 520.44
of cognition as the vehicle for costs is questioned (Green,
valued at 25% of
2007). Long-term effects, such as exhaustion of carers and
average wage
staff, which do not occur in the core period and symptoms,
Replacement cost 616.71 such as BPSD, which do not have a linear progressive course
(average wage for a (Ferris and Mittelman, 1996) are difficult to model. A model
social care is also linked, implicitly or explicitly, to a specific organiza-
professional) tion of care. The assumptions in any model must be criti-
PPPs instead of 647.60 cally analysed.
exchange rates
Source: Wimo, A., et al., Alzheimer’s Dementia., 9, 1–11, 2013a.
Abbreviation: PPPs, purchase power parities.

RCTs it is difficult to maintain the original design for many
years, but long-term follow-up studies have been used for
cholinesterase inhibitors (ChEIs) (Knopman et al., 1996;
Geldmacher et al., 2003; Wallin et al., 2004; Gustavsson
et al., 2012). However, there are several drawbacks, such
as selection bias, patients lost to follow-up and problems
defining controls. Another interesting option is to analyse
registry data and to merge databases, e.g. record linkage of
national care registers with quality-of-care registers and
population-based studies to analyse long-term effects in
real life with multilevel statistical methods. However, vari-
ous modelling approaches are the most common ways of
trying to analyse the long-term effects (Buxton et al., 1997;
37.4.4 EVALUATION OF
PHARMACEUTICALS
Even if it would be advantageous to design studies purely
for health economic purposes, pharmacoeconomics will
probably be part of comprehensive phase III/IV studies
(Hill and McGettigan, 1998). It is, however, important
to refine the methods used (Briggs and O’Brien, 2001).
It has also been debated whether pharmacoeconomic
aspects are best included in phase III or phase IV studies
(Schneider, 1998).
Several pharmacoeconomic evaluations have been pub-
lished, mainly on the ChEIs (some on memantine) with var-
ious approaches. The early tacrine studies focused on costs

and they are also based on the same efficacy study (Knapp
et al., 1994). Even if treatment seems to be cost saving, the
range is large in these studies, from about 1%–17%, indicat-
ing different methodological approaches but also problems.
Few studies are empirical (Table 37.4) and most evaluations
are based on models (Table 37.5). The empirical studies are
short term studies with weak statistical power for the cost
results. While most previous pharmacoeconomic models
have focused of ChEIs and memantine, new but so far not
proven disease-modifying treatment (DMT) options have
been of interest for modelling. As seen in Table 37.5, sev-
eral modelling methods have been used. In contrast to the
empirical studies, most models indicate cost-effectiveness,
either in terms of absolute dominance (<0) or versus a will-
ingness-to-pay for a gained QALY in the ICER (which often
is US$50,000 or more).
Drug trials are often criticized regarding representative-
ness. Schneider (Schneider et al., 1997) showed that study
populations in dementia drug trials only reflect about 7% of
a general dementia population. The progression rate of cog-
nition is slower in placebo groups in most clinical studies
than in population-based studies. Another issue is whether
study populations reflect the dementia care organization to
which the results are generalized.
New drugs need to meet requirements by several dif-
ferent regulatory bodies before being made available to
patients. While the marketing authorization process in the
European Union is harmonized and centralized through
the European Medicines Agency (EMA) (guidelines cur-
rently under revision) (EMA, 2014), decisions about pric-
ing and reimbursement are made on the country, regional
and local levels. In the United States, specific guidelines for
the treatment of the early stage AD have been presented by
the Food and Drug Administration (FDA), which focus on
Table 37.4 Randomized controlled trials with empirical pharmacoeconomic data (costs inflated to 2014)
Drug Country Duration
Donepezil Nordic 1 year
Donepezil Canada, France, 6 months
Australia
Donepezil United Kingdom 60 weeks
Memantine United States 6 months
228 (r), −11 (o),
Risperidone (r), United States 9 months Overall p = 0.02
olanzapine (o) and (placebo lower)
quetiapine (q)
Notes: ns, non-significant; WTP, willingness-to-pay.
a A positive value indicates net savings with treatment.
Health economic aspects of dementia 377
outcomes that demonstrate efficacy on both a cognitive and
a functional or global assessment scale (FDA, 2013).
Alzheimer Europe (AE) have repeatedly updated informa-
tion about access and reimbursement and still there is a vari-
ability in reimbursement in Europe regarding the ChEIs and
memantine (Alzheimer Europe, 2006, Alzheimer Europe,
2012) and the situation is even more pronounced from a world-
wide viewpoint (Suh et al., 2009). The U.K. controversy regard-
ing the recommendations from the National Institute for
Health and Care Excellence (NICE) for drug treatment in AD
highlights how delicate this issue is (NICE, 2009). The critical
question is the reimbursement decisions (Drummond, 2003).
For example, in Sweden, where the Dental and Pharmaceutical
Benefits Agency, TLV, a central government agency, decides
whether a pharmaceutical product or dental care procedure
should be reimbursed, the ChEIs are reimbursed like other
drugs. The experiences from Australia and Canada with drug
authorities demanding health economic evaluations as part of
the reimbursement decision process illustrate that this issue
is indeed complicated (Hill and McGettigan, 1998). The for-
mer Canadian Health Technology Assessment Guidelines
for Pharmacoeconomics (CCOHTA) (now Canadian Agency
for Drugs and Technologies in Health [CADTH]) focused on
meta-analysis and epidemiological data and emphasized the
use of CBA and CUA (CCOHTA, 1997).
37.4.5 EVALUATION OF CARE
PROGRAMMES
The term ‘non-pharmacological treatment’ is commonly
used to describe care interventions such as day care, carer
support, living arrangements and case management. We
think this term is inappropriate since in most cases it
Results Sensitivity
US$ 2005a analysis Source
1426 (ns) 654–1549 Wimo et al. (2003a)
365 (ns) 85–582 Feldman et al.
(2004)
−1137 (ns) Yes, but results Courtney et al.
not presented (2004)
9364 (p < 0.05) Yes, but results Wimo et al. (2003b)
not presented
(per month)
−235 (q)
Different WTP Rosenheck et al.
levels (2007)
 378 Dementia
Table 37.5 Cost-effectiveness models (costs are inflated as $US 2014)
Model Range in sensitivity
length Model ICER or analysis or similar of
Drug (Years) type Country Outcome Cost diff.a similarb ICER Source
Donepezil 5 Markov United Kingdom Severity −3,152 12,671 2,094–21,991 Stewart et al. (1998)
Donepezil 5 Markov Canada Severity 1,067 <0 <0–10,435 O’Brien et al. (1999)
Donepezil 5 Markov Sweden Severity 507 <0 <0–4,026 Jönsson et al. (1999b)
Donepezil 2 Markov United States QALYs 108 <0 <0–624,295 Neumann et al. (1999)
Donepezil 2 Markov Japan QALYs 303 <0 <0–52,913 Ikeda et al. (2002)
Rivastigmine 2 Survival Canada QALYs 522 <0 Threshold analysis Hauber et al. (2000)
different WTPs
Galantamine 10 AHEAD Canada QALYs 927 <0 <0–50,791 Getsios et al. (2001)
Galantamine 10.5 AHEAD Sweden NNT 3,823 <0 NA Garfield et al. (2002)
FTCc
Galantamine 10.5 AHEAD United States NNT FTC 4,988 <0 <0–18,539 Migliaccio-Walle
et al. (2003)
Galantamine 10 AHEAD The Netherlands QALYs 2,206 <0 <0–6,412 Caro et al. (2002)
Galantamine 10 AHEAD United Kingdom QALYs −972 17,547 11,727–35,184 Ward et al. (2003)
Memantine 2 Markov United Kingdom QALYs 3,882 <0 <0–291,670 Jones et al. (2004)
Memantine 5 Markov Finland Depend 2,061 <0 <0 in 94% of Monte François et al. (2004)
Carlo simulations
Memantine 5 Markov Canada QALYs 16,126 <0 <0 all scenarios Jönsson (2005)
Donepezil 10 DESd United Kingdom QALYs 9,597 <0 <0 in all scenarios Getsios et al. (2010)
Donepezil 2 Markov Japan QALYs −3,320 −5,428 −3,320 to −11,253 Kasuya and Meguro (2010)

DMTe 10 DES UK QALYs 77,520 <0 <0 in all scenarios Guo et al. (2014)
DMT 20 Markov Sweden QALYs −35,898 −43,998 −793 to −314,027 Skoldunger et al. (2013)

Abbreviations: Cost diff., cost difference; ICER, incremental cost-effectiveness ratio; QALYs, quality-adjusted life years; AHEAD, Assessment of Health Economics in Alzheimer’s
disease; NA, not available.
a A positive value indicates net savings with treatment with ChEIs.

b A positive value indicates a cost per gained QALY/avoided deterioration in severity; <0 cost savings and a positive outcome.

c Number needed to treat to avoid full-time care.

d Discrete events simulation.

e Disease-modifying treatment.

reflects basic care for people with dementia and therefore
we use the term ‘programmes’. We also regard multidomain
packages including lifestyle changes and basic drug treat-
ment as programmes. The economic literature in this field is
sparse and heterogenous, but some studies have been pub-
lished (Table 37.6), both with empirical data and with mod-
elling approaches. The problem with the empirical studies,
besides their heterogeneity, is that study samples are often
small, resulting in weak statistical power and wide confi-
dence intervals. Bootstrapping methods can partly com-
pensate for that.
37.4.6 HANDLING UNCERTAINTY
In any economic analysis, it is important to include a
discussion of uncertainty (Briggs and O’Brien, 2001)
and to test the robustness of the analysis in a sensitiv-
ity analysis. Roughly, there are two major approaches for
sensitivity analyses: deterministic and probabilistic sen-
sitivity analysis. With the deterministic approach (such
as one-way or two-way/multiple-way sensitivity analysis),
one or perhaps two inputs are varied at each occasion.
In a probabilistic sensitivity analysis, several inputs’ sta-
tistical variability (such as standard deviations) is var-
ied randomly and simultaneously with several iterations.
Examples of inputs that are varied in a sensitivity analy-
sis are unit costs for different items and discount rates.
In dementia, one of the most important cost drivers is
the cost of informal care. Both the quantities (What kind
of informal care activities are included?) and the costing
approach may be of interest to vary. The range in costs of
informal care can vary a lot depending on how it is quan-
tified and price fixed.
As shown in Table 37.2, it is obvious that dementia care
is very costly globally, but the great range in cost figures
from the sensitivity analysis in Table 37.3 illustrates that
depending on assumptions, the resulting costs may vary
considerably.
37.5 EVALUATION BY DISEASE
SEVERITY
37.5.1 COSTS AND DISEASE SEVERITY
There is a strong relationship between costs of dementia care
and the severity of dementia. In a population-based Swedish
COI study with a bottom-up approach (Wimo et al., 2009),
where costs were expressed in terms of the CDR, the cost
ratio between severe dementia and no decline was 6.5 (Table
37.7). There is also a strong association between costs and
functional decline (Quentin et al., 2009), and ADL capac-
ity is also a stronger predictor of costs than cognition
(Gustavsson et al., 2011; Lindholm et al., 2013).
Health economic aspects of dementia 379
37.5.2 MILD COGNITIVE IMPAIRMENT
(MCI)
With the hopes for DMT and prevention of dementia, there
is now an interest to include interventions that start in MCI
(or similar concepts) in economic evaluations. Such evalu-
ations also include cost-effectiveness discussions regarding
diagnostic methods, such as biomarkers. Health economic
evaluations of MCI can be divided into short-term and
long-term effects (Wimo and Winblad, 2003a). In the short
term, an intervention can perhaps result in a reduction of
informal care in terms of IADL. Thus it is questionable
whether the costs of an intervention will be offset from a
short-term viewpoint. In the long run, the question will be
whether survival is affected and whether there will be any
transitions of symptoms and resource use during the course
of the dementia. To design studies to answer these questions
is not easy. A synthetic approach with RCTs covering seg-
ments of the dementia course, modelling studies and open
follow-up studies probably will be needed, resulting in some
kind of ‘best guess’ judgement. Modelling seems to be the
most appropriate method and some of the modelling stud-
ies in Tables 37.6 and 37.7 starts in MCI. One model with
a hypothesized DMT starting in MCI showed no cost sav-
ings but with a standard willingness-to-pay level, the DMT
could be regarded as cost-effective (Skoldunger et al., 2013).
37.5.3 SEVERE DEMENTIA
Several years in the course of dementia are spent in the stage
of severe dementia (Winblad et al., 1999). In a model of a
Swedish cohort, the course of dementia with an estimated
survival up to 9 years was simulated (Wimo et al., 1998c).
About 75% of the total costs occurred in severe dementia,
indicating that the maximal span for benefits during the
total course in terms of cost reduction is only 25%, if efficacy
is shown only for mild-to-moderate dementia. The results
indicate that severe dementia must be the focus for improved
care and research. Many of the instruments we use for out-
come research show floor effects in severe dementia and
they are not sufficiently sensitive to detect clinically relevant
changes (Winblad et al., 1999). There are studies that have
shown positive effects in severe dementia for memantine
(Reisberg et al., 2003), donepezil (Winblad et al., 2006) and
to some extent galantamine (Burns et al., 2009), but health
economic studies for severe dementia are rare (one example
is a study on memantine [Wimo et al., 2003b]).
37.6 CONCLUSIONS
The health economics of dementia is still in a premature state,
even if the number of published studies is increasing. There is
a great need for methodological improvement. In view of the
increasing number of people with dementia and existing as
 380 Dementia
Table 37.6 Economic evaluations of programmes (costs are inflated as $US 2014)
Sensitivity
ICER in base analysis or
Programme Design Country Duration Outcome Results option similar Source
Day Care Prospective Sweden 6 months WY −4,018 11,941/WY NA Wimo et al. (1990)
non-RCT
Day Care Prospective Sweden 1 year QALYs 5,865 Neutral NA Wimo et al. (1994)
non-RCT
Caregiver Prospective RCT Canada 6 months QALYs 1,021 30,799/QALY NA Drummond et al. (1991)
support
Group Living Markov model Sweden 8 years QALYs 12,763 Dominance <0 in all Wimo et al. (1995)
scenarios
Caregiver CBA model Switzerland ? Monetary Dominance <0 in all Nocera et al. (2002)
support scenarios
Caregiver Markov model Finland 5 years QALYs 3,834 Dominance 71% of Monte Martikainen et al. (2004)
support Carlo
simulations
cost saving
and QALY
gaining
Case RCT + The Netherlands 6 months ‘Successful 294 5,167/unit 95% vs. WTP of Melis et al. (2008)
management bootstrapping treatment’ 37,800
Case RCT + The Netherlands 3 months ‘Successful 2,691 Dominance(94% 99% vs. WTP of Graff et al. (2008)
management bootstrapping treatment’ probability) 2,200 per
‘successful
treatment’
Case RCT + The Netherlands 1 year QALYs 100 2,129/QALY 72% vs. WTP of Wolfs et al. (2007)
management bootstrapping 50,000
Caregiver Prospective Sweden 5 years QALYs 90/month NA NA Dahlrup et al. (2013)
support non-RCT
Caregiver RCT + The Netherlands 1 years QALYs −6,326 240,164 <0 to 2,001,862 Joling et al. (2013)
support bootstrapping
Diagnostic + DES model United States Lifetime QALYs 12,029 Dominance <0 in all Guo et al. (2012)
donepezil scenarios
Multidomain Markov model Sweden/Finland 20 years QALYs 3,300 Dominance <0 to 64,105 Zhang et al. (2011)
package

Notes: CBA, cost–benefit analysis; RCT, randomized controlled trials; WY, well years.

Table 37.7 Societal costs of dementia in Sweden in relation
to Clinical Dementia Rating (CDR) (costs are inflated as
$US 2014)
Cognitive
CDR decline Gross costs Net costs
0 None 8,000 – Bergner, M., Bobbitt, R.A., Carter, W.B. and Gilson, B.S.
0.5 Light 22,000 – (1981). The Sickness Impact Profile: Development and
1 Mild 31,400 23,400
2 Moderate 43,000 35,000
3 Severe 51,900 43,900
Wimo, A. et al., Läkartidningen, 106, 1277–1282,
Source: 
2009.
well as new drugs in the pipeline, there is also great interest in
pharmacoeconomics among the drug authorities in different
countries and in the pharmaceutical companies engaged in
drug development. The sparse economic literature on differ-
ent care programmes and prevention is also a great challenge.
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Global challenge of dementia: What can be
done?
CLEUSA P. FERRI, MAËLENN GUERCHET AND MARTIN PRINCE
38.1 GLOBAL CHALLENGE OF
DEMENTIA
Demographic ageing has been a much more rapid process in
all world regions than anticipated, with the population aged
60 and over increasing at the fastest pace ever in developing
countries (World Population Prospects, 2003). Globally, the
numbers and proportion of older people are sharply increas-
ing. In 2012, 23% of the population in high income countries
was aged 60 years or over, and this is predicted to increase
to 32% by 2050. This proportion in low- and ­middle‑income
countries (LMIC) was just 9% in 2012 but will be more than
double by 2050, reaching 19%. Currently, 66% of the world’s
older population live in LMIC, and by 2050, 79% will do so
(World Population Prospects, 2013). Chronic non-commu-
nicable diseases, which have been under-prioritized in the
public health agenda for a long time, are now assuming a
greater significance in LMIC.
Co-morbid health conditions are particularly common
among older people with physical conditions affecting dif-
ferent organ systems coexisting with mental and cogni-
tive disorders. Dementia has a disproportionate impact on
dependency and disability and yet its global public health
importance is still underappreciated. There is a general lack
of awareness of Alzheimer’s and other dementias as medi-
cal conditions. Dementia is under-recognized, even in high-
income countries such as the United Kingdom, where the
national under-detection rate is about 52% (Department of
Health, 2013). This under-recognition seems to be accen-
tuated in LMIC, where they are commonly perceived as a
normal part of ageing (Patel and Prince, 2001; Lopez et al.,
2014). In India, Dias and Patel (2009) reported that 90%
of patients with dementia recruited into a trial in primary
care had not been diagnosed, and in Brazil rates of under-
diagnosis might be as high as 77% (Nakamura et al., 2015).
388
38
Lack of awareness directly affects help-seeking behaviour
and hence the recognition and management of the condi-
tion, which in turn contribute to the burden experienced by
the family and other main carers of people with dementia.
38.1.1 PREVALENCE
Alzheimer’s Disease International (ADI), the umbrella
organization for national Alzheimer’s associations (AA),
has been collating evidence since 2004 on the global preva-
lence of dementia, the projected increases over time and its
impact worldwide.
In 2004, ADI convened a panel of experts to review
the global evidence on the prevalence, numbers of people
affected and its impact. The figures from this consensus
exercise among experts (Ferri et al., 2005) were revisited for
the 2009 World Alzheimer’s Report (Alzheimer’s Disease
International, 2009) when a systematic review of the world
literature on the prevalence of dementia was conducted and
a quantitative meta-analysis was attempted to synthesize
the available evidence for some regions, rather than only
relying on expert consensus as had been done previously.
Since the consensus estimates were published, the global
evidence-base has expanded considerably. There have been
new studies from Europe (Lobo et al., 2007; Fernandez
et al., 2008) and the United States (Plassman et al., 2007),
and an explosion of studies from LMIC and other regions
and groups previously under-represented in the literature
(Alzheimer’s Disease International, 2009) (Latin America,
India, China, Korea, Thailand, Australia [indigenous peo-
ple], Guam, Poland and Turkey). By 2009, 41% (64/158) of
dementia prevalence studies had been conducted in LMIC.
A very different situation compared to 1998, when the 10/66
Dementia Research Group was founded – its title being
derived from the estimate that only 10% of population-based

research had been conducted in LMIC, relative to the two-
thirds of people with dementia living in those regions. The
total number of people with dementia was estimated at
35.6 million in 2010, 48.1 million in 2020 and 90.3 million in
2040, with a projection of numbers doubling every 20 years
(Alzheimer’s Disease International, 2009). Those estimates
were about 10% higher than the previous ones (Ferri et al.,
2005). In 2013, an update used a new systematic review of
the prevalence of dementia in China (Chan et al., 2013) com-
prising 75 studies, and identified seven studies from five sub-
Saharan African countries (Hendrie et al., 1995; Guerchet
et al., 2009; Guerchet et al., 2010; Paraiso et al., 2011; Yusuf
et al., 2011; Longdon et al., 2013; Guerchet et al., 2014), where
previously only one study from Nigeria had been available
(Hendrie et al., 1995). The regional prevalence of dementia
estimated from China and sub-Saharan Africa studies were
substantially higher than those used in 2009 (Prince et al.,
2013b). As more data becomes available, the variation in
prevalence between world regions is reduced.
The 2013 updated estimates were higher than the origi-
nal estimates reported in the 2009 World Alzheimer Report,
with the number of people living with dementia worldwide
estimated at 44.3 million in 2013, reaching 75.4 million in
2030 (15% higher) and 135.5 million in 2050 (17% higher)
(Prince et al., 2013b). Over the next 20 years, the number
of people with dementia is anticipated to increase by 35%
in Europe, 59% in North America, 65% in Southern Latin
America and 69% in developed Asia-Pacific. In comparison,
the percentage increase is expected to be 114% in South East
Asia, 106%–120% in Latin America and 88% in Africa. From
2013 to 2050, the number of people with dementia will have
increased slightly less than twofold in Europe, more than two-
fold in North America, threefold in Asia and fourfold in Latin
America and Africa. While 38% of people with dementia live
in high-income countries, 62% live in LMICs. By 2050, this
proportion will have increased to 71% (Prince et al., 2013b).
38.1.2 INCIDENCE
The most recent available estimates for the global inci-
dence of dementia come from the systematic review con-
ducted for the 2012 World Health Organization (WHO)/
ADI joint report (World Health Organization, 2012) where
34 fully eligible studies were identified. While the evidence
base from Europe and North America dominated, 13 of the
34 studies were from outside these regions, and 10 studies
were conducted in countries with low or middle income.
The incidence of dementia increased exponentially with
increasing age. For all the studies combined, the incidence
of dementia doubled with every 5.9-year increase in age,
from 3.1/1000 person years (pyr) at age 60–64 to 175.0/1000
pyr at age 95 or more. Estimates of the global annual num-
bers of new cases were derived for the year 2010. Number of
new cases increased and then declined with increasing age
in each region; in Europe and the Americas peak incidence
was among those aged 80–89 years, in Asia it was among
those aged 75–84 and in Africa among those aged 70–79.
Global challenge of dementia: What can be done? 389
Worldwide, 7.7 million new cases of dementia were antici-
pated each year, implying one new case every 4.1 seconds;
3.6 million (46%) would impact in Asia, 2.3 million (31%) in
Europe, 1.2 million (16%) in the Americas and 0.5 million (7%)
in Africa.
For the year 2010, prevalence (35.6 million cases) was 4.6
times annual incidence, suggesting an approximate average
survival from onset of 4.6 years, broadly consistent with
earlier estimates from case series (Fitzpatrick et al., 2005).
38.1.3 BURDEN
The number of people worldwide affected by dementia
provides one indicator of the impact of the disease, with-
out fully capturing the problem for the individual affected,
their families and society. The impact of dementia can be
understood at three levels: (1) The person with dementia,
who experiences ill health, disability, impaired quality of
life and reduced life expectancy; (2) The family and friends
of the person with dementia, who in all world regions, pro-
vide the cornerstone of care and support for the person with
dementia; (3) Wider society, health and long-term care sys-
tems and lost productivity.
The Global Burden of Disease study shows that non-
communicable diseases are rapidly becoming the dominant
causes of ill-health in all developing regions except sub-
Saharan Africa (Fuster and Voute, 2005). Dementia is one
of the main causes of disability in later life, but it is impor-
tant to understand the contribution of dementia, relative
to that of other chronic diseases. The estimates contained
in the WHO’s Global Burden of Disease (GBD) Study, first
published in 1996 and updated to 2010, provide important
evidence in this respect (World Health Organization, 1996;
World Health Organization, 2006; Murray et al., 2012a).
These are highly influential in terms of prioritization for
policymaking and planning at national, regional and inter-
national levels. The key indicator is the disability-adjusted
life year (DALY), a single integrated measure of disease
burden calculated as the sum of years lived with disability
(YLD) and years of life lost (YLL). In the 2010 GBD study,
disability weights were measured for 220 unique health
states after a large-scale empirical survey using a scale from
0 (implying no loss of health) to 1 (implying a health loss
equivalent to death). Disability from dementia was accorded
a disability weight from 0.082 for mild dementia to 0.438
for severe dementia (Salomon et al., 2012), a lower weight
than the one (0.67) attributed in the previous GBD report
(World Health Organization, 2004a). These weights were
equivalent to the disability weights for having tuberculosis
with HIV infection, untreated epilepsy or a major depres-
sive disorder, and slightly lower than those for metastatic
cancer and severe stroke (Salomon et al., 2012). A weight
of 0.44 signifies that each year lived with severe dementia
entails the loss of almost a half of one DALY. According to
the GBD, at the global level, dementia accounted for 11.3
million DALYs and was one of the 15 causes with the largest
increase. Alzheimer’s disease (AD) and other dementia were
390 Dementia
ranked the 49th leading cause of DALYs in 2010 globally,
but were the 11th and 12th in Western Europe and high-
income North America, respectively (Murray et al., 2012b).
Around half of all people with dementia need personal
care and the others will develop such needs over time. People
with dementia have special needs for care. Compared with
other long-term care users they need more personal care,
more hours of care and more supervision, all of which is
associated with greater caregiver strain, and higher costs
of care. Inevitably, the number of dependent older people,
including those with dementia, will increase markedly in
the coming decades, particularly in middle-income coun-
tries (Prince et al., 2013c).
The economic costs of dementia are enormous. These
can include the costs of (1) ‘formal care’ – healthcare, social/
community care, respite and long-term residential or nurs-
ing home care and (2) ‘informal care’ – unpaid care by family
members including their lost opportunity to earn income.
The total estimated worldwide costs of dementia were
US$604 billion in 2010, equivalent to 1% of the world’s gross
domestic product (Wimo et al., 2013). Low-income countries
accounted for just less than 1% of total worldwide costs (but
14% of the prevalence), middle-income countries for 10%
of the costs (but 40% of the prevalence) and high-income
countries for 89% of the costs (but 46% of the prevalence).
About 70% of the global costs occurred in just two regions:
Western Europe and North America. These discrepancies
are accounted for by the much lower costs per person in
lower-income countries – US$868 in low-income countries,
US$3,109 in lower-middle-income, US$6,827 in upper-mid-
dle-income and US$32,865 in high-income countries.
These costs are driven mainly by social care needs;
healthcare costs account for a small proportion of the total,
given the low diagnosis rate, limited therapeutic options
and the underutilization of existing evidence-based inter-
ventions (Prince et al., 2011b). In all world regions, informal
care provided by family, friends and the community is the
cornerstone of the care system. In lower-income countries,
these informal care costs predominate, accounting for 58%
and 65% of all costs in low-income and middle-income
countries, respectively, compared with 40% in high-income
countries. Conversely, in high-income countries, the direct
costs of social care (professional care in the community, and
the costs of residential and nursing home care) account for
the largest element of costs – 42%, compared with only 14%
in LMIC where such services are not generally available. In
LMIC, despite larger, extended families, the psychologi-
cal and economic strain on family caregivers is substan-
tial (Honyashiki et al., 2011; Prince et al., 2012). Typically,
around a fifth of carers have cut back on paid work, and
paid carers are becoming common in some cities adding to
the economic burden; compensatory benefits are practically
non-existent (Alzheimer’s Disease International, 2009).
Worldwide, the costs of dementia are set to soar. The
World Alzheimer Report 2010 tentatively estimated an 85%
increase in costs by 2030, based only on predicted increases
in the numbers of people with dementia (Wimo et al., 2010).
Costs in LMIC are likely to rise faster than in high-
income countries, for several reasons. Wage levels are rising
rapidly, and hence, so is the opportunity cost or replacement
cost of informal care. While currently very few people with
dementia in those regions live in care homes, this sector is
expanding rapidly, particularly in urban settings in mid-
dle-income countries, boosted by demographic and social
changes that reduce the availability of family members to
provide care. Medical help-seeking is relatively unusual;
demand for medical care is likely to increase in the future,
with improved awareness, better coverage of evidence-based
interventions, and, possibly, more effective treatments.
The 10/66 Dementia Research Group has also examined
the economic impact of dementia in its pilot study of 706
persons with dementia, and their caregivers, living in Latin
America, India, China and Nigeria (Prince, 2004). One of the
key findings from this study, from the development perspec-
tive, was that caregiving in the developing world is associated
with substantial economic disadvantage. A high proportion
of caregivers had to cut back on their paid work to care. Many
carers needed and obtained additional support, and while
this was often informal unpaid care from friends and other
family members, paid caregivers were also relatively com-
mon. People with dementia were heavy users of health ser-
vices, and associated direct costs were high. Compensatory
financial support was negligible; few older people in devel-
oping countries receive government or occupational pen-
sions, and virtually none of the people with dementia in the
10/66 study received disability pensions. Carers were com-
monly in paid employment, and almost none received any
form of carer allowance (Prince, 2004). The combination of
reduced family incomes and increased family expenditure
on care is obviously particularly stressful in lower-income
countries where so many households exist at or near to
subsistence level. While healthcare services are cheaper in
low-income countries, in relative terms, families from the
poorer countries spend a greater proportion of their income
on healthcare for the person with dementia. They also tend
selectively to use the more expensive services of private doc-
tors. Numerous studies have shown that the costs of caring
can extend beyond demands on time and money and can
affect the carer’s health and morale for a longer term.
38.1.4 FUTURE TRENDS IN THE
PREVALENCE, INCIDENCE OF
DEMENTIA AND SURVIVAL WITH
DEMENTIA
All current projections of the scale of the coming dementia
epidemic, including those published by ADI (Alzheimer’s
Disease International, 2009; Prince et al., 2013b), assume
that the age- and gender-specific prevalence of dementia
will not vary over time, and that population ageing alone
(increasing the number of older people at risk) drives the
projected increases (Ferri et al., 2005; Alzheimer’s Disease
International, 2009; Prince et al., 2013a; Prince et al., 2013b).

The basis for this assumption is uncertain, since preva-
lence is a product of incidence and survival with dementia,
and a fall in either or both of these indicators would lead
to a fall in age-specific prevalence (Alzheimer’s Disease
International, 2009). A decline in age-specific incidence, at
least in high-income countries, was theoretically possible,
driven by changes in exposure to suspected developmental,
lifestyle and cardiovascular risk factors for dementia.
The 2014 World Alzheimer Report focused upon demen-
tia risk reduction; the evidence-base for modifiable risk
factors for dementia (Prince et al., 2014a). The strongest
evidence for possible causal associations with dementia was
those of low education in early life, hypertension in midlife,
and smoking and diabetes across the life course.
In most world regions, each generation is better edu-
cated than the one before. Although trends differ between
countries, genders, age groups and time periods, there has
been a general trend in high-income countries towards less
smoking, falling total cholesterol and blood pressure levels
and increasing physical activity. However, the prevalence
of obesity and diabetes has been increasing in most devel-
oped countries. The trends in cardiovascular health among
older people in many low- and particularly middle-income
countries are in an adverse direction (Prince et al., 2015),
with a pattern of increasing stroke (Feigin et al., 2009) and
ischaemic heart disease (Critchley et al., 2004; Gupta et al.,
2008; Gaziano et al., 2010) morbidity and mortality, linked
to an epidemic of obesity, and increasing blood pressure lev-
els (Anand and Yusuf, 2011).
After a lag period, to the extent that these factors are gen-
uinely causally associated with dementia, one would expect
to see corresponding reductions (or increases) in the inci-
dence of dementia. The net effect on survival with dementia
is harder to estimate, and other factors, for example, stan-
dards of health and social care for people with dementia,
and provision of life-prolonging critical interventions,
might also be expected to have an influence.
In 2009, very few data that were available from certain
high-income countries did not suggest any clear pattern of
a decline or increase over time in either the incidence or
prevalence of dementia (Alzheimer’s Disease International,
2009). Meta-analyses of European studies conducted since
1980 did not suggest any secular trend in prevalence (Prince
et al., 2013a, 2014).
Just a few years later, and linked to a greatly increased
interest in the potential for prevention of dementia by
targeting modifiable risk factors (Barnes and Yaffe, 2011;
Lincoln et al., 2014), the quality and extent of the evidence
has expanded greatly, with several studies monitoring
trends in prevalence and/or incidence and dementia mor-
tality within defined populations, using identical or similar
research methodology over time.
Findings across these studies conducted, mainly, in
high-income countries, are currently too inconsistent to
reach firm and generalizable conclusions regarding under-
lying trends. While some studies have suggested substantial
recent declines in the prevalence (Lobo et al., 2007; Langa
Global challenge of dementia: What can be done? 391
et al., 2008; Matthews et al., 2013), or incidence of dementia
(Schrijvers et al., 2012; Gao et al., 2014; Satizabal et al., 2014)
this has not been consistently replicated in all other studies
of this type (Sekita et al., 2010; Mathillas et al., 2011; Rocca
et al., 2011; Qiu et al., 2013; Gao et al., 2014).
The relationship between trends in prevalence, inci-
dence and mortality are particularly unclear, particularly
since in none of the studies were all three of these param-
eters directly observed. If the onset of dementia occurs
close to the end of the natural life span, fewer years will
be lived with dementia. Langa et al. (2008) described this
phenomenon as ‘the compression of cognitive morbidity’,
a desirable outcome for public health and individual qual-
ity of life, resulting in longer, healthier lives, with fewer
years spent in a state of reduced independence and need-
ing care.
Two studies suggest that decline in incidence may be
greater in younger age groups, suggesting that the incidence
of dementia may be being deferred into older age (Gao
et al., 2014; Satizabal et al., 2014). In two other studies, sur-
vival with dementia seemed to be decreasing (Langa et al.,
2008; Doblhammer et al., 2014), supporting the notion of
‘compression of cognitive morbidity’ (Langa et al., 2008).
However, in other studies survival with dementia seemed to
be increasing (Schrijvers et al., 2012; Qiu et al., 2013), or this
could be inferred from a pattern of stable prevalence with
declining incidence (Gao et al., 2014; Rocca et al., 2011).
There is some suggestion that favourable trends are less
evident in more deprived high-income country populations
(Rocca et al., 2011). Only two studies have been conducted
outside of Europe or the United States; in Japan, prevalence
had increased (Sekita et al., 2010), while in Nigeria incidence
was stable (Gao et al., 2014).
Evidence from systematic reviews of prevalence studies
in China and other East Asian countries suggests a worry-
ing trend towards an increase in the prevalence of dementia
over the last 20 years (Chan et al., 2013; Wu et al., 2014). This
would be consistent with adverse changes in cardiovascular
health in this region. A recent modelling exercise assessed
the likely impact of recent increases in obesity among
middle-aged Chinese on dementia prevalence, assuming
a causal link with dementia; it concluded that the future
dementia prevalence in China may have been underesti-
mated by up to 19% given the additional impact of epide-
miologic transition (Loef and Walach, 2012).
The future course of the global dementia epidemic,
through to 2050 is therefore likely to depend upon the suc-
cess or otherwise of continuing efforts to improve public
health (Prince et al., 2014; Lincoln et al., 2014). Those who
will be old in 2050, were born around the 1970s, and have
already received their basic education. They are now in
their third and fourth decades of life, a crucial ‘sensitive
period’ where, evidence suggests, efforts to prevent, detect
and control obesity, hypertension, diabetes and high cho-
lesterol are likely to have maximum positive impact upon
brain health and dementia risk in late-life (Prince et al.,
2014; Lincoln et al., 2014).
392 Dementia
Previous modelling exercises have sought to predict
what might happen to the prevalence of dementia, given
our best estimates of risk associations, and possible changes
in those risk factor profiles over time (Loef and Walach,
2012; Norton et al., 2014). An alternative approach is to
observe and correlate actual changes in risk factor profiles
and dementia incidence over time. This is a well-estab-
lished modelling approach in the cardiovascular disease
field and has contributed greatly to our understanding of
the potential for prevention, and the attribution of changes
in disease incidence to specific factors (Laatikainen et al.,
2005; Ford et al., 2007; Vartiainen et al., 2010). Similar
studies could, in the future, be carried out to monitor the
impact of prevention programmes on the future scale of
the dementia epidemic.
38.2 WHAT CAN BE DONE?
The increasing global burden of dementia will require strong
commitment and leadership from different parts of society,
especially from policymakers and health professionals to
place dementia higher up in the global health agenda, to
improve the lives of people with dementia. Concrete actions
can be taken to build quality into the process of care and
support for people with dementia and their caregivers.
Dementia has already become and is becoming a health
priority in an increasing number of countries, including
Australia, Denmark, England, Finland, France, Israel, the
Netherlands, Norway, Scotland, South Korea, Switzerland,
Taiwan and the United States. The key elements of these
countries plans are: to raise awareness; to improve diagno-
sis and treatment; and to increase the capacity of healthcare
systems to respond to the challenge of the increasing num-
ber of people with dementia.
The key elements for countries with limited resources
will differ in its contents and process of implementation and
they should start with initiatives that have the maximum
impact for as many people as possible. ADI has developed
a graduated approach for countries with limited resources
(Alzheimer’s Disease International, 2009), illustrated in
Table 38.1 A graduated approach to dementia service development
Awareness and
understanding Capacity building Risk reduction
The public • Family carers • Diet
Health and care • Primary healthcare • Exercise
service decision workers • Social interaction
makers • Resource
acquisition
• Legislative and
policy
framework
Source: Alzheimer’s Disease International, World Alzheimer Report 2009, Alzheimer’s Disease International, London, 2009.
Table 38.1. This focuses initial attention on awareness and
understanding and from this, moves on to risk reduction
and the underlying issues of capacity building and resource
development. Service development starts in primary care,
before secondary care can be considered because this will be
more equitable, benefiting more people with dementia and
their families. It has the potential to prevent or at least delay
the need for expensive institutional services that few families
can afford.
38.2.1 INCREASING AWARENESS –
DECREASING STIGMA
Awareness raising and increasing understanding are impor-
tant to counter the fatalism and stigma that are often asso-
ciated with dementia. The heart of awareness raising is to
explain that dementia is an illness/disease, that it is not an
inevitable consequence of ageing, and that it is worth assist-
ing family carers and people with dementia to live as normal
a life as possible for as long as possible. Efforts to increase
awareness must be accompanied by health system and ser-
vice reform, so that help-seeking is met with a supply of
better-prepared and more responsive services. Awareness
raising and increasing understanding is also essential for all
those involved in decision making about dementia services.
Without a basic understanding of the nature of the illness,
its social and economic consequences and the practical steps
that can be taken, it is unlikely that either existing services
will be redesigned or enhanced or that new services will be
considered.
ADI identified raising awareness of dementia among
people in general, carers and health workers as a global pri-
ority (Graham and Brodaty, 1997) as follows:
1. A critical mass of informed carers can assist aware-
ness-raising, provide advice and support to families,
and can work with Alzheimer’s associations to lobby
for more services that better meet their needs.
2. Community solidarity can effect change through sup-
port for policies based on equity and justice – equal
access to health and social care, and welfare benefits.
Aware communities can provide support, and reduce
Service development Service development
• Primary care • Secondary care
• Community • Institutional care
support for
families

stigma and exclusion of those with dementia and
their carers. Policymakers can be held to account
by media campaigns and advocacy from committed
non-governmental organizations (NGOs). In high-
income countries awareness is growing rapidly, with
the media playing an important part (Prince et al.,
2008). Recent evidence-based reports from the United
Kingdom and the Australian Alzheimer associations
garnered media attention and were instrumental in
making dementia a national priority. Media in LMIC
can be receptive to these stories, informing the public
and stimulating debate, but efforts are required to
alert them to the importance of ageing and demen-
tia, and to build their capacity to report the problem
(Prince et al., 2008).
3. Intergenerational solidarity can be promoted through
awareness-raising among children and young adults.
In many LMIC, children or children-in-law are the
most frequent carers for people with dementia (Choo
et al., 2003; Prince, 2004; Dias et al., 2004), and the
most likely to initiate help-seeking. A high proportion
of people with dementia in LMIC live in multigen-
erational households with young children, and their
carers will have divided responsibilities. Children
will be future carers of older parents, and future older
people. They are receptive, and easily accessed through
schools.
4. The provision of disability pensions and carer ben-
efits will inevitably increase requests for diagnostic
assessment.
5. Increasingly the voices of people who have been
diagnosed with dementia are being heard, either singly
(Taylor, 2009) or collectively (Group SDW, 2009).
By describing their experiences of how it feels to be
diagnosed with dementia and their need for support-
ive services, they are challenging the stigma associated
with dementia and the lack of public understanding of
dementia.
38.2.2 IMPROVING THE CAPACITY OF
EXISTING SERVICES
38.2.2.1 Recognition and diagnosis
Dementia is a hidden problem, especially in LMICs, with
little help-seeking despite the high burden it poses to
carers and families. Dementia is in many settings seen
as ‘normal’ ageing and there is reluctance from family,
patients and health workers to dementia diagnosis as it
carries an important burden of stigma. However, recogni-
tion is the first step in enhancing the capacity of family
carers to look after their relative with dementia, and to
empower them in their interaction with service provid-
ers. It can be boosted by community dissemination of
information from government, healthcare providers and
Global challenge of dementia: What can be done? 393
media. Also, help-seeking can be promoted by proac-
tive case finding. In India and Brazil, community health
workers (CHWs), after brief training, were able to identify
likely cases of dementia in the community with a posi-
tive predictive value of 66% (Shaji et al., 2002; Ramos-
Cerqueira et al., 2005).
Another step in recognizing/diagnosing dementia is test-
ing. Population screening is not considered cost effective,
even in high-income countries (National Collaborating
Centre for Mental Health, 2007). Only a few trials evalu-
ating dementia screening in primary care have been per-
formed, with little evidence on its benefits and potential
harms (Brayne et al., 2007). Selective screening of those
having a prior index of suspicion can be carried out either
by cognitive testing, or informant report of cognitive and
functional decline. The mini-mental state examination
(MMSE) (Folstein et al., 1975) is the most widely used cog-
nitive screen, and adapted versions have been normed for
use in many LMIC (Bird et al., 1987; Ganguli et al., 1995;
Brucki et al., 2003; Xu et al., 2003; Castro-Costa et al., 2008).
However, it takes 10 minutes to administer and is prone to
educational and cultural bias (Black et al., 1992; Ng et al.,
2007). A systematic review of 16 brief screening assess-
ments identified three (the General Practitioner Assessment
of Cognition, Mini-Cog, and Memory Impairment Screen),
taking less than five minutes to administer, that were con-
sidered suitable and valid for routine use in general practice,
but they have not been validated in poorer settings (Brodaty
et al., 2006).
In high-income countries, diagnosis would typically
be carried out by specialist dementia services, not widely
available in LMIC. The 10/66 Dementia Research Group’s
culture and education-fair diagnostic protocol is validated
across many LMIC countries, cultures and languages
(Prince et al., 2003; Liu et al., 2005), but would need adap-
tation for routine clinical use. Good practice guidelines
(National Collaborating Centre for Mental Health, 2007)
advocate a ‘dementia screen’ to exclude treatable causes
of dementia; haematology, biochemistry (electrolytes, cal-
cium, glucose, renal and liver function), thyroid function
tests, serum vitamin B12 and folate levels are routinely rec-
ommended, testing for syphilis or HIV is indicated only
for those at risk. Feasibility and cost effectiveness needs to
be tested in LMIC.
Disclosure of dementia diagnosis is considered by pri-
mary care physicians the most difficult area in dementia
management (Bamford et al., 2004). A recent systematic
review identified eight domains of good practice for dis-
closing dementia diagnosis – preparation; integrating fam-
ily members; exploring the patient’s perspective; disclosing
the diagnosis; responding to patient reactions; focusing on
quality of life and well-being; planning for the future; and
communicating effectively (Lecouturier et al., 2008) The
person being assessed should be asked if they, and/or oth-
ers wish to be told the diagnosis. They should then be pro-
vided with information about the signs and symptoms of
dementia, course and prognosis, available treatments, local
394 Dementia
care and support services. Medicolegal issues may be dis-
cussed, including financial and testamentary capacity and
driving safety.
38.2.2.2 Prevention
Emerging evidence, based mainly upon systematic
reviews and meta-analyses of observational epidemiologi-
cal data supports the notion that the future scale of the
dementia epidemic may be reduced by action taken now
to reduce exposure to modifiable risk factors. In January
2014, a meeting in Blackfriars, London, United Kingdom
was hosted by the UK Health Forum and Public Health
England to discuss the relationship between risk factors
for dementia and cardiovascular diseases. The result-
ing ‘Blackfriars Consensus’ statement was published in
the Lancet (Lincoln et al., 2014), and is supported by 60
experts and organizations in dementia and non-commu-
nicable diseases (NCD) prevention. The statement includes
the recommendation that
Recent evidence suggests that risk in the popu-
lation might be reduced so that fewer people at
particular ages develop dementia. The scientific
evidence is evolving rapidly and sufficient to jus-
tify considered action and further research on
dementia risk reduction, both by reducing the
modifiable risk factors and improving the recog-
nised protective factors.
In September 2014, ADI launched the World Alzheimer
Report 2014 – Dementia and Risk Reduction: An Analysis
of Modifiable Risk Factors (Prince et al., 2014). The report
systematically reviews the evidence in four domains: devel-
opmental, psychological and psychosocial, lifestyle and
cardiovascular risk factors. The conclusion is that there is
particularly robust evidence that low education, hyperten-
sion in midlife and diabetes and smoking from mid- to late-
life increase the risk of developing dementia.
A recent systematic review of the epidemiological evi-
dence for AD risk reduction focusing on seven risk fac-
tors for which there was evidence of independent effects
on AD incidence; diabetes, midlife hypertension and
obesity, depression, physical inactivity, smoking and low
education; assessing evidence pertaining to the United
States and the population worldwide (Norton et al., 2014).
Relative risks were combined with the prevalence of the
risk factor in the population to compute a population
attributable risk (PAR) – the proportion of cases of AD in
the population that might be prevented if the risk factor
could be removed entirely. From the worldwide perspec-
tive, the most promising strategies for prevention were
the elimination of physical inactivity (12.7% of AD cases
prevented), smoking (13.9%) and low education (19.1%).
This is because these factors are both relatively common
and strongly associated with incident AD. If all of the
risk factors were eliminated, then a total of up to 28.2%
of all cases of AD worldwide might be prevented. This is
implausible – a more realistic 10% reduction in the preva-
lence of the risk exposures would lead to an 8% reduction
in the prevalence of dementia through to 2050, while a
20% reduction in exposure prevalence would lead to a 15%
reduction in dementia prevalence (Norton et al., 2014).
Prevention could in principle be highly cost effective,
considering the high cost attached to the care and treatment
of those with dementia. With changing lifestyles, expo-
sure levels to cardiovascular disease risk factors and rates
of cardiovascular disease are rising rapidly in many LMICs
(Prince et al., 2015).
In comparison with the situation in most high-income
countries, efforts to prevent and control the coming epi-
demic of cardiovascular and other chronic diseases in
most of the LMICs are in their infancy (Epping-Jordan
et al., 2005). Advocated measures include the implementa-
tion of tobacco-free policies, taxation of tobacco products,
comprehensive bans on advertising of tobacco products,
salt reduction through voluntary agreements with the food
industry, reduction in alcohol intake, increases in activ-
ity levels and combination drug therapy for those at high
risk of cardiovascular disease (Beaglehole et al., 2012). The
detection and control of hypertension, hyperlipidaemia,
diabetes and metabolic syndrome is poorly implemented
by overstretched primary care services that struggle to
cope with the double burden of historic priorities (mater-
nal, child and communicable diseases) and the increase of
chronic disease in adults.
38.2.2.3 Improving treatment
The 10/66 Dementia Research Group’s carer pilot study
conducted in several developing countries (World Health
Organization, 2006) indicated that the people with demen-
tia were using primary and secondary care health services.
Only 33% of people with dementia in India, 11% in China
and South East Asia and 18% in Latin America had used
no health services at all in the previous 3 months. There
was also a heavy use of private medical services, which
might be a reflection of the carer’s perception of the unre-
sponsiveness of services provided by the government.
Many developing countries have in place a comprehensive
community-based primary care system staffed by doctors,
nurses and generic multipurpose health workers, yet pri-
mary healthcare services in LMIC fail older people with
dementia as they are clinic-based and preoccupied with
simple curative interventions, orientated towards acute
rather than chronic conditions (Patel and Prince, 2001;
Shaji et al., 2002; Dias et al., 2004; Prince et al., 2007). A
paradigm shift is needed to encompass continuing care
and support as part of a wider chronic disease strategy.
Given the frailty of many older people with dementia,
there is also a need for outreach, assessing and managing
patients in their own homes. The WHO Innovative Care for
Chronic Conditions (ICCC) framework (Epping-Jordan

et al., 2004) makes no mention of dementia, but the princi-
ples are highly applicable; a dialogue to build commitment
for change; extended, regular healthcare contact; a multi-
sectoral approach; centring care on patients and families,
supporting patients in the community; and an emphasis
on prevention. Dementia care should be an essential com-
ponent of chronic disease care strategies.
Needs for care and support differ for each families, and
ways to make care more person-centred need to be found,
packages of care should be more flexible and individual-
ized. Families need to be guided and supported in accessing
information and exercising choice, with case managers who
can provide continuity and advocacy from early stages and
across the disease progression (Prince et al., 2013c).
38.2.2.4 Reducing costs of treatment
Costs of cholinesterase inhibitors (ChEIs) are now reim-
bursed in many middle-income countries, and prices have
fallen as agents come off patent protection and cheaper
generics become available. This is an active field for drug
development, particularly following the launch of the G7
Global Action Against Dementia, with the stated the aim
of finding a disease modifying treatment or cure by 2025
(RDD/10495, 2013). Any newly developed and effective anti-
dementia drugs are likely to be very expensive, and scaling
up coverage globally, in an equitable way, would raise huge
ethical and practical challenges, most particularly to ensure
access to the two-thirds of people with dementia in LMIC.
The challenges would be similar in many ways to those
addressed by the Global Fund and President’s Emergency
Plan for AIDS Relief (PEPFAR) initiatives for HIV/AIDS.
This would, of necessity, include strengthening the capac-
ity of primary care to diagnose dementia and deliver treat-
ment and care, as part of wider improvements in primary
healthcare for older people (World Health Organization
Maximizing Positive Synergies Collaborative Group et al.,
2009). Costs of primary care and community interven-
tions can be minimized through task shifting to non-
specialist and paraprofessional staff and integration with
more broadly based chronic disease (Epping-Jordan et al.,
2004), disability and elder care programmes (World Health
Organization, 2004; United Nations, 2002).
38.2.3 DELIVERING EFFICACIOUS
TREATMENT
38.2.3.1 General principles to promote
scaling up coverage of dementia
care
In resource-poor countries with few specialists, as for
other mental and neurological priority conditions, task
shifting and sharing to trained and supported non-spe-
cialist health workers is likely to be an essential feature
Global challenge of dementia: What can be done? 395
of any attempt to increase coverage of services for people
with dementia in resource poor settings (Lund et al., 2012;
Hanlon et al., 2014). These non-specialist health workers
would be trained to deliver evidence-based ‘packages of
care’. Packages of care for people with dementia (Prince
et al., 2009) (and other priority mental and neurologi-
cal disorders, including depression) have been developed
by WHO as part of their Mental Health Gap Action
Programme (mhGAP, http://www.who.int/mental_health/
mhgap/). However, as yet, these have not been taken up,
implemented or evaluated for older people. Such single
condition, vertical programmes have limited appeal to pol-
icymakers who struggle to provide equitable access even to
basic age-appropriate medical care for frail and dependent
older people. Structural barriers to progress include health
systems tailored to the provision of acute rather than con-
tinuing care, out-of-pocket user fees that mount up with
chronic disease, and staff who are neither trained nor
experienced in holistic needs-based assessment of older
clients (Albanese et al., 2011). Crucially, access to services
depends upon the ability to attend a primary care facility,
often at some distance from the home.
Since dementia is very often co-morbid with depres-
sion and physical impairments (including undernutrition,
reduced mobility, pain, hearing and vision problems, and
incontinence) (Prince et al., 2011), horizontally struc-
tured comprehensive assessment and intervention, target-
ing frailty and dependence may be the best and simplest
approach to increase coverage of care for older people with
dementia and mood disorders. A new WHO evidence-based
clinical guideline, WHO-COPE (Care for Older People)
is currently being developed by the WHO Department of
Ageing and Life Course to address this need (http://www.
who.int/ageing/about/who_activities/en/index1.html).
WHO-COPE comprises: (1) community case finding of
frail dependent older adults by CHWs; (2) structured com-
prehensive home-based assessment of mental, cognitive and
physical impairments, care arrangements and carer strain;
(3) evidence-based interventions for low mood, confusion,
behaviour disturbance, undernutrition, reduced mobility,
incontinence, low vision and hearing problems.
Wider adoption of packages of care, including invest-
ment and scaling up will only occur with political will
supported by effective dissemination of evidence on cost
effectiveness, detailed manualization, and information
on planning and resource implications for implementa-
tion. Cultural factors will impact on care arrangements,
and how these are best supported, and on the design of
some intervention components to enhance acceptability.
Health system factors, particularly human resources and
regulation will impact on feasibility, with different levels
and types of CHW cadres each with their own capacities
and training needs. It will thus be necessary to test feasi-
bility, acceptability and effectiveness in a range of settings,
making necessary culture and system-specific adaptations
before full implementation.
396 Dementia
Some of the key features of packages of care for people
with dementia are outlined in the following text.
38.2.3.2 Practice-based programmes
Although many LMIC aim to have in place comprehen-
sive community-based primary care system staffed by
doctors, nurses and generic multipurpose health workers,
most have insufficient specialists (psychiatrists, neurolo-
gists, elderly care physicians) dedicated to dementia care
to provide national front line dementia services (Prince
et al., 2009). Initial diagnosis and needs assessment can
be conducted in primary care, although specialist input
would be desirable. A commitment to continuing care is
essential, with regular review, coupled with updated and
holistic assessments of health and social care needs. Case
managers can coordinate this process; this collaborative
care model has been shown to enhance person-centred
care, improve outcomes for people with dementia and
reduce inefficient service use, in some but not all studies,
conducted exclusively in high-income country settings
(Prince et al., 2013c). Specialists, where available, can help
with advice, inpatient or outpatient review of refractory
behavioural and psychotic symptoms of dementia (BPSD)
and respite care.
38.2.3.3 Community-based programmes
Those with dementia are mostly cared for by their families,
especially in LMIC. The 10/66 pilot study (World Health
Organization, 2006) shows that levels of caregiver strain and
psychological morbidity are at least as high as in the devel-
oped world. Carer support programmes are essential for the
management of dementia, and can be delivered by trained
CHWs or peer-to-peer by more experienced carers. Carer
strain should trigger more intensive intervention compris-
ing, as indicated, psychological assessment and treatment
for the carer, respite, and carer education and training. In
practice, such interventions, especially in LMIC, may be
usefully incorporated into horizontally constructed com-
munity-based programmes addressing the generic needs
of frail, dependent older people and their carers, whether
arising from cognitive, mental or physical disorders (Prince
et al., 2009).
Respite care might be an important level of care, as it
aims to decrease caregiver burden and contribute to
increase the time the person with dementia can live at
home. Despite the satisfaction manifested by carers, there is
no clear evidence on its benefits. A recent systematic review
(Lee and Cameron, 2004) that included three randomized
control trials found no evidence of efficacy of respite care
for people with dementia or for their caregivers. However,
the authors found methodological problems in the trials
and suggest that there is a need for more methodologically
sound research before any firm conclusion can be drawn.
Day care and residential care are often more expensive than
targeted home care supplementing family support and care,
and unlikely to be a priority for government investment,
when the housing conditions of the general population are
poor. Nevertheless, even in some of the poorest developing
countries (e.g. China and India), nursing and residential
care homes are opening up in the private sector to meet
the demand from the growing affluent middle class. Good
quality, well-regulated residential care has a role to play
in all societies, for those with no family support, and for
those where family support capacity is exhausted, both as
temporary respite and for provision of longer-term care.
Nevertheless over investment in residential care reduces
the capacity to develop community- and home-based sup-
port services, especially in settings with poor resources. It is
therefore important to balance the development of residen-
tial care and community services for people with dementia.
Absence of regulation, staff training and quality assurance
is a serious concern in developed and developing countries
alike. Important priorities would include a system of regis-
tration and inspection of homes, training of care workers
and provision of medical services for residents to create the
best possible quality care.
Family carers and paid caregivers share much in
common, carrying out difficult, demanding and socially
useful roles, with minimal training and preparation.
Paid carers are usually paid around the minimum wage
and experience low job satisfaction while caregivers are
paid nothing and often experience out-of-pocket costs.
Undervaluing caregivers have a negative impact on qual-
ity of care. All caregivers should be valued and recog-
nized, and recompensed appropriately: incentives to
encourage family to provide care at home, skills devel-
opment and career progression among paid care workers
(Prince et al., 2013c).
Table 38.2 shows ADI’s vision for the pattern of demen-
tia service development (Alzheimer’s Disease International,
2009). It is based on the graduated approach to service
development (see Table 38.1) and recognizes that progress
will depend on the resources available.
We began by stating that the healthcare needs of older
people have been under-prioritized. The full implications
of demographic ageing, the prevalence of dementia and
their impact on both people with dementia and health-
care systems are only just beginning to be recognized.
Nevertheless, there are grounds for optimism: some gov-
ernments have made dementia a national health priority
and we have shown that it is possible for LMICs to take
steps to improve dementia care through primary care
and support for people with chronic illnesses. Now is the
time for governments to act and learn from their emerg-
ing experiences. Future research will play an important
role in evaluating new dementia initiatives and filling
our gaps in knowledge about how to prevent and treat
this disease.
 Global challenge of dementia: What can be done? 397

Table 38.2 Alzheimer’s Disease International’s vision for the pattern of dementia service development
LMICs
Awareness and Public education – dementia as an illness, not an
understanding inevitable part of old age; where to go for help
and information
Risk reduction as part of general health
promotion
Campaigns against stigma and discrimination
Capacity Integrate dementia awareness and understanding
building into primary healthcare planning
Education/training for healthcare professionals,
auxiliary health workers and care workers
Information and training for family carers
Integrate dementia into curricula
Services Detection and diagnosis in primary healthcare
Information, advice and support for family carers
through auxiliary health workers
Treatment of cognitive impairment with ChEIs
where affordable
Care workers employed by families of people
with dementia
Advice and support from primary care if BPSD
become problematic
Source: Alzheimer’s Disease International, World Alzheimer Report 2009, Alzheimer’s Disease International, London, 2009.
Abbreviations: BPSD, behavioural and psychological symptoms of dementia; ChEIs, cholinesterase inhibitors; LMICs, low- and middle-income
countries.
High-income countries
Public education – dementia as an illness, not an
inevitable part of old age; where to go for help
and information
Risk reduction as part of general health promotion
Campaigns for early help-seeking and recognition
of dementia
Campaigns against stigma and discrimination
National plans for dementia services, from
diagnosis to palliative care
Budgets specifically for dementia
Education/training for healthcare professionals,
auxiliary health workers and care workers
Information and training for family carers
Integrate dementia into curricula for healthcare
professionals
Detection and diagnosis shared between primary
and secondary healthcare
Treatment of cognitive impairment with ChEIs
Post-diagnosis support for people with dementia
Information, advice and support for family carers
through self-help groups and specialist
dementia workers
Community-based services for people with
dementia to provide stimulation and help
maintain skills while providing respite for family
carers
Extra support for people with dementia
experiencing BPSD including secondary medical
care
Continuing care in the person with dementia’s
own home for as long as possible
High-quality care homes for people with dementia
no longer able to care for themselves in their
own homes
End of life palliative care

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The international challenge of dementia
KARIM SAAD
39.1 
INTRODUCTION
It may be over a century since Alois Alzheimer published
his report ‘about a peculiar disease of the cerebral cor-
tex’, yet the global challenges of dementia in general and
Alzheimer’s disease (AD) in particular are only just being
recognized as urgent healthcare priorities.
The last decade has ushered in progressive international
engagement and acknowledgement although disease-mod-
ifying treatments, let alone a cure, remain inaccessible, and
inaction is not an option.
What follows is a sample of initiatives, driven by global,
continental and/or visionary individuals, organizations and
countries, propelled by the rising phenomenon of state-
owned dementia plans.
39.2 A GLOBAL PUBLIC HEALTH
PRIORITY
Alzheimer Disease International (ADI), a worldwide fed-
eration of Alzheimer associations representing people with
dementia and their families, has been instrumental in fixing
a global spotlight on AD and other dementias. Established
in 1984, ADI now comprises over 80 member organizations.
ADI has released five World Alzheimer Reports since
2009, outlining the global plight of people with dementia
and the demography of AD and other dementias both in
developed and developing countries (Prince, 2009; Prince,
Bryce and Ferri, 2011). The 10/66 group, refers to the two-
thirds (66%) of people with dementia in low- to middle-
income countries and the 10% of population-based research
carried out in those regions.
In 2013, the global prevalence of dementia, described as
an epidemic, was estimated at 44.4 million people with an
incidence of 7.7 million new cases annually; a new case of
402
39
dementia somewhere in the world being diagnosed every 4
seconds (Alzheimer Disease International, 2013). If we do
nothing, this will increase to an estimated 75.6 million in
2030 and 135.5 million in 2050.
Although, dementia mainly affects older people, 2%–10%
of all cases start before the age of 65. Furthermore, 62% of this
rising prevalence is occurring in developing countries and
by 2050, this will rise to a staggering 71%. The fastest growth
in the elderly population is occurring in China, India, their
south Asian and western Pacific neighbours and Sub-Saharan
African regions. In the next few decades, the global burden of
dementia will shift inexorably to poorer countries, particularly,
rapidly developing middle-income countries that are members
of the G20, but not the Group of Seven countries (G7).
39.3 GLOBAL ECONOMIC IMPACT
The worldwide costs of dementia, estimated at $US604 bil-
lion in 2010, amounted to more than 1% of global gross
domestic product (GDP), varying from 0.24% of GDP in
low-income countries to 1.24% in high-income countries
(Alzheimer Disease International, 2010). Based on cur-
rent financial estimates, if dementia care were a country, it
would be the world’s eighteenth largest economy, ranking
somewhere between Turkey and Indonesia. Social care and
informal care altogether account to over 80% of those costs.
39.4 GLOBAL BURDEN OF CARE
Dementia is one of the main causes of dependence and dis-
ability in old age. As the world population ages, the tra-
ditional system of ‘informal’ care by family, friends and
community will require much greater support (World
Health Organization, 2012). Globally, 13% of people aged
60 or above require long-term care, which is predominantly

about caring for people with dementia; around half of all
older people who need personal care and 80% of older peo-
ple in nursing homes are living with dementia.
In 2008, WHO launched the Mental Health Gap Action
Programme (mhGAP) (World Health Organization, 2008),
which has since then included dementia as a priority condi-
tion. In 2011, the United Nations General Assembly on pre-
vention and control of non-communicable diseases adopted
a political declaration acknowledging that the global burden
of non-communicable diseases (NCDs), including AD, con-
stituted a major challenge for development in this century.
39.5 EMERGENCE OF NATIONAL
DEMENTIA PLANS
Stigma and widespread misconceptions mean that many
people currently living with dementia cannot access a for-
mal diagnosis and therefore, lack access to treatment, care
and advance planning.
Missed diagnosis rates range from 20% to 50% (Olafsdottir
et al., 2000; Valcour et al., 2000; Boustani et al., 2005; Wilkins
et al., 2007) and the estimates are as high as 93% (Dias and
Patel, 2009; Chen et al., 2013). The 2012 World Alzheimer
Report (Alzheimer Disease International, 2012) called for the
creation of high-level governmental plans customized to the
unique culture and demographics of each country. Key rec-
ommendations include the following:
1. Every country should have a national dementia strat-
egy promoting earlier diagnosis, raising awareness and
adequate workforce training.
2. All primary care services should have basic compe-
tency in early detection of dementia, making and
imparting a provisional dementia diagnosis and initial
management of dementia.
3. Where feasible, networks of specialist diagnostic and
treatment centres should be established.
Consequently, the last decade marked an unprecedented
emergence of dementia plans. Australia, England, France,
Norway, Netherlands, Denmark and Republic of Korea were
among the first to launch their plans. France, Australia,
Netherlands and Scotland are examples of countries imple-
menting subsequent plans.
In many countries, sub-national plans are also in process
as the most appropriate level of government to plan strategi-
cally include Australia, Canada, Switzerland and the United
States.
39.5.1 AUSTRALIA
Australia’s first national dementia plan (2006–2010) focused
on healthcare and support dimensions that can best be
achieved nationally, with the cooperation of the Australian
State and Territory Governments, rather than on any
The international challenge of dementia 403
individual jurisdiction’s initiatives. This provided an oppor-
tunity to create a strategic, collaborative and cost effective
response to dementia across Australia.
Australia’s second Framework (Alzheimer’s Australia,
2013) builds on the achievements of the first plan and fol-
lows the stages of dementia care most people will experi-
ence in their journey including: risk reduction, awareness;
assessment, diagnosis, post-diagnostic support and end-of-
life care.
Alzheimer’s Australia has established useful resources,
including support groups, a support hotline and the world’s
first risk reduction ‘Brainy App’ co-developed with Bupa
Health Foundation for smartphones (Brainy App, 2011).
39.5.2 ASIA
With a huge ageing population, dementia care is recognized
as a major public health challenge in this region. Over half of
the global dementia population will be part of Asia by 2030.
In China alone, where an estimated 9.2 million people
were living with dementia in 2010, determinants of under-
detection reported to be 93.1% (Chan et al., 2013) and
included low education levels and living in rural areas,
highlighting the need to target these populations in future
public health campaigns (Chen et al., 2013).
In many Asian countries, dementia is regarded as a
shameful illness and carries a stigma that may lead to reluc-
tance in seeking diagnosis and treatment.
39.5.3 JAPAN
In 2004, the term for dementia used in Japan was officially
changed from chihō (foolish, stupid, absent minded) to
ninchishō (cognitive symptoms and syndrome) (Miyamoto
et al., 2011).
New nomenclature had to be simple, short, devoid of
pejorative connotations, easily understandable and per-
tinent in medicine, government and the public spheres. A
public opinion survey subsequently clinched one out of a
possible six replacement names.
In 2005, the Alzheimer’s Association of Japan changed
its name to accommodate the new terminology, replacing
the words ‘elderly’ (recognizing the increase in young onset
of dementia) with ‘persons with dementia’ as well as their
‘family caregivers’, thus becoming ‘the Association of per-
sons with dementia and their families’.
A ‘Campaign to Understand Dementia and Build
Community Networks’ in Japan comprising four major
projects concentrated on the following:
1. A nationwide initiative to train 1 million supporters
for dementia
2. An initiative to build a dementia-friendly community
3. The development of support groups for people with
dementia and their caregivers
4. Care management fully involving people with demen-
tia and their families
404 Dementia
39.5.4 REPUBLIC OF KOREA
A low birth rate, rapidly ageing society, rapid escalation in
medical costs and dwindling informal support provided by
family caregivers have led the government to place dementia
as a national healthcare priority, setting up long-term care
insurance and in 2010, the declaration of ‘War on Dementia’
took place.
Early diagnosis, a key objective in the Korean plan (Lee,
2010), was enabled by expanding public health centres and
increasing the number of trained dementia specialists to
6000 by 2012.
39.5.5 EUROPE
An estimated 6.37 million people live with dementia in the
European Union (EU) costing €105 million per year with
total societal costs per case assessed to be eight times higher
in Northern Europe than in Eastern Europe (Wimo et al.,
2011). Regional variation across European memory clinics
(Hausner et al., 2010) suggest that Northern European coun-
tries will see the healthiest dementia populations present-
ing earlier stages in dementia, with the lowest concomitant
prescription of psychotropics. Contrast this with southern
states where people with dementia will have the shortest
education period, presenting late stages in the disease, with
least access to cholinesterase inhibitors or the ability to live
with family caregivers.
39.5.5.1 The Paris declaration
A century after the description of AD, Alzheimer’s Europe
called upon European countries (Alzheimer Europe, 2006,
2008a) to accord all forms of dementia and offer the politi-
cal priority they deserve.
Countries including Cyprus, Greece, Malta, Portugal,
Slovenia and Spain are developing national plans (Alzheimer
Europe Survey, 2014), with Italy the latest to launch a national
strategy at the time of writing the report on the survey.
Other countries, e.g. Croatia, Estonia, Germany, Latvia,
have no dedicated national strategies, yet dementia is
included within other policy initiatives.
39.5.5.2 The 2009 European Parliament
written declaration
In 2009, the European Parliament adopted a written decla-
ration calling upon the European Commission and Member
States to develop a European Action Plan and to collaborate
in order to improve early diagnosis and quality of life for
people with dementia and their caregivers. The European
Commission responded with a commitment to support
member states in ensuring effective and efficient recogni-
tion, prevention, diagnosis, treatment, care and research
for dementia. Consequently, three initiatives were funded,
which are as follows:
39.5.5.2.1 
THE EU JOINT PROGRAMMING
NEURODEGENERATIVE DISORDERS
(JPND)
Launched in 2008, the JPND is an initiative pooling together
European research funds and aligning national research
programmes. JPND comprises 28 countries, including non-
EU states such as Canada. As such, it constitutes one of the
largest global research initiatives in the field of neurodegen-
erative disorders. Priorities of the programme include find-
ing causes, developing cures and improving effective care
structures (EU JPND research, 2014).
39.5.5.2.2 
EUROPEAN INNOVATION PARTNERSHIP
ON ACTIVE AND HEALTHY AGEING (EIP
AHA)
Launched in 2011, this collaboration is designed to identify
promising regional innovations and scale them accordingly
to benefit EU countries. The EIP AHA aims to improve the
quality of life of older people in Europe, including those with
cognitive impairment and to increase the average healthy
life years of EU citizens by 2 years by the year 2020. The
partnership brings together key stakeholders in the innova-
tion cycle (end users, public authorities, industry).
39.5.5.2.3 ALZHEIMER COOPERATIVE VALUATION IN
EUROPE (ALCOVE)
The ALzheimer COoperative Valuation in Europe (2013)
Joint Action is a multinational European collaboration
co-financed by the EU Health Programme 2008–2013. Its
53 recommendations were presented in Paris on 28 March
2013 and are available online, which covers the following:
39.5.5.2.3.1 Timely diagnosis
ALCOVE defined the factors contributing to under-
diagnosis or late diagnosis, including stigma, variable
post-diagnostic support and inadequate training of general
practitioners in diagnosing dementia and recognizing its
early signs.
Early medical assessment when cognitive changes ensue
is supported because various conditions can cause cogni-
tive impairment, many of which are treatable. Conversely,
undergoing an assessment for dementia may predispose the
person and their family to face fears of the disease and the
stigma of suffering from the same.
Early diagnosis should be ‘timely’ to those seeking it
(Brooker et al., 2014), occurring at a point when the person
and their family are ready to undergo assessment. ALCOVE
proposes incremental strategies to support timely and accu-
rate diagnosis at local and national levels.
Case finding is supported to identify people to increase
detection rates in circumstances where there are services
available that will benefit the person at risk and their fam-
ily. As such, targeted or opportunistic case finding within
primary care, acute hospitals or care homes should be
undertaken and steps taken to ensure that adequate post-
diagnostic services and support is available.

General population screening is not recommended until
there is better evidence of the reliability of screening along-
side ways of preventing or delaying dementia.
A consensus is required on how early cognitive changes
(e.g. mild cognitive impairment) are to be managed in clini-
cal practice. Meanwhile, when people are informed that
they may have early cognitive changes, advice and support
should be given alongside clear pathways for monitoring
and subsequent follow-up of the symptoms.
39.5.5.2.3.2 Epidemiology
ALCOVE reviews the prevalence rate for dementia in
Europe, using the same terms that the EuroCoDe proj-
ect (2006–2008) had adopted for systematic reviews
(Alzheimer Europe, 2008). On the basis of the highest
quality epidemiological studies, ALCOVE estimated a
new European dementia prevalence rate of 7.23% in the
population aged 65 years or older, corresponding to an
estimated number of 6.37 million cases (EU-27 Countries,
2011). This estimate was 22% lower than earlier estimates
from EuroCoDe (prevalence rate: 9.28%, 8.3 million
cases). Based on this, ALCOVE identified recommenda-
tions for future data collection on estimates of prevalence
of dementia in Europe.
ALCOVE estimates that antipsychotics are overpre-
scribed for 35.6% of people with dementia residing in
European nursing homes (ranging from 25.8% in Norway
to 60% in Italy) compared to an estimated 10.6% of the gen-
eral elderly population. The United Kingdom, Sweden and
France have carried out successful campaigns to reduce
exposure to antipsychotics.
Furthermore, overuse of antidepressants, prolonged use
of antipsychotics, concomitant use (two antipsychotics or
with other psychotropics, e.g. hypnotics) or absence of use
as second-line after a non-pharmacological approach, are
also reported.
The Joint Action underscored the global safety and
ethical concerns resulting from overprescribing of antipsy-
chotics for behaviour that is one of the biggest challenges
in dementia and makes a number of recommendations
to prevent and reduce inappropriate prescribing, includ-
ing an online toolbox created as a resource to identify risk
exposure and reduction measures, linking safer prescrib-
ing to timely diagnosis, ethical principles underpinning
prescribing and sharing European programmes to prevent
and manage behavioural and psychological symptoms of
dementia (BPSD).
39.5.5.2.3.3 Strategy for BPSD
ALCOVE reviewed all intervention models for BPSD man-
agement at home, in hospital and in care homes, including
ambulatory structures and care organizations to prevent
and manage BPSD.
Psychosocial individualized interventions for people
with dementia and their carers were found to be effective
in preventing BPSD and delaying institutionalization, in
The international challenge of dementia 405
particular, psycho-educational programmes and multicom-
ponent interventions.
Guidelines on BPSD management made available to
patients, family caregivers and the workforce providing
care for people with dementia are integral to quality and
safety programmes.
39.5.5.2.3.4 Ethics
ALCOVE upholds the principle of respecting the rights of
people with dementia, including balancing autonomy and
protection. To achieve this, recommendations were identi-
fied for the assessment of competence (including four mod-
els for competence assessments) and the drawing up and use
of advance directives.
A second ALCOVE joint action, commencing March
2015 for 3 years included a focus on post-diagnostic sup-
port, improvement of care pathways, safe prescribing, care-
giver support, workforce skills and quality residential care.
39.5.6 FRANCE
France became the first European country to launch a
national dementia plan (2001–2005) to address the rising
prevalence of dementia, of which half its cases remained
undiagnosed. AD is now recognized as a chronic disease by
the French social security system. The second French Plan
concluded in 2007.
President Nicolas Sarkozy launched the third French
Alzheimer plan in 2008 at the arrival of the recession and
commented that dementia cannot wait for the worst eco-
nomic crises (Alzheimer’s Europe 2008b). Even doing very
little is not an option and thereby, 1.6 billion of public funds
pledged to a 5-year French plan that sought to understand,
cure and care.
Specialists (geriatricians or neurologists) were given the
task to diagnose dementia in France. Service improvements
included a reduced average waiting time for diagnosis and sub-
sequent access to a simplified personalized integrated demen-
tia pathway delivered via an expansion of memory units with
dedicated case managers. Quality improvements included
reduced hospitalization, reduced exposure to antipsychotic
drugs and specialist cognitive rehabilitation to improve
autonomy at home and enhance quality of life post-diagnosis.
Support for people with dementia in crisis (behavioural units
in hospital) reported that over a half of the population were
successfully discharged back home and 18,000 caregivers
received education (2-day training programmes) to improve
quality of life and reduce institutionalization.
National centres for early onset of dementia (in Rouen,
Lille and Paris) were created to focus research, improve
awareness and improve care environments.
Evaluations of the French plan’s impact on research
(Ankri and Broeckhoven, 2013; Devos et al., 2014) suggested
a link between national funding and scientific research
output.
406 Dementia
In November 2014, France issued a Fourth National Plan
incorporating dementia with other chronic neurodegenera-
tive diseases (Stratégie National de Sante, 2014).
39.5.7 THE NETHERLANDS
The 3-year Dutch Dementia Care Plan was announced
in 2008 outlining three key aims: creating a coordinated
range of personalized care options, delivering sufficient
guidance and support for people with dementia and
their carers, and measuring the quality of dementia care
annually.
The plan called for easily accessible information, sup-
ported by Alzheimer Nederland, to facilitate identifica-
tion at an individual level. Municipalities under the Social
Support Act played a crucial role in policy development for
early-detection of dementia.
General practitioners (GPs) regarded as pivotal in achiev-
ing earlier diagnosis, were to be knowledgeable in detecting
early symptoms, supported by financial incentives involved
in diagnosing dementia.
In 2013 Dementia Care Standards, financed by insur-
ers, reflected a steady increase in service user satisfaction.
Deltaplan Dementia, a second 4-year plan, with public/pri-
vate funding is built on three pillars, which are as follows:
1. Developing an e-health portal
2. Establishing a national dementia registry
3. Investing in and implementing new programmes for
scientific research
39.5.8 NORWAY
Regarded as the best place to grow older in the world
(Global Age Watch Index, 2014), Norway was one of the
first countries to launch its national strategy (Dementia
Plan 2015, 2007) and is in the process of launching its
2015–2020 plan.
One notable innovation from Norway has been the
development of ‘Active Care’ day programmes supported by
municipality grants promoting cognitive stimulation, cul-
tural activities and ‘green’ care on farms. The aim is to pre-
vent institutionalization and support well-being and social
integration while offering relief to family caregivers.
When it is necessary to move to a care home, these care
centres are typically for small groups with direct access to
adapted outdoor activities, run by small organizations and
a skilled workforce (Engedal and Haugen, 2009).
39.5.9 ENGLAND
A 5-year National Strategy, (Department of Health, 2009)
was superseded by the Prime Minister’s Challenge on
Dementia (Department of Health, 2012). Mr. Cameron, who
commented: ‘dementia now stands alongside cancer as one
of the greatest enemies of humanity’, set out to address three
challenges, which are as follows:
1. Driving improvements in health and care
2. Creating dementia-friendly communities
3. Improving dementia research
By 2014, improvements were evident including the fol-
lowing advancements (Annual Report of Progress, 2013):
1. A scheme enabling towns, cities and villages across
England to become dementia-friendly environments,
where people with dementia are empowered to have
high aspirations and feel confident, knowing they can
contribute and participate in personally meaningful
activities.
For every person with dementia who is able to live at
home within a dementia-friendly community rather
than in residential care, an evaluation of such com-
munities (Green and Lakey, 2013) estimated savings
of £11,296 per year or £941 per month. Delaying 5%
admissions to care homes for 1 year was estimated to
save the United Kingdom £55 million annually.
At the time of writing, over 70 communities across
England had registered to become ‘Dementia-Friendly’
and over 500,000 ‘Dementia Friends’ were trained.
Other innovations include a dementia education pio-
neer programme launched in schools across England
(Saad, 2012) educating young people about demen-
tia, its causes and the challenges faced by caregivers.
Outputs and resources from this initiative are driv-
ing a campaign to spread intergenerational exchange
opportunities across England (Department of Health,
2013; Alzheimer’s Society Website, 2015).
2. A national ambition to identify 67% of people with
dementia while improving post-diagnosis support
was achieved by March 2015. In 2012, 42% of people
in England were able to access a formal diagnosis,
increasing to 58% in January 2015.
3. Over 108,000 National Health Service (NHS) staff
have received foundation level dementia training with
a further 250,000 NHS staff who received training by
March 2015.
4. In hospital settings, a commissioning incentive gener-
ated around 4000 hospital referrals of people worried
about their memory signposts for subsequent diagno-
sis each month.
5. Research spending on dementia has increased by
nearly 50% since 2010, with an ambition to further
spend double the amount over the subsequent decade.
The Medical Research Council, United Kingdom,
announced the world’s biggest research sample
(Medical Research Council, 2014) involving a 2 mil-
lion strong cohort, while the Alzheimer’s Society
pledged £100 million towards research.

The G8 Dementia Summit in London 2013, during the
UK presidency of the EU, initiated an unprecedented Global
Action Against Dementia, uniting international efforts to
fight dementia (Department of Health, 2013), subsequently
establishing the World Dementia Council and the appoint-
ment of a World Dementia Envoy.
The World Dementia Council now comprising of 18
members, appointed by the World Dementia Envoy, will
work to build an international effort to fund doubly for
dementia research, increase the number of people involved
in clinical trials and to set an ambition to identify a cure or
disease-modifying therapy for dementia by 2025 (Annual
Report of Progress, 2013).
Given that, during 1998–2011, only four dementia drugs
successfully made it to market out of over 100 experimental
drugs, the Council set four priorities in its drive to speed up
research, which are as follows:
1. Optimizing the path of medicines from research to
market, so that new treatments are developed in a
timely manner.
2. Exploring ways to increase investment in funding
dementia innovation by exploring new types of fund-
ing products.
3. Unleashing the potential of open science for sharing
information and knowledge to accelerate progress
in developing new treatments and care approaches,
avoiding duplication of effort, assisted by the World
Health Organization (WHO) and Organization for
Economic Cooperation and Development (OECD).
4. Reviewing the evidence into existing research on
dementia risk reduction and strengthening public
health messaging on lifestyle and prevention.
The global action against dementia has since expanded
to include academic institutions, non-governmental organi-
zations and civil societies, and now embraces commitment
from developing countries. As the burden of dementia is
heavier in non-G7 countries, all outputs need to be global.
Learning from other conditions, e.g. HIV and cancer,
and aligning with emerging initiatives, e.g. JPND and the
ALCOVE Joint Action, are recognized as useful global
strategies.
The global action against dementia has since held a series
of legacy events (each focusing on a specific theme), the last
of which was in Tokyo, Japan, in November 2014.
39.5.10 SCOTLAND
Quick to adopt national dementia plans, Scotland launched
its second 3-year National Strategy in 2013 (Scottish
Government, 2010).
Key improvement areas are diagnosis and post-diagnos-
tic support, hospitals and modelling proactive eight-pillar
community-based support.
The international challenge of dementia 407
Dementia diagnosis rates in Scotland currently stand at
64%, higher than other parts of the United Kingdom. All
those diagnosed from April 2014 are entitled to support
workers to help them and their families understand demen-
tia and make advance plans.
39.5.10.1 The Glasgow Declaration
(October 2014)
This declaration calls for the creation of a European Dementia
Strategy and for world leaders to recognize dementia as a
public health priority and to develop a global action plan on
dementia. It affirms that every person living with dementia
has the right to
1. A timely diagnosis
2. Access quality post-diagnostic support
3. Person-centred, coordinated quality care
4. Equitable access to treatments and therapeutic
interventions
5. Be respected as an individual in their community
39.5.11 THE UNITED STATES
President Obama signed into law the National Alzheimer’s
Project Act (NAPA) (2011). NAPA’s aims are as follows:
1. Prevent and effectively treat AD by 2025
2. Enhance care quality and efficiency
3. Expand support for people with dementia and their
families
4. Enhance public awareness and engagement
5. Improve data to track progress
The term ‘dementia’ has now been replaced in American
medical terminology. The Diagnostic and Statistical Manual
of Mental Disorders, Fifth Edition (American Psychiatric
Association, 2013) has included a category named neuro-
cognitive disorder, formally known in The Diagnostic and
Statistical Manual of Mental Disorders, Fourth Edition
(DSM-IV) as ‘dementia, delirium, amnestic and other cog-
nitive disorders’.
39.5.12 CANADA
In 2014, funding was allocated for the creation of the
Canadian Consortium on Neurodegeneration in Aging
(CCNA) to focus on dementia. The CCNA is supported with
funding over 5 years from the Government of Canada and a
public/private partnership, including the Alzheimer Society
of Canada.
Canada, a leader in dementia research, co-hosted one of
four global actions against dementia legacy events (together
with France).
408 Dementia
39.6 PREVENTION AND RISK
REDUCTION
Best estimates (World Alzheimer Report, 2014) combining
a comprehensive approach from all sectors collaborating
to reduce the risks associated with dementia, suggest that
the future scale of the dementia epidemic may be blunted
through improvements in population health.
There is mounting evidence that the population at risk of
suffering from dementia can be modified through a reduc-
tion in tobacco use, alongside better treatment for hyperten-
sion and diabetes during mid-life. Education and life-long
learning may improve the brain health of those entering old
age and reduce the incidence of dementia (Barnes and Yaffe,
2011; Matthews et al., 2013).
The European Dementia Prevention Initiative (EDPI),
launched in 2011 in Stockholm, Sweden, allows researchers
to collaborate in prevention studies. EDPI incorporates three
large randomized controlled trials with a fourth prevention
study (Healthy Ageing Through Internet Counseling in the
Elderly) adopting innovative internet-based interventions
recently added (HATICE, 2014).
The International Database on Aging and Dementia
(IDAD) and EDPI are examples of ongoing international
efforts aiming to improve the methodology of preventive
studies and provide the basis for larger intervention trials
(Solomon et al., 2014).
Public health authorities must seize the opportunities
to do more in promoting the message on risk reduction.
Emerging research suggests some dementias are prevent-
able diseases and that it is never too early or too late to pro-
mote public health messages. The UK Department of Health
now adopts new principles (Lincoln et al., 2014) outlining
the need for future policy to promote a range of risk reduc-
tion strategies enshrined in service planning.
39.7 CONCLUSIONS
An unprecedented increasingly robust global platform
for dementia is extending across Europe, Australasia and
North America. Whether countries change the wording for
dementia or decide to tackle the stigma of ‘dementia’ head-
on, a long overdue upsurge is accruing at present, during
what could be dubbed the decade of dementia.
The plight of individuals with dementia, their caregiv-
ers and their governments as a result of inadequate health
and care provision are played out across the world. National
plans have shown the way and now people with dementia
must be empowered, supported by appropriate communi-
cation within the public domain, media and educational
institutions.
Effective international collaboration to harness and
maintain momentum is necessary between and within
countries to provide continuity, promote a common pur-
pose and implement improvements in care, cure and pre-
vention synchronously, globally and locally. Pursuing a cure
or disease-modifying treatment must not be at the expense
of developing and improving care and prevention for the
patients.
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The pharmaceutical industry and dementia:
How can clinicians, researchers and industry
work together for the betterment of people
with dementia and their families? Continuous
vigilance and transparency is the answer
MARTIN M. BEDNAR AND LEON FLICKER
If I have seen further it is by standing on ye shoulders of Giants.
40.1 ACADEMIC HEALTHCARE
INVESTIGATORS, THE
PHARMACEUTICAL INDUSTRY
AND DEMENTIA
40.1.1 THE RELATIONSHIP CAN BE
PRODUCTIVE
The therapeutic advances that have improved the lives of
individuals with dementia, most notably Alzheimer’s dis-
ease (AD), are the culmination of scientific innovation
emanating from very distinct sectors of the scientific com-
munity. The successful ‘handoff’ of scientific information,
often obtained from publicly funded endeavours seemed, in
a sense, well-orchestrated albeit not pre-planned. While aca-
demic healthcare investigators demonstrated a critical defi-
ciency of the neurotransmitter acetylcholine in the brains of
AD patients in the 1970s (Davies and Maloney, 1976; Davies
and Verth, 1977), the use of available agents such as cho-
line supplements did not meaningfully improve the lives
40
—Sir Isaac Newton, 1676
and memory of AD patients. In parallel, the pharmaceutical
industry, recognizing the importance of the structural and
biochemical derangements in the brains of AD patients, was
able to produce a class of therapeutics known as acetylcho-
linesterase inhibitors. Initial reports (e.g. Summers et al.,
1986) necessitated a standardized approach to evaluation of
dementia drugs (Leber, 1990). After successful multicentre
randomized trials (e.g. Davis et al., 1992), tacrine was the
first drug approved in 1993 by the United States Food and
Drug Administration (FDA) and heralded a major advance
in the treatment of people with AD.
The history of the development of acetylcholinesterase
inhibitors for the treatment of AD is notable for several rea-
sons. It is an example of rational drug design that has domi-
nated drug development since the 1950s, largely (though
not completely) replacing accidental drug discovery that
was prevalent in the first half of the twentieth century and
the reliance on folklore prior to the twentieth century. It
is also an excellent example of how the cross-fertilization
of diverse groups of scientists and clinicians within both
academia and pharma, with different skill sets and goals,
resulted in a significant therapeutic advance to the benefit
411
412 Dementia
of patients. What is clear is that neither group could have
accomplished this goal anywhere near as effectively on
their own. It is also clear that each group contributed to
the success of the other by providing critical data, access
to patients and feedback (forward and back translation)
over the 15-plus years it took from concept to the first drug
approval for AD as well as for the 15-plus years since that
first drug approval. This is but one example of many where
academia and pharma have complemented, enriched and
enhanced the professional roles of each other for the bet-
terment of society.
The key aspect of the academic investigator–pharma
relationship outlined above, defining disease targets (mech-
anisms) that, in turn, facilitate drug design, has been primar-
ily opportunistic and has not required prospective codified
guidelines (rules) for engagement. However, more inter-
dependent activities readily demonstrate points of friction
within this success story. Some of these include defining the
value, financial and medical, of acetylcholinesterase inhibi-
tors, for a given country or world region or for a particular
stage of illness (mild, moderate and severe). This was par-
ticularly important with drugs such as tacrine, which not
only had major financial costs but large numbers of patients
who developed hepatotoxicity (Ames et al., 1990). Variable
patient access to needed medicines, usually on the basis of
cost, is another issue that deserves attention to ensure that
needed medicines are available to the patients in need of
them. Increasingly there are mechanisms to evaluate the
cost-effectiveness so as to determine which medications will
be supported by third-party payers, although decisions can
vary widely from country to country (Bae et al., 2015).
40.1.2 THERE IS A POTENTIAL FOR
CONFLICT OF INTERESTS,
PARTICULARLY WITH CLINICIAN
RESEARCHERS
Another aspect is the question of innovation ver-
sus ­incremental improvement of a medicine or class of
medicines – e.g. pharmacokinetics, route of delivery, safety
and efficacy advantages within this class of therapeutics. Is
each of these characteristics truly driving innovation and
providing enhanced value for the patient or are they simply
strategies used by the pharmaceutical industry to maintain
Table 40.1 Academia–pharma: complementarya skill sets
Academia
Original basic science idea, e.g. novel receptor,
biochemical action
Research focus allows for digression to follow novel
observations that may not be related to the original
research question
Novel observations typically anecdotal
a Though not intended to suggest, they are mutually exclusive.
patent protection, market share and revenue? Thus, there
may be a key conflict in the academia–pharma relation-
ship: on one hand, pharma’s advancement of applied science
to create and market new medicines that also create share-
holder value versus academia’s pursuit of advancements in
basic and clinical science as well as the fiduciary responsibil-
ity of the healthcare professional to do what is in the best
interest of the patient.
The group of academic researchers who are also active
clinicians, are particularly prone to a duality of interests,
which often are congruent but sometimes conflicting. They
have simultaneous duties to develop new medications that
will provide their sponsors with an increase in share value
and society with better treatments, but also a duty to their
patients to provide the best available treatment for that indi-
vidual. This duality of interests frequently coexist without
conflict, but sometimes there is conflict between these com-
peting demands.
With this historical backdrop, the path forward should
acknowledge that a relationship between academic health-
care investigators and pharma is in the best interest of soci-
ety and the patient. Each has complementary skill sets (see
Table 40.1), resources and goals that, if appropriately har-
nessed, can compensate for knowledge and resource gaps of
each party. The key issue is how to effectively and efficiently
use these resources, skills and knowledge in a way that
acknowledges potential conflicts (both between and within
pharma and academia; see Table 40.2), minimizes or elimi-
nates the potential for personal gain to supersede societal
benefit and provides the needed transparency.
Thus, it is reasonably certain that pharma will continue
to rely on academic healthcare investigators to conduct basic
research that better defines the pathophysiology of disease
and that identifies new therapeutic targets, paving the way
for the development of innovative medicines. Pharma will
also continue to look to academic healthcare investigators
to facilitate access to consenting patients necessary for the
conduct of clinical trials for these potential new medicines.
A significant perturbation of these ‘traditional’ roles for
pharma and academia seems both unlikely to occur and of
doubtful value. The current limited infrastructure of aca-
demia does not lend itself to forging new pathways for the
academic healthcare investigator to translate promising
therapeutic targets into proven treatment strategies.
Pharmaceutical Industry
Applied creativity, e.g. druggable chemical series
Rational drug design maintains focus on operationalization
Rigor of safety and efficacy of a therapeutic must meet
regulatory (societal) demands before being marketed
 The pharmaceutical industry and dementia 413

Table 40.2 Confounders in the healthcare–pharma relationship

Does disclosure of conflict of interest by healthcare professionals genuinely alleviate the potential of bias or simply serve
to remove attention from it (Kassirer, 2009)?
Limited numbers of opinion leaders who sway national and international prescribing. Alternatively, pharma seek prominent
healthcare professionals to improve credibility. The potential for coercion and abuse exist.
Loss of potential healthcare leaders, the clinician–scientist, due to both reduced funding and the dedicated time to do so
(vicious cycle).
Physicians must remain unbiased and devoted to patient care, but they are already influenced by federal constraints,
managed care regulations and reimbursement.
Primary goals of an academic institution (e.g. physician hours involved with direct patient care, the rise of for-profit
academic medical centres and also private practice consortiums that conflict with the traditional charitable/altruistic
service of the physician) may not align with the goals of the healthcare professional, where publications and grants can
be the most significant factor in promotions.
The need for pharma to sponsor/subsidize healthcare research, meetings, etc. has increased as traditional sources of
funding diminish. Some degree of regulation has now been brought into play.
Academia-led research does not undergo the same degree of scrutiny as that in pharma-reverse bias (Doogan, 2009).
The potential for data fraud both by healthcare professionals and pharma for secondary gain.
Knowledge sharing versus the protection of intellectual property (both academia and pharma).
Some companies are interested in orphan diseases that may not generate blockbuster profits or significant shareholder
value either as part of their overall mission (typically larger pharma) or because even a modest revenue is sufficient for
their business model (smaller, biotech companies).

On the other hand, to conclude that the responsibility 40.1.3 PARTICULAR ISSUES IN

of the academic healthcare investigator to always act in the
best interest of the patient is in opposition to pharma’s goal
to generate financial value from the creation of new medi-
cines is misleading, but nonetheless frequently cited. The
fiduciary responsibility of the academic healthcare inves-
tigator to their patients actually relies on the interaction
of the healthcare professional with pharma to facilitate
improvements in health care, including the bidirectional
exchange of information regarding translational medicine
(bench-to-bedside and bedside-to-bench) and to provide
(directly and through regulatory agencies and other gov-
ernance bodies) information sharing on marketed prod-
ucts. Indeed, pharma has been one of leaders in public and
professional education of AD (and most other diseases),
raising awareness and allowing therapies to reach many
more individuals than would otherwise have been possi-
ble. Thus, to a certain degree, it is this bidirectional flow of
information that helps to mitigate idiosyncratic physician
practice patterns and that facilitates physician knowledge
and competency, which serves as the foundation of the
physician’s role in the care of the patient. Also of note is
the emergence of the precompetitive consortia and public–­
private partnerships whereby pharma and academic
experts, in addition to government agencies and vari-
ous societies/advocacy groups have openly collaborated
to achieve advances in the field that might not have been
possible or, at the very least, would have been significantly
delayed. The Alzheimer’s Disease Neuroimaging Initiative
(ADNI) and the Australian Imaging, Biomarkers and
Lifestyle Flagship Study of Ageing (AIBL) are two excel-
lent examples of this collaborative effort in the field of AD,
which has since spawned similar initiatives worldwide.
DEALING WITH PEOPLE WITH
DEMENTIA – CHALLENGES FOR
BOTH CLINICIANS AND
RESEARCHERS
There are a number of issues in the treatment of dementia
that, if not unique, are certainly more prominent and they
add additional complexity to the relationship of healthcare
professionals and the pharmaceutical industry. The most
obvious of these is the disease itself. With varying degrees
of dementia, the patient may have limited or no capacity
to understand the nature of the research and its risks and
benefits. This results in family members and/or caregiv-
ers serving as both the patient proxy for consent as well as
being involved in judging the efficacy of a potential new
medicine. Does the relationship between patient and care-
giver alter the way that the physician provides informa-
tion in seeking informed consent? If the trial is targeting
challenging behaviours associated with dementia this may
be particularly problematic. Similar issues are faced by
clinicians treating people with dementia and challenging
behaviours. Whose symptoms are we managing and how
valid is this?
The role of the physician and also of the family/care-
giver to act on behalf of the patient can be biased by the
type of medical facility, which is chosen to be involved in
clinical trials. Is it the physician or is it the site which is
interested in participating in clinical trials? Are the ther-
apies studied at a particular site those showing greatest
promise or those of most interest to a particular physician
(the two are not mutually exclusive)? Many of the putative
414 Dementia
disease-­modifying therapies now in clinical development
must be administered parenterally. If a hospital or clinic is
not equipped to support this paradigm, clinical trial options
for their patients to consider will be much more limited.
The pharmaceutical industry must also struggle with
major pragmatic issues. One of these is the cost of clini-
cal trials for dementia. For drugs that may be potentially
disease-modifying, late-stage clinical trials are long (at least
18–24 months), expensive and carry a very high risk of fail-
ure due to their unprecedented nature. Of course, the risk
is not only to pharma but also to patients, where the true
risk of participating in the clinical trial is never certain and
the benefit for an AD disease-modifying agent is unclear.
The analogous experience with acute stroke is edifying,
where the great risk and clinical trial expense are contribut-
ing factors to the current paucity of neuroprotective trials.
The 1990s were heralded as the decade of the brain in the
United States and the approval of tissue plasminogen activa-
tor (tPA) in 1995 provided great promise. Now 20 years later,
not a single neuroprotective therapy has been approved for
stroke. Similarly, not a single disease-modifying agent has
been proven to be effective for AD dementia to date.
There is also the issue of when is the most favour-
able time to treat patients with cognitive impairment.
Traditionally, clinical trials had targeted patients who are
in the mild-to-moderate stage of the disease. This is, in
part, a carry over of the clinical development for symp-
tomatic therapies such as acetylcholinesterase inhibi-
tors where there was concern that patients at the severe
end of the spectrum may fail to benefit from therapy due
to the widespread and prolonged nature of their disease.
However, the question regarding the timing and duration
of therapy remains not only about late-stage disease but
also about earlier treatment. Most clinicians would hope
that patients could be diagnosed with AD well before they
reach the stage of dementia. The terminology of mild cog-
nitive impairment (MCI) or, more recently mild neuro-
cognitive disorder due to AD seeks to characterize those
with objective but modest cognitive decline who are still
independent in everyday activities (American Psychiatric
Association, 2013). These people are likely to develop
dementia (convert) within a relatively brief period of sev-
eral years. However, while many feel that there is clear merit
in the treatment of AD at earlier stages before there is sig-
nificant loss of brain function (much like treating patients
with heart disease before there is significant heart failure),
there remain others who feel that this is an industry-led
example of ‘disease mongering’, an attempt to increase
the commercial market and hence drug sales (Doran and
Henry, 2008). As mentioned with the precompetitive con-
sortia such as ADNI, AIBL and now many others, there is
strong agreement across pharma, academia and regulators
to treat this disease as soon as possible. There are a number
of examples where either the criteria for diagnosing dis-
ease have been redefined or where distinct ‘new’ diseases
have been introduced (e.g. fibromyalgia) followed by the
introduction of a medicine to treat it. This segmentation of
the population with a disease under study has the poten-
tial to benefit everyone involved, from the patient to the
third-party payer by providing an increasing likelihood
that a new medicine will improve either patients at a spe-
cific stage of the disease and/or their specific set of signs
and symptoms in a much more precise manner. Federal
regulators, third-party payers and the public must care-
fully review the data to determine the societal benefit and
risk, both in the short and long term, when approving
and paying for these new medicines. Critical participants
in this debate are the academic healthcare investigators.
Their influence is considerable and speaks to the need for
collaboration of academia and pharma, from defining the
pathophysiology of disease to the education of society. Not
only will the academic healthcare investigators continue
to be recognized as the spokespersons for the patient and
other clinicians (and, by extension, for society) but will
also have an important role in the creation, validation and
societal uptake for the various tests and scales that will be
used to both assess patients during the various stages of
their disease and judge the efficacy of potential new medi-
cines for treatment.
40.2 FUTURE DIRECTIONS
We have discussed the historical perspective of the
academia–pharma relationship. This relationship has
­
evolved over the past several decades to create a significant
degree of interdependency, despite the fact that at least some
of their goals are neither mutual nor similarly prioritized.
This has the potential to create an inefficient and ineffective
system filled with conflict.
In looking ahead, there is a need better to understand how
clinicians, academic healthcare investigators and pharma can
all benefit without issues of conflict of interest overwhelming
these relationships. This chapter has cited the development of
acetylcholinesterase inhibitors as a successful, albeit opportu-
nistic collaboration between pharma and academic healthcare
investigators. In the future, a more proactive strategic align-
ment will assist in ensuring the timely and efficient develop-
ment of improved models of healthcare and new medicines for
patients, e.g. precompetitive consortia.
40.2.1 ARE THERE PROBLEMS THAT NEED
TO BE FIXED?
As can be seen, the relationship between prescribers, other
health professionals, academia and the pharmaceutical
industry is complex and multilayered. Despite this, there
are substantial benefits to be obtained for patients if this
collaboration can be managed successfully. A complex rela-
tionship can still be very functional. Is there evidence that
these evolving interrelationships have become dysfunc-
tional? If so, how these difficulties can be proactively solved?
Below are provided some examples where there have been
issues of conflict and potential solutions.

40.2.2 INCOMPLETE REPORTING OF
TRIAL EVIDENCE
There are many people who benefit from the performance
of well-conducted scientific studies. Academics receive
accolades and promotion by the conduct of major stud-
ies particularly if the reports are published in prestigious
journals. Companies may make substantial profits if a
new class of drugs is shown to be therapeutic resulting in
blockbuster status for these drugs. Future generations of
patients will benefit from efficacious treatments to help
prevent and alleviate their symptoms. The people who bear
the most risk from studies and have the least likelihood
of benefits are the subjects of these studies. These people
consent to randomization to either ineffective treatments
(placebo) or drugs that potentially may yield no benefits
and may have unknown side effects. This group of people
participates for many reasons but for most it is not just
the desperation of seeking effective treatment. Many are
driven by an altruistic desire to benefit not just themselves,
but for future generations. The gift of participation of
these individuals places an obligation on all the organiza-
tions and study investigators who may potentially benefit
that, the participation of these subjects should firstly be
reported, and the report should be an accurate and true
record of the subjects’ participation.
For this reason, it is most important that every subject
in a randomized trial (i.e. trials which are hypothesis test-
ing) should have their data incorporated into the results
of that trial and that all these trials should be reported.
Unfortunately whenever this is reviewed, the conclusion is
that negative trials are much less likely to be reported than
positive studies. For example, in the early trials of rivastig-
mine, of the four pivotal phase 3 studies, only two were
reported, and these two reported studies showed a greater
response than the two unreported studies (Birks et al.,
2009). It is not just the pharmaceutical industry who finds it
difficult to report negative or similar results. It is difficult to
convince journals to publish such studies especially if there
have been other studies, which have yielded positive results.
However, one of the stated purposes of Cochrane is that
all randomized controlled trials (RCTs) will be placed in a
repository and then subsequently incorporated into at least
one systematic review. This approach has heightened the
imperative to report all RCTS and fulfil the obligation that
all parties have to the patients who participated in these
trials. This strategy may improve the reporting of clinical
trials, which is typically noted to be at extremely low levels,
both by academics (perhaps to a greater extent) and pharma
(Anderson, 2015).
Since the last edition of this textbook, there have
been further examples of withholding of valuable anal-
yses from the public eye. An example of this is dabi-
gatran, one of the classes of novel oral anticoagulants
(NOACs). Although the drug is safe and efficacious,
internal documents from the manufacturer reported
The pharmaceutical industry and dementia 415
analyses demonstrating that the risk of major bleeding
episodes could be reduced substantially if plasma levels
of the drug were monitored (Cohen, 2014). Is seems that
commercial interest was one of the reasons that these
data were not made available (Cohen, 2014). As noted by
Doshi et al. (2013), making raw data from clinical trials
widely publicly available should reduce selective report-
ing biases and enhance the reproducibility of and trust
in clinical research.
40.2.3 SOLUTION
These concerns have resulted in the creation of trial reg-
istries, and the adoption of the position by many journals
that trials will not be published unless they have been
prospectively registered. The problem is that there is no
compunction that the now known studies’ data should be
widely available. One solution would be that repositories
for unpublished trials should become widely available
and a requirement from institutional ethics committees
that simple tables of the results of the primary efficacy
variables be placed in such repositories within 5 years of
study completion. The responsibility for completion of this
requirement will need to be shared between the academic
researcher and the sponsoring company. It is imperative
that all relevant human data are made available in a trans-
parent fashion.
40.2.4 DELIBERATE MANUFACTURE OR
CONCEALMENT OF PATIENT DATA
For some years concerns have been raised regarding the
deliberate manufacture of patient results. The situation is
almost certainly very uncommon but the question of how
often it occurs, as opposed to its detection, remains unre-
solved. An example of this practice was discovered in the
Second European Stroke Prevention Study (ESPS-2), a
major clinical trial to prevent repeat strokes. It was found,
rather inadvertently, that one of the investigators had fab-
ricated data on subjects. This occurred without the trial’s
sponsor’s knowledge (Enserink, 1996).
The lure of benefits has not just affected those researchers
involved in pharmaceutical studies. Some academics, have
also fabricated patient data so as to increase their impor-
tance in the field overall (e.g. Hagmann, 2000). Fortunately
because this study’s results conflicted dramatically with
other investigators’ work, the fabrication was detected early
and did not result in the inappropriate management of
patients been widely adopted. A more recent example from
an academic research group in Japan claiming a simplified
strategy to transform adult cells into pluripotent stem cells
was uncovered in a similar manner (Nature Editorial, 2014).
One of the difficulties with studies that arise from academia
is that because of their limited budgets such studies do not
have the extensive auditing procedures that are used in
pharmaceutical studies. Continuous vigilance is required
416 Dementia
to ensure that such fraud does not become more common-
place. The propensity to fraud will always exist when there
are perverse incentives for the dishonest researcher who is
willing to cut corners and bow to the increasing pressure to
maintain ‘productivity’.
The issues become even more complex with pharma-
ceutical studies. Not only is there the perverse incentive of
academic advancement but also there is the added impe-
tus of monetary gain for the investigators for recruitment
of subjects and also the requirement for all pharmaceu-
tical companies to maximize the return to shareholders.
The recent inexplicable failure to report deaths in a large
study of rofecoxib may point to bias by the pharmaceutical
industry to suppress negative findings (Krumholz et al.,
2007). Many journals now have such safeguards in place,
requiring acknowledgement that all writing was the effort
of the authors at the time the article is initially submitted.
Such shortcomings have severe consequences for both the
general public but also the company itself if these short-
comings are exposed.
40.2.5 SOLUTION
The perverse incentives in academia need to be addressed
to discourage output for its own sake. Such pressure has
been found to underlie many cases of scientific fraud. This
is an issue for academic departments whose oversight of
individual academic’s practices often ranges from cur-
sory to non-existent. This is not the responsibility of the
institutional ethics committee to police such practices,
as in some instances the ethics committee may not even
be aware that fraudulent ‘trials’ are even taking place
(Hagmann, 2000). The benefits of scientific publication
and grants are usually shared by the academic investiga-
tor’s institution, but these benefits should be tied to the
responsibility of ensuring proper academic conduct.
The controversy surrounding rofecoxib has caused
greater scrutiny on the relationship between academic
researchers and pharma. Late-stage clinical studies in
particular may require additional safeguards. These could
include storage of data independently to the sponsor and
analysis by independent investigators. Independent data
and safety monitoring boards need not be under the con-
trol of the sponsor, and could be under the direct control
of an independent academic institution. The practices of
‘ghostwriting’ and false claims of full access to all relevant
data should be eliminated (Krumholz et al., 2007). It is in
the interests of the pharmaceutical industry to lead such
change as the risk for maintaining the status quo may ­­be
large.
Additionally, the FDA has implemented additional
actions to ensure that investigators who are non-­compliant
with the FDA’s statutes and regulations intended to pro-
tect study subjects or who knowingly reporting inaccurate
study findings are not allowed to continue to participate
in clinical trials. These additional actions are aimed in to
expedite the review process as well as to ensure that those
engaged in misconduct are readily identified to spon-
sors of drug or device trials (website: http://www.gao.gov/
assets/300/296033.html).
40.2.6 EDUCATION OF CLINICIANS
The pharmaceutical industry not only has a legitimate
right to educate doctors and the general public about the
advances in treatment that have been achieved but also has
a responsibility. It is the methods that are employed, which
have raised concerns.
40.2.7 TREATMENT GUIDED BY EVIDENCE
OR TRUSTED AUTHORITIES?
Both physicians and the general public believe that evi-
dence should guide rational prescribing. Unfortunately
when doctors are ‘shadowed’ this is not the mechanism by
which doctors seek solutions to clinical problems. Doctors
seek solutions from other doctors and due to the hierarchi-
cal relationship of this transfer of information, a relatively
small number of opinion leaders guide national and inter-
national prescribing patterns. The pharmaceutical indus-
try has a societal responsibility to contract such opinion
leaders, to educate them about their products and to seek
their advice as to how to further investigate the benefit–risk
ratio for a particular medicine. One problem has been that
historically these contractual relationships are covert and
unregulated and this has led to questions such as ‘when
does reimbursement for services rendered become coer-
cion’? More recently, hospitals and medical centres have
begun to mandate the reporting of any perceived conflict
of interest, a policy that will improve transparency and the
perception of the relationship between pharma and health-
care professionals.
40.2.8 SOLUTION
There is a need for greater transparency in the relationships
between opinion leaders and industry. Learned colleges and
medical associations have argued for such transparency
but these organizations have not indicated how compliance
with these guidelines will be monitored or what would be
the consequences of non-compliance to the practitioner, the
industry and the colleges themselves. The level of transpar-
ency required has to be sufficient so that those people reliant
on information can judge whether any reimbursement may
have influenced the opinion leader and by how much. There
should be limits placed on the compensation provided for
different tasks, e.g. speaking at a meeting. Unfortunately,
there is no evidence that such disclosure has any influence
on the prescribing habits of those who have been influenced
by individual opinion leaders. The provision of excessive
gifts or travel grants to nonspeaking participants at inter-
national conferences would appear to be frank coercion and

these practices should cease. Fortunately, these safeguards
are now commonplace, although not universal.
40.3 CONCLUSIONS
In general, the relationships between clinicians, academic
researchers and the pharmaceutical industry have been
healthy and conducive to the best interests of patients. They
have produced results for patients which would have been
unachievable by the individual parties. There are particu-
lar issues regarding people with dementia that may make
these relationships even more complex. There have been
some recent incidents, which have resulted in some ten-
sions to appear in these relationships, which may erode the
essential trust on which these relationships are founded. An
ongoing dialogue between pharma, healthcare profession-
als and learned colleges and regulators is critical for both
understanding the issues and finding constructive solu-
tions. Several changes are suggested that will allow greater
transparency for all the parties concerned.
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 2
Part    

Mild Cognitive Impairment

41 Mild cognitive impairment (MCI): A historical perspective 419

Karen Ritchie and Sylvaine Artero
42 Clinical characteristics of mild cognitive impairment 426
Yonas E. Geda, Janina Krell-Roesch, Anna Pink, Kathleen A. Spangehl and Ronald C. Petersen
43 Managing the patient with mild cognitive impairment 439
Nicola T. Lautenschlager and Alexander F. Kurz

Mild cognitive impairment (MCI): A historical
perspective
KAREN RITCHIE AND SYLVAINE ARTERO
41.1 COGNITIVE IMPAIRMENT AS A
FEATURE OF NORMAL AGEING
Alterations in cognitive functioning in the absence of
dementia have long been considered a normal aspect of age-
ing related to the changes in brain. Affecting, principally
episodic verbal memory, such changes are generally dis-
tinguished from neurodegenerative disorders by their far
slower progression, their lesser impact on ability to perform
activities of daily living and the relative sparing of linguistic
and visuospatial functions. Increased interest in the nature
and long-term prognosis of ageing-related modifications
in cognitive performance has now led to the question as
to what extent they may be considered ‘normal’. The past
50 years have seen numerous attempts to define these sub-
clinical alterations in cognitive functioning and to estab-
lish their aetiology with greater precision than the general
notion of ‘ageing brain changes’ to which they have formerly
been attributed.
One of the earliest attempts to clinically character-
ize normal ageing-related cognitive change as opposed to
dementia (dotage) is Gulliver’s description of the eternal
elderly of Luggnagg. ‘In talking, they forget the common
appellation of things, and the names of persons, even of
those who are their nearest friends and relations …. The least
miserable among them appear to be those who turn to dot-
age, and entirely lose their memories; these meet with more
pity and assistance’ (Swift, 1726). Two centuries later Kral’s
notion of benign senescent forgetfulness (BSF) (Kral, 1962)
provides further clinical precision to Swift’s observation,
describing normal cognitive ageing as patient complaints of
a persistent difficulty in recalling detail, commonly featur-
ing depressive symptoms. While Kral initially considered
such complaints to characterize a depressive state, which
41
he referred to as ‘depressive pseudo-dementia’, long-term
follow-up of some of these patients showed that a significant
proportion went on to develop vascular dementia. BSF was
diagnosed by Kral by an open psychiatric interview and no
formal algorithm was proposed. Formal diagnostic criteria
for non-dementia cognitive impairment were first proposed
by Crook et al. in 1986 for the National Institute of Mental
Health. Referring to ‘age-associated memory impairment’
(AAMI), they defined these changes as subjective com-
plaints of memory loss in elderly persons verified by a decre-
ment of at least one standard deviation on a formal memory
test in comparison with means established for young adults.
Blackford and La Rue (1989) later suggested suitable tests
of non-verbal and verbal secondary memory tests, propos-
ing that AAMI be defined as at least one standard deviation
performance below the mean for young adults for one or
more of these tests. They also differentiate AAMI from the
more severe state of ‘late-life forgetfulness’ (LLF), defined
as performance between 1 and 2 standard deviations below
the mean on at least 50% of a battery of minimum four tests.
Levy et al. (1994) argued that there is little reason a
priori that cognitive decline in normal old age should be
confined to memory functions exclusively and in collabo-
ration with the International Psychogeriatric Association
(IPA) and the World Health Organization (WHO), pro-
posed an alternative concept of ageing-associated cog-
nitive decline (AACD). The criteria for AACD not only
admits to the possibility of a wider range of cognitive
functions being affected (attention, memory, learning,
thinking, language, visuospatial function) but also stipu-
lates that the deficit should be defined in relation to norms
for elderly and not young adults to avoid confounding
of decline with age cohort effects. This refinement takes
into account the early observations of researchers such
as Schaie and Willis (1991) who have demonstrated that
419
420 Dementia
much of the difference in cognitive performance observed
between young and elderly cohorts is attributable to gen-
eration differences (notably in education and healthcare)
rather than in ageing-related changes in the brain. A com-
parison of the performance of AACD and AAMI criteria
in the general practice setting concluded that they do not
identify the same individuals within general population
studies, AACD targeting a severe state of impairment
within a larger AAMI group (Richards et al., 1999).
Recognition of the major international classifications
of disease of subclinical cognitive deterioration linked
to the normal ageing process began with the appear-
ance in Diagnostic and Statistical Manual of Mental
Disorders, Fourth Edition (DSM-IV) (American Psychiatric
Association, 1994) related to the concept of age-related cog-
nitive decline (ARCD). Like AACD, it refers to an objective
decline in cognitive functioning due to the physiological
process of ageing, however, no operational criteria or cog-
nitive testing procedures are specified. It is rather loosely
defined as a complaint of difficulties in recalling names,
appointments or in problem-solving, which cannot be
related to a specific mental problem or a neurological dis-
order. The concepts of ARCD and AACD, while clinically
meaningful, are now rarely used in research principally
because of the difficulty in proving that such changes are
‘normal’ and not part of an unidentified subclinical pathol-
ogy. Many early studies employing these categories found
them to be subsequently associated with underlying vascu-
lar pathology and high rates of evolution towards dementia
on follow-up (Celsis et al., 1997; Di Carlo et al., 2000; Ritchie
et al., 2001).
41.2 DISEASE MODELS OF
SUBCLINICAL COGNITIVE
IMPAIRMENT
The early conceptualizations of age-related cognitive loss
described above had in common the theoretical assump-
tion that such changes are distinct from dementia and
other pathologies, being the consequence of inevitable,
thus normal, ageing-related cerebral changes, such as atro-
phy and vascular fragility. As parallel research into the
causes of dementia and cerebrovascular disease has now
led to a clearer understanding of their aetiology, it has
also been shown that many of the physiological abnor-
malities seen in these disorders are also present to a lesser
extent in subjects identified as AAMI, ARCD and AACD.
Consequently, elderly persons with subclinical cogni-
tive deficits have become the subject of neurological as
well as psychogeriatric research, the underlying question
being whether cognitive deficits of this type may be due
to underlying brain pathology, which might be potentially
treatable. Alternative concepts have subsequently appeared
in the literature linking cognitive disorder to various
forms of underlying pathology. The 10th revision of the
International Classification of Diseases (ICD-10) (World
Health Organisation, 1993), described, for example, ‘mild
cognitive disorder’ (MCD), which refers to disorders of
memory, learning and concentration, often accompanied
by mental fatigue, which must be demonstrated by formal
neuropsychological testing and attributable to cerebral
disease or damage, or systemic physical disease known to
cause dysfunction. MCD is secondary to physical illness
or impairment, excluding dementia, amnesic syndrome,
concussion, or post-encephalitic syndrome. The concept
of MCD, which was principally developed to describe the
cognitive consequences of autoimmune deficiency syn-
drome, expanded to include other disorders in which cog-
nitive change is secondary to another disease process; it is
applicable to all ages, not just the elderly. Attempts to apply
MCD criteria to population studies of elderly persons sug-
gest it to be of limited value in this context, casting doubt
on its validity as a nosological entity (Christensen et al.,
1995) for this age group. DSM-IV (American Psychiatric
Association, 1994) has proposed a similar entity, mild
neurocognitive disorder (MNCD), which encompasses
not only memory and learning difficulties but also per-
ceptual-motor, linguistic and central executive functions.
While the concepts proposed by the two international clas-
sifications, MCD and MNCD do not constitute adequate
algorithms for application in a research context, they do
provide formal recognition of subclinical cognitive dis-
order as a pathological state requiring treatment and as
a source of handicap and are thus, likely to be important
within a legal context.
A similar concept of cognitive change, secondary
to multiple underlying disease processes, but in this
case referring to elderly populations, is that of cogni-
tive impairment not dementia (CIND). The concept was
developed within the context of the Canadian Study of
Health and Aging and is defined with reference to neuro-
psychological testing and clinical examination (Graham
et al., 1997). Persons with CIND, like MCD and MNCD,
are considered to have cognitive impairment attributable
to an underlying physical disorder, but may also have a
‘circumscribed memory impairment’, which is a modi-
fied form of AAMI. CIND encompasses a wider range of
underlying pathologies (and therefore has higher preva-
lence rates) than MCD and MNCD, including disorders
such as delirium, substance abuse and psychiatric illness,
which are excluded from the ICD and DSM categories.
More recently (see below), a new entity has appeared in
Diagnostic and Statistical Manual of Mental Disorders,
Fifth Edition (DSM-5) (American Psychiatric Association,
2013) called ‘mild neurocognitive disorder (mNCD)’
defined by a noticeable decrement in cognitive function-
ing that goes beyond normal changes seen in ageing. It
is a disorder that may or may not progress to dementia
because mNCD is recognized as a heterogeneous group
of disorders occurring throughout life. Although mNCD

has been defined in relation to findings relating to mild
cognitive impairment (MCI), it clearly covers more than
a pre-dementia syndrome including stable states of poor
cognitive functioning.
41.3 MCI – SUBCLINICAL COGNITIVE
CHANGE AS PRODROMAL
DEMENTIA
MCD, MNCD and CIND are constructs that have been
developed principally for research purposes and consider
cognitive disorder in the elderly to be heterogeneous, not
necessarily progressive, with treatment being determined
by the nature of the underlying primary systemic dis-
ease. On the other hand, many clinical observations of the
long-term outcome of cognitive complaints, particularly
those presented to memory clinics and neurology depart-
ments, led to the general conclusion by many neurologists
that subclinical cognitive disorder in the elderly is in fact
principally, if not exclusively, early-stage dementia. Thus,
whereas dementia was considered by many in the early
1990s to be an upward extension of a ‘normal’ process of
progressive ageing-related cognitive deterioration, by the
end of the decade subclinical cognitive deficit began to be
perceived as a downward extension of a neurodegenerative
process. In 1997, Petersen et al. proposed diagnostic crite-
ria for MCI, initially defined as consisting of complaints of
defective memory and demonstration of abnormal memory
functioning for age, with normal general cognitive func-
tioning and conserved ability to perform activities of daily
living, this was then considered to be a prodromal form of
Alzheimer’s disease. MCI criteria proved difficult to apply
as they referred to poor cognitive functioning as assessed at
one point in time, thus precluding appreciation of decline
over time and difficult to differentiate from cohort effects,
low intelligence quotient (IQ) and education. A later defi-
nition refined the initial concept by referring to memory
impairment beyond that expected for both age and educa-
tion level (Petersen et al., 1999). An alternative approach
has been to define it in terms of early-stage dementia. For
example, Krasuki et al. (1998) refer to cognitive impair-
ment with a score of 20 or more on the Mini–Mental State
Examination (MMSE) and Zaudig (1992) defines MCI
with a score of more than 22 on MMSE or from 34 to 47
on the Score from Structured Interview for Diagnosis of
Dementia of the Alzheimer Type (SIDAM) scale. Others
have referred to criteria based on the Clinical Dementia
Rating Scale or Global Deterioration Scale scores (Flicker
et al., 1991; Kluger et al., 1997). The concept of MCI sub-
sequently moved from being a non-benign, non-specific
form of memory impairment to a dementia prodromal
form. As such, it became the focus of considerable interest
as it opened up the possibility of wide scale treatment of a
subclinical state by the new anticholinergic therapy being
developed at this time for Alzheimer’s disease.
Mild cognitive impairment (MCI): A historical perspective 421
41.4 OPERATIONALIZING MCI
CRITERIA
Subsequent studies using MCI criteria encountered numer-
ous difficulties. These were principally due to a lack of con-
sensus as to whether the concept referred to memory loss is
a cause for dementia or specifically, Alzheimer’s disease and
because of the lack of a working definition of memory loss.
The result has been that population prevalence, the clini-
cal features of subjects identified with MCI and their clini-
cal outcomes vary widely between studies and even within
studies where there has been longitudinal follow-up. A con-
sensus conference held in Chicago in 1999 confronted the
many difficulties facing the MCI concept (Petersen et al.,
2001), notably its two underlying assumptions that it should
be confined exclusively to isolated memory impairment and
the dilemma whether it should refer exclusively to a prodro-
mal form of Alzheimer’s disease, or alternatively to a more
clinically heterogeneous group with an increased risk of
dementia due to any cause. While there is some limited evi-
dence that a purely amnesic syndrome may exist (Richards
et al., 1999), this category appears to represent only a
very small proportion (6%) of elderly persons with cogni-
tive deficit when the full range of cognitive functions are
examined. Higher rates of ‘circumscribed memory deficit’
(31.7% of CIND cases) are observed within the Canadian
Longitudinal Study (Graham et al., 1997), but only subjects
with a score below cut-off on the MMSE are examined and
the test battery itself consists predominantly of memory
tasks. Memory tests also involve cognitive capacities other
than memory, notably attentional and linguistic capacities,
so that it is difficult in the absence of a detailed neuropsy-
chological examination to conclude that an individual has
an isolated mnesic impairment. Many of the studies which
observe principally memory deficits in MCI have used
almost exclusively memory tests in their diagnostic exami-
nation, a self-fulfilling prophecy.
The Chicago consensus group concluded that subjects
with MCI have a condition which is different from normal
ageing and are likely to progress to Alzheimer’s disease at an
accelerated rate; however, they may also progress to another
form of dementia or their condition might improve. This
group, thus proposed subtypes of MCI according to the type
of cognitive deficit and clinical outcome, distinguishing
MCI-amnestic (MCI with pronounced memory impairment
progressing to Alzheimer’s disease), MCI multiple domain
(slight impairment across several cognitive domains leading
to Alzheimer’s disease, vascular dementia or stabilizing in
the case of normal brain ageing changes) and MCI single
non-memory domain (significant impairment in a cognitive
domain other than memory leading to Alzheimer’s disease
or another form of dementia). It has subsequently been sug-
gested that MCI can be further subdivided according to the
suspected aetiology of the cognitive impairment, in keeping
with international classifications of dementia disorders: for
422 Dementia

example, mild cognitive impairment–Alzheimer’s disease
(MCI-AD), mild cognitive impairment with Lewy body
dementia (MCI-LBD), mild cognitive impairment and fron-
totemporal dementia (MCI-FTD) and so on, however, clini-
cal studies have been unable to provide consistent empirical
evidence for these subdivisions. On the basis of evidence
from population studies presented at this conference, it was
also accepted that MCI subjects could have difficulties in
everyday functioning. A study has confirmed functional
loss to be a characteristic of all MCI subtypes (Aretouli and
Brandt, 2010) and application of the revised criteria to a gen-
eral population cohort has been shown to greatly increase
the ability of the algorithms to differentiate a pre-dementia
syndrome for other syndromes (Artero et al., 2006).
41.5 THE FUTURE OF MCI
A number of concepts now exist to describe subclinical cog-
nitive disorder in the elderly. Application of these concepts
in general population studies gives quite different prevalence
rates both between emerging concepts and even between
studies conducted using the same concept (Table 41.1).
Clearly, such deficits have multiple causes. Longitudinal
population studies of subclinical cognitive deficits have
demonstrated multiple patterns of cognitive change with
variable clinical outcomes including dementia, depression,
cardiovascular and respiratory disorders (Ritchie et al.,
1996; Lopez et al., 2003; Palmer et al., 2003; Matthews et al.,
2008). However, it is the identification of those cases likely
to evolve towards dementia which has been given priority,
especially, given the d ­ evelopment of treatments that may
delay onset of dementia. The ­potential ­treatment window for
dementia is large, with twin ­studies ­indicating that insidi-
ous changes in ­cognitive ­performance may occur up to 20
years of age before disease onset (La Rue and JarviK, 1987).
For this reason, at a conceptual level, MCI has been the
principal focus of interest as ­longitudinal ­studies ­confirm
the high risk rates of MCI for dementia, with conversion
estimates ­ranging from 10% to 15% per year (Petersen
et al., 1997), 40% over every 2 years (Johnson et al., 1998),
20% over every 3 years (Wolf et al., 1998), 30% over 3 years
(Black, 1999), 53% over 3 years (McKelvey et al., 1999),
to 100% over 4.5 years (Krasuki et al., 1998). Population
­studies show, ­however, lower ­dementia ­conversion rates
(2%–8% per annum) (Tierney et al., 1996; Johanssen and
Zarit, 1997; Kluger et al., 1999; Hogan and Ebly, 2000;
Artero et al., 2001; Morris et al., 2001) than those observed
in ­clinical studies (12%–31%) (Bowen et al., 1997; Devanand
et al., 1997; Flicker et al., 1991; Huang et al., 2000; Bozoki
et al., 2001; Stephan et al., 2008) as they include a wider
range of ­cognitive i­mpairments, which are probably less
severe than those presented in clinical s­ettings as well.
Although, persons labelled as MCI have a greater risk of
dementia, many do not experience a f­urther cognitive

Table 41.1 Characteristics and estimated prevalence rates (where available) of nosological entities defining cognitive
impairment in elderly persons without dementia

Population
Concept Criteria prevalence %
BSF Kral (1962) Memory complaints, forgetting details, depression
AAMI Crook et al. (1986) Memory impairment with decrement on formal cognitive test 7–38
compared to young adults
LLF Blackford and La Rue (1989) AAMI with greater decrement on 50% of a test battery
AACD Levy et al. (1994) Impairment on any formal cognitive tests compared to peers 21–27
ARCD DSM-IV Objective decline in cognitive functioning due to old age 8
MCD ICD-10 Disorders of memory learning and concentration demonstrated by 4
testing due to disease
MNCD DSM-IV Difficulties in memory, learning, perceptual-motor, linguistic and
central executive functioning due to disease
CIND Graham et al. (1997) Circumscribed memory impairment and low MMSE score due to 11–80
disease or old age
MCI Petersen et al. (1997) Complaints of defective memory, demonstrated by deficit in 3–15
cognitive tests conducted with normal general intellectual
functioning compared to peers due to dementia
mNCD DSM-5 Difficulties in memory and learning, language, complex attention,
executive function, perceptual-motor function, social cognition
compared to peers due to dementia or other reasons
Abbreviations: 
BSF, benign senescent forgetfulness; AAMI, age-associated memory impairment; LLF, late-life forgetfulness; AACD,
­ageingassociated cognitive decline; ARCD, age-related cognitive decline; DSM-IV, Diagnostic and Statistical Manual of
Mental Disorders, Fourth Edition; MCD, mild cognitive disorder; ICD-10, International Classification of Diseases,
10th Revision; MNCD, mild ­neurocognitive disorder; CIND, cognitive impairment not dementia; MMSE, Mini–Mental State
Examination; MCI, mild ­cognitive impairment; mNCD, mild neurocognitive disorder.

decline and may even revert to normal status (Wada-Isoe
et al., 2012; Ward et al., 2012). Population studies further
indicate that current criteria have poor specificity in the
general ­population ­setting and may also miss many per-
sons who will develop dementia within a few years, but that
age-adjusted ­cognitive measures in conjunction with mea-
sures of d ­ isability, depression and anatomical changes on
cerebral imaging (volume loss in hippocampal and ento-
rhinal cortex) may ultimately p ­ rovide better dementia pre-
dictions (Tierney et al., 1996; Touchon and Ritchie, 1999;
Artero et al., 2001; Ritchie et al., 2001; Visser et al., 2002;
Artero et al., 2003; Palmer et al., 2003). Moreover, risk fac-
tors and clinical ­presentation of MCI may be different for
men and women, such that greater specificity in detection
may be achieved if sex-specific diagnostic algorithms are
proposed (Artero et al., 2008; Ritchie et al., 2010).
It has also been suggested that the addition of biological
markers to definitions of MCI may also improve prediction.
For example, longitudinal population studies have consis-
tently shown that severe white matter lesions significantly
increase the risk of developing MCI and dementia, particu-
larly, when located in temporal regions (Mortamais et al.,
2013; 2014).
Markers more closely associated with onset of AD, nota-
bly amyloid beta protein and tau ratios in cerebrospinal
fluid also appear to improve MCI case identification and
prognostic ability (Frankfort et al., 2008) along with less
disease-specific markers such as acute-phase proteins, cyto-
kines, isoprostanes, homocysteine and cholesterol (Song
et al., 2009). With regard to genetic markers, apart from the
well-established association of MCI with the ApoE ε4 allele,
epigenetic regulators including microRNA have also been
proposed as a means of better identification of MCI cases
with high risk of evolution towards dementia (Sheinerman
et al., 2012). Many of these biomarkers, however, have high-
est discriminability at preclinical stages when it may be
difficult to demonstrate the cognitive deficit, which is cen-
tral to the notion of MCI. To this end, much finer tests will
therefore need to be developed, focusing on the earliest sites
of brain marker change, such as the posterior hippocampus
and entorhinal cortex.
While the recognition of MCI as a potentially patho-
logical entity marks an early step towards the recognition
of non-dementia cognitive disorder as an important clini-
cal problem with a potential treatment, it does not meet the
necessary validation criteria for a formal nosological entity
(Ritchie et al., 2001). The feasibility of wide-scale treatment
will very much depend on the development of precise diag-
nostic criteria. Premature application of MCI criteria for the
identification of subjects for clinical trials is likely to lead to
either the inclusion of high numbers of non-cases (yielding
high failure rates and subsequent discreditation of a treat-
ment, which may have been successful on sample subgroups)
or alternatively by restriction to subjects already manifest-
ing early dementia in reality, in which case it may be too
late to demonstrate potential preventive/delaying effects.
The future of MCI development will depend very much on
Mild cognitive impairment (MCI): A historical perspective 423
close collaboration between specialist clinical units refining
clinical criteria and epidemiologists monitoring screening
efficiency within the general population, where MCI will
principally be detected.
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Clinical characteristics of mild cognitive
impairment
YONAS E. GEDA, JANINA KRELL-ROESCH, ANNA PINK, KATHLEEN A. SPANGEHL AND
RONALD C. PETERSEN
42.1 INTRODUCTION
The promotion of health and prevention of disease is a time
honoured axiomatic truth (Geda et al., 2006). This is partic-
ularly true of Alzheimer’s disease (AD), the most common
cause of dementia (Chong and Sahadevan, 2005).
It is crucial to delay the onset of dementia, one of the lead-
ing causes of mortality and morbidity in late-life for compel-
ling reasons (see Chapters 2, 3, 7 and 15). If it were possible
to delay the onset of dementia by about 2 years, the global
prevalence of AD would decrease by 22.8 million cases.
Effective prevention, as well as intervention, could dramati-
cally reduce disease onset and progression. The identification
of mild cognitive impairment (MCI) contributes to the early
detection and prevention effort (Petersen et al., 1999b).
MCI refers to an intermediate stage between the cognitive
changes of normal ageing and very early dementia (Petersen
et al., 2005) (Figure 42.1). Individuals with MCI show cog-
nitive impairment greater than expected for their age, but
otherwise function independently and do not meet the com-
monly accepted criteria for dementia (Petersen et al., 1999b).
42.2 HISTORICAL GENESIS OF MCI
In the past decades, a growing research effort has been
devoted to the identification of clinical and epidemiologi-
cal characteristics as well as probable causes of dementia.
During this progress, clinicians and investigators observed
some elderly persons who were neither demented nor cogni-
tively normal for their age. This observation prompted them
to investigate the intermediate stage between intact cogni-
tive functioning and clinical dementia.
426
42
Reisberg et al. were perhaps the first to coin the term MCI
(Reisberg et al., 1982; Flicker et al., 1991; Reisberg et al., 2008).
They defined MCI using the Global Deterioration Scale (GDS).
The GDS is an ordinal scale of 1 to 7 with 1 being normal and
7 signifying severe dementia. A GDS score of 3 is defined as
MCI. In 1962, V.A. Kral used the term senescent forgetfulness
as the first attempt to characterize memory concerns with age-
ing. An initiative of the National Institute of Mental Health
coined the term ‘age-associated memory impairment (AAMI)’
(Crook et al., 1986). The concept of AAMI further accelerated
the research work in the grey zone between ageing and demen-
tia. However, AAMI was noted to have limitations, such as its
­restriction to memory domain only. Moreover, AAMI was
based on a comparison of memory function in older adults to
that of young adults (at least one standard deviation below the
mean for young adults). Such limitations led some to remark that,
depending on the memory test selected, up to 90% of those older
than 50 years would be labelled as impaired (Smith et al., 1991).
To address the weaknesses of AAMI, the International
Psychogeriatric Association defined the term ‘age-asso-
ciated cognitive decline (AACD)’ (Levy, 1994). AACD
addressed memory decline plus criteria for a variety of
cognitive domains presumed to decline in normal ageing.
Age and education adjusted normative values were also
described. In addition to AAMI and AACD several other
terms and definitions were proposed (Blackford and La Rue,
1989; Graham et al., 1997) including ‘questionable demen-
tia’ (Devanand et al., 1997) as defined by a score of 0.5 on
the Clinical Dementia Rating Scale (CDR) (Morris, 1993).
While both GDS and CDR are reliable scales when rating
severity of MCI along the continuum of cognitive impair-
ment, they do not necessarily coincide with various stages
of impairment. Actually, patients with a GDS of 3 or CDR of
0.5 may in fact fulfil criteria for mild dementia or AD.

Normal
Mild cognitive
impairment
Alzheimer’s disease
Figure 42.1 Conceptual model of mild cognitive
­impairment (MCI).
Out of the different constructs and terms proposed during
the past decades, MCI is probably the most empirically inves-
tigated construct as evidenced by the exponential increase
in publications and citation numbers pertaining to MCI. In
addition, the American Academy of Neurology (AAN) stated
that MCI is worthy of attention since individuals with MCI
have a high rate (10%–15% per year) of developing dementia
compared to the rate for the general population of 1%–2%
per year (Petersen et al., 2001). The criteria for amnestic MCI
(aMCI) were first proposed in 1999 following an empirically
validated prospective and population-based cohort study
in Rochester, Minnesota (Petersen et al., 1999a). A num-
ber of factors facilitated the development of this construct.
Researchers noted: (1) the existence of an intermediate zone
of cognitive impairment not captured by a clinical definition;
(2) a rising importance of dementia for public health; (3) an
emerging clinical need for a construct beyond the binary
diagnosis of present/absent dementia (Petersen et al., 2014)
and (4) a diagnosis of MCI allows both, patients and caregiv-
ers, to plan for future familial challenges while the patient is
still able to make conscious decisions. The Mayo Clinic core
criteria published in 1999 were mainly focused on memory
impairment. The core required the presence of self or infor-
mant reported memory complaints and objective memory
impairment with essentially preserved cognitive functioning.
In Stockholm, Sweden 2003, a Key Symposium of experts
in the field of cognitive ageing revised the Mayo Clinic crite-
ria. The newly developed International criteria of MCI were
broadened to include other areas of cognitive impairment
and were no longer restricted to memory. This revision led
to a new understanding of MCI, which became a clinical
syndrome with multiple clinical profiles due to various aeti-
ologies (Petersen et al., 2014).
42.2.3 MCI DUE TO AD (NATIONAL
INSTITUTE ON AGING [NIA]–
ALZHEIMER’S ASSOCIATION [AA]
CRITERIA)
In 2011, a work group of investigators from the NIA and
the AA published guidelines for the diagnosis of MCI due
to AD (Albert et al., 2011). The work group recommended
Clinical characteristics of mild cognitive impairment 427
the combination of both clinical features and biomarker
measures for a diagnosis of MCI due to AD. Petersen et al.
noted that the NIA-AA criteria and especially the newly
added biomarker criteria are valid in most MCI subjects
in community and clinical trial settings. However, a num-
ber of subjects also showed conflicting biomarker results
inconsistent with the proposed AD model i.e. neurodegen-
eration without amyloid deposition (Petersen et al., 2013).
The reader is referred to the Section 42.5 of this chapter for
more details.
42.2.4 MILD NEUROCOGNITIVE
DISORDERS (THE NEW DSM-5
CRITERIA)
In the fifth edition of the Diagnostic and Statistical Manual
of Mental Disorders (DSM-5), the American Psychiatric
Association proposes a new construct of ‘Neurocognitive
Disorders (NCD)’, which covers the three entities: delir-
ium, major NCD and mild NCD (American Psychiatric
Association and American Psychiatric Association DSM-5
Task Force, 2013). The mild NCD criteria are similar to the
international criteria of MCI. In fact, the DSM-5 discusses
the epidemiology and diagnostic markers of mild NCD
by drawing congruence between MCI and mild NCD. The
main difference between the two constructs is that mild
NCD is defined as acquired cognitive disorders pertinent
to all age groups, whereas MCI is based on research done
in the context of geriatric populations, although age is not
a part of the MCI definition. Mild NCD may improve the
reliability of diagnoses; however, it has yet to withstand the
empirical scrutiny needed to be considered as a valid con-
struct (Stokin et al., 2015).
42.3 CLINICAL FEATURES
Physicians often encounter a clinical scenario in which an
elderly person presents with memory concerns. The patient
is often interested in finding out whether AD is a possible
diagnosis. While such concerns could represent other states
such as late-life depression or the so-called ‘worried-well’
state, memory concerns may also be suggestive of an evolv-
ing AD. Consider, for example, a typical clinical scenario
described below.
42.3.1 CASE RECORD OF PATIENT A
A 73-year-old right-handed male patient presents with
forgetfulness for recent events and future engagements.
Family members and close friends notice these changes
as well. The patient has difficulty identifying the onset
of these symptoms, but felt that they started insidi-
ously and progressed gradually over a period of 2–3
years. Otherwise, he is living independently and has
428 Dementia
no difficulty carrying out activities of daily living, such
as handling his own finances, cooking and driving. He
denies depression, stress or other complicating medi-
cal issues. He requests an appointment with a physician
in order to determine if this memory problem should
be pursued further. The clinical evaluation i.e. meticu-
lous history and physical examination, including bed-
side cognitive screening using the short test of mental
status, is suggestive of cognitive impairment but not
severe enough to warrant the diagnosis of dementia,
hence a clinical diagnosis of MCI is made. Investigations
including psychometric testing and magnetic resonance
imaging (MRI) are ordered. The neuropsychological test-
ing confirms the clinical diagnosis. It reveals memory
impairment, particularly on measures of learning and
delayed recall beyond what is felt to be normal for age;
but other cognitive domains such as language and visuo-
spatial skills are relatively intact. An MRI of the head
revealed mild hippocampal atrophy.
42.3.2 COMMENT
This patient probably has aMCI. He is becoming slightly
more forgetful, and this is noticeable to his family and
friends. The most salient feature of the history concerns
forgetfulness of insidious onset that gradually progresses
over a year or so. All other cognitive domains i.e. language,
comportment-executive function and visuospatial skills
are intact. The individual does not have a decline in func-
tion. This finding likely represents an early disease process
involving the medial temporal lobe since meaningful infor-
mation can no longer be encoded in an efficient manner, nor
recalled well.
42.3.3 DIAGNOSTIC ALGORITHM FOR
MCI SUBTYPES
The diagnosis of MCI is anchored upon clinical data, i.e.
detailed history, thorough physical ­examination and bed-
side cognitive screening, e.g. Mini-Mental State Examination
(MMSE) (Folstein et al., 1975) or equivalent scales (Kokmen
et al., 1987) to objectively confirm self- or informant-
reported cognitive complaints. Even though aMCI is the
most widely studied and empirically validated construct,
additional subtypes are also the subject of intense investiga-
tion (Winblad et al., 2004).
Figure 42.2 depicts the diagnostic algorithm used to
identify a particular subtype of MCI. This procedure is
initiated when a patient or informant, usually the spouse,
reports cognitive complaints such as forgetfulness for recent
events and future engagements. The clinician should first
determine the patient to be neither demented nor of normal
cognition for age and education. Next there should be no
substantial functional decline or if present, the functional
decline should not be of sufficient magnitude as to warrant
the diagnosis of very mild dementia.
If these conditions are met, a diagnosis of MCI may
be assumed and the clinician can proceed to identify the
number and types of cognitive domains impaired. A diag-
nosis of aMCI-single domain is assumed if the impairment
involves only memory domain. aMCI-multiple domain per-
tains to impairments in the memory domain plus at least
one other cognitive domain, such as language, executive
function or visuospatial skills. Likewise, a diagnosis of non-
amnestic MCI (naMCI)-single domain is assumed if there
is impairment in a single non-memory domain, whereas
naMCI-multiple domain refers to impairments in multiple
non-memory domains.
Figure 42.3 depicts the presumed aetiologies along
with clinical subtypes of MCI. The single- and multiple-
domain aMCI subtypes with presumed degenerative aeti-
ology likely represent a prodromal form of AD (Winblad
et al., 2004). The non-amnestic subtypes that emphasise
impairments in other cognitive domains aside from mem-
ory may have a higher likelihood of progressing to a non-
AD dementia, e.g. dementia with Lewy bodies (Winblad
et al., 2004).
42.4 EPIDEMIOLOGY OF MCI
Three epidemiological indices are derived from descriptive
studies of MCI: the prevalence, the incidence and the con-
version rate of MCI to dementia. Numerous studies have
been conducted to investigate both the prevalence and inci-
dence of MCI.
The Cardiovascular Health Study (CHS) was perhaps the
first population-based study to estimate the prevalence of
MCI subtypes. The study was originally designed to exam-
ine cardiovascular risk factors (Fried et al., 1991). The CHS
reported an overall prevalence of MCI to be 22% with aMCI
accounting for 6% and multi-domain MCI representing
16% (Lopez et al., 2003).
Researchers in Japan retrofitted the MCI criteria in a
cohort of over 65-year-olds and estimated the prevalence of
MCI to be in the range of 1.7%–16.6% (Sasaki et al., 2009).
Retrofitting the MCI criteria might have introduced mea-
surement bias in the Japanese study. An Australian research
group found the prevalence of MCI to be 3.8% and AACD
to be 3.1% in subjects 60–64 years old (Kumar et al., 2005).
Although the Australian study design was optimal, the
cohort involved a younger age group, thus the prevalence
rate was understandably low.
A population-based study utilizing the operational crite-
ria of MCI in the elderly is likely to minimize sampling and
measurement bias, thus leading to more precise estimates
of prevalence and incidence rates. One such example is the
population-based Mayo Clinic Study of Aging (MCSA)
launched in Olmsted County, Minnesota on the prevalence
date of 1 October 2004 (Roberts et al., 2008). The preva-
lence of MCI from this study is estimated at approximately
 Clinical characteristics of mild cognitive impairment 429

Mild cognitive impairment

Cognitive complaint

Not normal for age

Not demented
Cognitive decline
Essentially normal functional activities

MCI

Yes Memory impaired? No

Amnestic MCI Non-amnestic MCI

Single non-memory
Memory
Yes No Yes cognitive domain No
impairment only?
impaired?

Amnestic MCI Amnestic MCI Non-amnestic MCI Non-amnestic MCI

single domain multiple domain single domain multiple domain

Figure 42.2 Flow chart of decision process for making diagnosis of subtypes of MCI.

Aetiology
Degenerative Vascular Psychiatric Trauma

Single
AD Depression
domain

Amnestic
MCI
Clinical classification

Multiple
AD VaD Depression
domain

Single
FTD
domain
Non-
amnestic
MCI
Multiple
DLB VaD
domain

Figure 42.3 Classification of clinical subtypes of MCI with presumed aetiology.

15%, with a 2:1 ratio of aMCI to naMCI (Petersen, 2009).
Prevalence of MCI increased with age, was found to be
higher in men than women, in those who were not mar-
ried and in carriers of the apoprotein E-ε4 (APOE-ε4) allele
(Petersen et al., 2010). Prevalence of MCI decreased, how-
ever, with increasing years of education (Petersen et al.,
2010). A recent review of the literature by experts in the field
indicated that the prevalence of MCI could be as high as
18.9%, as measured by the expanded Mayo Clinic criteria
(Petersen et al., 2014).
42.4.1 INCIDENCE OF MCI
The incidence of MCI ranges from 1% to 6% per year
while prevalence estimates range from 3% to 22% per year
(Bennett et al., 2002; Hanninen et al., 2002; Larrieu et al.,
2002; DeCarli, 2003; Lopez et al., 2003; Ganguli et al., 2004).
This variability can in part be explained by sampling and
measurement biases (Sackett, 1979). Sampling methods that
may have yielded variability include using advertisements to
recruit research participants (introducing a non-respondent/
430 Dementia
volunteer bias) (Sackett, 1979). Measurement bias may be
introduced when retrofitting MCI criteria into a cohort
assembled for non-MCI study. Furthermore, older research
mainly focused on the Mayo Clinic core criteria of MCI
and was restricted to memory impairment, whereas, recent
investigations utilise the expanded MCI criteria to include
memory impairment plus other cognitive domains. Due to
the above heterogeneity it is not surprising that prevalence
and incidence rates can vary significantly.
Past incidence estimates of MCI were primarily based
on clinical samples. However, in the past few years, sev-
eral population-based studies have been conducted to
estimate the incidence of MCI. For example, the MCSA
conducted a population-based prospective cohort study
in i­ndividuals aged 70 years and older and reported
an incidence rate of 63.6 per 1000 person-years, with a
higher rate in men (72.4) than in women (57.3) (Roberts
et al., 2012).
In addition to studies on the progression from normal
ageing to incident MCI, investigators have also examined
several studies that have estimated the progression rate of
MCI to dementia (Flicker et al., 1991; Tierney et al., 1996;
Petersen et al., 1999a; Daly et al., 2000; Petersen et al., 2005;
Fischer et al., 2007). The findings vary depending upon the
study design and measurement instruments used. Researchers
from Harvard University recruited study participants via
advertisement. They prospectively followed a cohort of sub-
jects with MCI and reported a conversion rate of 6% per
year (Daly et al., 2000). Alternatively, a recent multicentre,
randomized, double-blind, placebo-controlled clinical trial
reported a conversion rate of 16% per year (Petersen et al.,
2005). A further community-based birth cohort study exam-
ining progression rates between amnestic and non-amnestic
subtypes of MCI to AD showed the annual rate of conver-
sion to AD for aMCI to be 19%, compared to almost 11% for
naMCI subjects (Fischer et al., 2007). Researchers from the
Karolinska Institute in Sweden reported in 2008 that 33.3%
of aMCI patients, 10% of naMCI-single domain patients and
75.0% of naMCI-multiple domain patients progressed to AD
after 3 years of follow-up (Palmer et al., 2008). Hence, the
rather small rate reported by the Harvard group could be
attributed to non-respondent/volunteer bias (Sackett, 1979).
The higher percentages from the community-based cohort
study may be due to prevalence/incidence bias where in MCI
subjects with advanced cognitive impairment (prevalent
MCI) may have higher conversion rates to dementia (Fischer
et al., 2007; Mitchell and Shiri-Feshki, 2008). The common
theme in all the studies is that MCI c­ onstitutes a high-risk
group for dementia.
There is an ongoing controversy regarding the ‘insta-
bility’ of the MCI construct (Ritchie et al., 2001; Larrieu
et al., 2002). Larrieu et al. from France reported a rever-
sion rate (i.e. from MCI back to normal cognitive ageing)
to be as high as 40% over a 2–3 years follow-up. However,
one major limitation of their study was how they defined
MCI, based on only one single memory measurement,
the Benton Visual Retention Test (Benton, 1983). Despite
this, recent evidence indicates that an MCI diagnosis
(with or without reversion to cognitively normal status)
is associated with an increased risk of dementia (Roberts
et al., 2014).
42.4.2 NEUROPSYCHIATRIC FEATURES
Although the neurological, psychometric and neuroimag-
ing aspects of MCI have been researched (Petersen et al.,
1999a; Jack et al., 2000; Jack et al., 2009), there has been
little investigation in the neuropsychiatric aspect of MCI. It
is reasonable to address this issue because the medial tem-
poral lobe and its connections with the prefrontal cortex
and other structures not only play a critical role in cognitive
function but may also be involved in emotional behaviour
(Mesulam, 1998). The first population-based investigation
of neuropsychiatric symptoms of MCI was reported in 2002
(Lyketsos et al., 2002). Since then, there have been similar
studies on these features involving samples from primary
or tertiary care settings (Feldman et al., 2004; Geda et al.,
2004; Hwang et al., 2004; Beaulieu-Bonneau and Hudon,
2009; Edwards et al., 2009).
The MCSA has reported the population-based preva-
lence of neuropsychiatric symptoms in normal ageing and
MCI. The investigators observed that the three most com-
mon neuropsychiatric symptoms in MCI were depression
(27%), apathy (18.5%) and irritability (19.4%) (Geda et al.,
2008). Lyketsos et al. (2002) reported similar, but slightly
smaller frequencies of depression (20%), apathy (15%) and
irritability (15%) in the CHS. The CHS group suggested that
selection bias might have led to an underestimation of their
prevalence estimates. This bias may account for the differ-
ences in crude frequency rates across the two studies. The
Cache County population-based study reported prevalence
figures for depression (7.2%), apathy (3.2%) and irritabil-
ity of (4.6%) in cognitively normal persons (Lyketsos et al.,
2000). The Mayo Clinic group did observe slightly higher
figures for depression (11.5%), apathy (4.8%) and irritability
(7.6%) in normal ageing (Geda et al., 2008).
42.4.3 INCIDENCE OF MCI BY BASELINE
NEUROPSYCHIATRIC STATUS
There are limited data on the incidence of MCI as predi-
cated by baseline neuropsychiatric symptoms (Wilson
et al., 2007; Brodaty et al., 2012; Geda et al., 2014). The
Sydney Memory and Ageing Study reported that agitation
and anxiety predicted cognitive decline in 873 individuals
aged 70–90 years. (Brodaty et al., 2012). The Chicago Health
and Ageing Project reported that the ‘distress-prone’ elderly
subjects were more likely to develop incident MCI as com-
pared to those who were less distress prone (Wilson et al.,
2007). Recently, the MCSA prospectively followed 1587 cog-
nitively normal elderly (70 years and older) to the outcome
of incident MCI, as predicted by baseline neuropsychiatric
 Clinical characteristics of mild cognitive impairment 431

symptoms. The investigators observed that baseline psychi-
atric symptoms were of similar or greater magnitude as bio-
markers (genetic and structural MRI) in predicting the risk
of incident MCI (Geda et al., 2014).
42.4.4 PROPOSED MECHANISMS LINKING
NEUROPSYCHIATRIC SYMPTOMS
WITH COGNITIVE OUTCOMES
In the past, the following four possible theoretical models
that may explain the link between neuropsychiatric symp-
toms and MCI/AD have been proposed (Geda et al., 2013):
(1) neuropsychiatric symptoms as ‘risk factors’: a specific
neuropsychiatric symptom may have a direct deleterious
effect on the brain and therefore lead to MCI/AD; (2) shared
risk factor or confounding pathway: a biological risk factor
for MCI/AD may lead to both cognitive outcome and neu-
ropsychiatric symptoms; (3) a synergistic interaction: a neu-
ropsychiatric symptom and a biological factor may interact
to have a synergistic effect of elevating the risk of MCI/AD;
(4) reverse causality: a subject may show reactive depression
and/or other neuropsychiatric symptoms after the person
starts noticing cognitive decline. It should be noted that
the four theoretical models are not mutually exclusive
and may interact. Furthermore, these proposed theoreti-
cal models remain to be hypothetical and speculative until
confirmed by mechanistic research (Geda et al., 2013)
(Figure 42.4).
42.5 BIOMARKERS
The neurodegenerative process of AD likely precedes the
development of clinical manifestations of AD by several
years if not decades (Braak and Braak, 1991; Shaw et al.,
2007). About 30% of cognitively normal elderly subjects
meet criteria for AD based on their pathology at autopsy
(Price and Morris, 1999; Knopman et al., 2012). Biomarkers
can measure pathological processes in vivo. The most
common underlying pathological process in MCI is AD.
Biomarkers in AD can provide evidence of AD pathology
in MCI via markers of amyloid deposition and neurode-
generation (Albert et al., 2011). The most widely used bio-
markers are neuroimaging and cerebrospinal fluid (CSF)
derived measures. Biomarkers of amyloid positron emission

(a) Neuropsychiatric Unknown Brain DAT/MCI

symptoms mechanism damage

Neuropsychtric
(b) symptoms
Susceptibility
gene variant
or other
risk factor DAT/MCI

(c) Preclinical Neuropsychatric

DAT/MCI DAT/MCI
symptoms

(d)
Susceptibility
gene variant Interaction DAT/MCI
or other
risk factor

Neuropsychiatric
symptoms

Figure 42.4 Four hypotheses of the possible mechanisms linking depression to MCI: (a) Aetiologic pathway, (b) confound-
ing, (c) reverse casualty and (d) interaction.
432 Dementia
tomography (PET) imaging or amyloid β42 (Aβ42) mea-
surement in CSF provide direct evidence of amyloid deposi-
tion in the brain. In contrast, tau deposition in the form of
neurofibrillary tangles (NFT) may reflect neurodegenera-
tion. Other measures of neurodegeneration include brain
atrophy as measured by MRI, and brain hypometabolism as
measured by fluorodeoxyglucose-PET (FDG-PET).
42.5.1 BIOMARKERS OF AMYLOID AND
TAU DEPOSITION
The plaques that are formed during the pathologic process
of AD consist of extracellular deposits of amyloid β-protein
(Aβ), which primarily form filamentous fibrils. This process
can be detected via imaging (Clark et al., 2011) and CSF bio-
markers of amyloid deposition.
42.5.1.1 PET amyloid imaging
The development of the amyloid-imaging PET tracer,
Pittsburgh Compound-B (PiB), is an important contribution
to the study of ageing (Klunk et al., 2004). A few studies have
examined the serial properties of PiB over time (Klunk et al.,
2006; see Chapter 12. Current data suggest that 20%–30%
of cognitively normal subjects have positive PiB scans while
about 60% of MCI subjects have positive scans (Lopresti et al.,
2005). Furthermore, another PET tracer, 18F-florbetapir, has
a relatively long radioactive half-life, and this in part has con-
tributed for this agent to get Food and Drug Administration
(FDA) approval (Wong et al., 2010).
AD patients show widespread cortical amyloid uptake
with the most prominent uptake in the frontal cortex and
precuneus followed by the parietal and temporal cortices
(Kemppainen et al., 2006). A positive PiB (Wolk et al., 2009;
Villemagne et al., 2011) or 18F-florbetapir (Doraiswamy
et al., 2012; Landau et al., 2012) amyloid imaging scan is
associated with progression from MCI to AD. It should be
noted, however, that more research is needed on this area, to
develop precise prediction models.
42.5.1.2 Tau imaging
Recently, investigations of tauopathy, employing tau imaging
ligands, has begun. Studies have been conducted in tauopa-
thy mouse models (Maruyama et al., 2013) and preliminary
studies have also been conducted involving human subjects
(Chien et al., 2013). However, tau imaging is currently in its
rudimentary stage in the investigation of ageing and MCI.
42.5.1.3 CSF amyloid β42
Aβ42 is the primary protein in amyloid plaques. Aβ42 is a
42-amino acid peptide formed by mutations on the amyloid
precursor protein (APP) and processing pathways (Hardy
and Selkoe, 2002) Amyloid deposition in the brain is asso-
ciated with reduced levels of CSF amyloid. This has been
demonstrated by studies showing that positive amyloid scans
correlate with low CSF Aβ42 (Fagan et al., 2006; Grimmer
et al., 2009; Jagust et al., 2009; Tolboom et al., 2009) Studies
have shown that low CSF Aβ42 has been associated with AD
diagnosis at autopsy (Clark et al., 2003, Strozyk et al., 2003).
In addition, low CSF Aβ42 has been shown to predict con-
version of MCI to dementia (Riemenschneider et al., 2002;
Hansson et al., 2006, Mattsson et al., 2009).
42.5.2 BIOMARKERS OF
NEURODEGENERATION
42.5.2.1 Magnetic resonance imaging
Structural MRI can measure cerebral atrophy. Cerebral
atrophy is associated with neuronal loss (Bobinski et al.,
2000). This can be shown in volumetric MRI studies investi-
gating hippocampal atrophy, ventricular volume expansion,
whole brain atrophy or cortical thinning and may reflect
neurodegeneration. Furthermore, MRI studies have been
shown to predict future progression to dementia in subjects
with MCI (Jack et al., 1999; Bakkour et al., 2009).
42.5.2.2 Fluorodeoxyglucose-PET
The metabolic activity of the brain is associated with synaptic
activity (Schwartz et al., 1979; Attwell and Laughlin, 2001).
Therefore, hypometabolism as measured by FDG-PET may
indicate neurodegeneration. Subjects with AD show a charac-
teristic pattern of hypometabolism in bilateral temporopari-
etal regions, including the posterior cingulate and precuneus
(Hoffman et al., 2000; Jagust et al., 2007). Hypometabolism
in temporoparietal regions also predicts conversion from
MCI to dementia (Chetelat et al., 2003; Landau et al., 2010).
42.5.2.3 CSF tau
Tau protein in healthy individuals is involved in the out-
growth of neuronal processes by promoting and stabiliz-
ing microtubules. Abnormal phosphorylation affects the
binding affinity of tau resulting in neuronal aggregations of
NFT. High CSF phosphorylated tau (P-tau) correlates with
NFT (Tapiola et al., 1997; Clark et al., 2003). While total tau
is nonspecific and is increased in various neurologic condi-
tions, such as stroke, traumatic brain injury or prion dis-
eases (Hesse et al., 2001; Otto et al., 2002; Ost et al., 2006),
P-tau seems more specific to AD and may help in distin-
guishing AD from frontotemporal dementia (Sjogren et al.,
2001) or dementia with Lewy bodies (Parnetti et al., 2001).
Total tau levels have been more frequently studied than
P-tau (Blennow and Hampel, 2003). In addition, elevated
levels of CSF total tau and P-tau independently predict
conversion from MCI to dementia (Riemenschneider et al.,
2002; Herukka et al., 2005; Hansson et al., 2006; Mattsson
et al., 2009).

Table 42.1 Clinical trials in mild cognitive impairment
Sponsor Duration
ADCS a 3 years
Merck 2–3 years
Novartis 3 years
Janssen 2 years
Pfizer 6 months
UCB 1 year
Elan, Myriad, Neurochem and 8 years (median
GlaxoSmithKline follow-up: 6.1 years)
Viatris 1 year
Department of Veterans Affairs, the 21 days
Institute for the Study on Aging and
National Institute on Aging
Abbreviations: AD, Alzheimer’s disease; UCB, Union chimique belge.
a Alzheimer’s Disease Cooperative Study supported by National Institute on Aging, Pfizer, Inc., Eisai, Inc. and Roche Vitamins.
A meta-analysis that examined the diagnostic accuracy
of combining the three CSF biomarkers (i.e. Aβ42, total tau
and P-tau) reported that the best predictor of conversion
from MCI to dementia was an abnormal ratio of Aβ42 to
total tau or abnormal levels of both markers; however, the
addition of P-tau did not increase diagnostic accuracy (Van
Rossum et al., 2010).
The field of ageing increasingly emphasizes the use of
biomarkers for research and potential long-term clinical
use. In 2011, the NIAand the AA published guidelines for
the identification of preclinical AD and MCI due to AD
(NIA–AA criteria) and placed an unprecedented empha-
sis on biomarkers of AD pathophysiology. The preclinical
AD criteria are the following: Stage 0, no abnormal amyloid
(A) or neurodegeneration (N) biomarkers (A−/N−); Stage 1,
abnormal amyloid only (A+/N−); Stage 2, abnormal amy-
loid and neurodegeneration (A+/N+); and Stage 3, same as
Stage 2 plus subtle cognitive changes that do not meet MCI
criteria (Albert et al., 2011; Jack et al., 2011; McKhann et al.,
2011; Sperling et al., 2011).
The authors of a recent study showed that the NIA–AA
criteria could be applied to most MCI subjects; however, a
considerable number of subjects had conflicting biomarker
results inconsistent with the proposed AD model i.e. neu-
rodegeneration without amyloid deposition. About 23%
of cognitively normal subjects showed neurodegeneration
without evidence of amyloid deposition, and the authors
have referred to this entity as suspected non-Alzheimer’s
pathophysiology (SNAP) (Jack et al., 2012; Petersen et al.,
2013). Imaging and chemical biomarkers are having an
increasing role in the field of ageing; however, they are far
removed from being used in clinical practice. Future trans-
lational research needs to be carried out to reliably and accu-
rately identify subjects in the presymptomatic stages of AD.
Clinical characteristics of mild cognitive impairment 433
End point Treatments
AD Vitamin E Donepezil
AD Rofecoxib
AD Rivastigmine
Symptoms Galantamine
Symptoms Donepezil
Symptoms Piracetam
AD Ginkgo biloba (not effective on
progression rate)
Symptoms Vitamin B6
Aerobic exercise
(walking helped improve memory
[men], attention [women])
Symptoms Intranasal insulin (retained more verbal
information after a delay)
42.6 TREATMENT
There is no standard treatment for MCI (see Chapter 43),
however, as the focus of AD research moves towards preven-
tion, numerous clinical trials are being undertaken, since
MCI is considered to be the optimum stage for interven-
tional studies to delay the onset of dementia (Chertkow,
2002; Bhalla et al., 2009). Table 42.1 outlines the clinical trials
targeting MCI currently under way or recently completed.
The reader is referred elsewhere for a detailed discussion
of clinical trials targeting MCI (Petersen et al., 2001; Jelic et
al., 2006; Petersen, 2007). One major clinical trial that targeted
MCI was the Alzheimer’s Disease Cooperative Study (ADCS)
funded by the NIA, with additional funding from Pfizer, Inc.,
Eisai, Inc. and Roche Vitamins. It involved 70 North American
medical centres, and was a randomized, double-blind, pla-
cebo-controlled study involving three arms to assess the safety
and efficacy of high-dose vitamin E (2000 IU per day) and
donepezil (10 mg per day) (Petersen et al., 2005) and was pow-
ered to decrease the conversion rate from MCI to AD from an
estimated 45% down to 30% over the course of 3 years.
Seven hundred and sixty-nine subjects were random-
ized and the annual conversion rate from MCI to AD was
approximately 16% per year. Over the course of the study,
donepezil reduced the risk of progressing to AD for the
first 18 months of the trial while vitamin E had no thera-
peutic effect. The secondary cognitive measures supported
the overall group progression rates. No unexpected adverse
events were observed. This was the first therapeutic trial
to demonstrate an ability to delay the clinical diagnosis of
AD using donepezil at least over the 18 months of the trial.
Donepezil has also been investigated as a therapy in other
trials (Doody et al., 2009; Lu et al., 2009; Petrella et al., 2009).
434 Dementia
Clinical trials have not been limited to pharmacological
agents and have examined exercise (Lautenschlager et al., 2008)
and leisure activities/cognitive activities such as reading, writ-
ing and playing board games (Verghese et al., 2003, 2006, 2009).
Both forms of intervention appeared helpful (see Chapter 43).
Although there are several ongoing clinical trials, no
generally effective pharmacological interventions have
been demonstrated in MCI. Nonetheless, as MCI is a rap-
idly evolving area of investigation, more effective treatment
options are likely to be forthcoming.
42.7 SUMMARY
The field of ageing and dementia has increasingly empha-
sized the early detection and treatment of cognitive impair-
ment. The construct of MCI, defined as the intermediate
stage between normal cognitive ageing and dementia, meets
this need. Currently various clinical trials are targeting MCI
or equivalent conditions. Furthermore, the development of
biomarkers has accelerated research work addressing both
the presymptomatic and prodromal phases of dementia.
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Managing the patient with mild cognitive
impairment
NICOLA T. LAUTENSCHLAGER AND ALEXANDER F. KURZ
43.1 INTRODUCTION
There is an abundance of publications focusing on cognitive
changes during old age, including mild cognitive impair-
ment (MCI). The majority of these articles focus on diagnostic
issues and prognostic prediction for future cognitive decline.
More recently, the topic of prevention of dementia or dementia
risk reduction has also had an impact on research and clinical
management of MCI. In addition to pharmacological trials,
non-pharmacological interventions investigating the role of
modifiable and potentially protective factors are being trialled
among populations with MCI. However, publications discuss-
ing how to best manage the patient with MCI outside research
studies are less common. With increasing awareness and
knowledge among the population in relation to Alzheimer’s
disease (AD), specialists and memory clinics receive more
referrals of younger patients, who, often still in the workforce,
worry about their cognitive function. Managing strategies for
adults with subjective memory complaints (SMC) and MCI
need to be individually tailored as they target individuals
from midlife to old age. This chapter focuses on the current
practical issues of managing a patient with MCI.
43.2 DISCLOSURE AND THE IMPACT
OF DIAGNOSIS
The process from first raising concerns in a clinical set-
ting regarding the cognitive performance of a person later
diagnosed with MCI to giving information on the diagnos-
tic process and outcome, management options and regular
follow-up appointments is a journey that can last for several
years and often ultimately results in a dementia diagnosis.
43
Usually the diagnostic ‘label’ of MCI is given by a special-
ist such as a neurologist, geriatrician or psychiatrist (e.g. in
a memory clinic) to whom the family doctor might have
referred the patient. While initially the term MCI was very
much restricted to research studies, it is now used more
frequently in clinical settings (Petersen, 2007), but the cri-
teria used for diagnosing MCI can vary widely. However,
the consensus criteria of the International Working Group
on MCI in 2004 are often used now (Winblad et al., 2004).
More recent diagnostic concepts such as ‘mild neurocog-
nitive disorder’ in the Diagnostic and Statistical Manual
of Mental Disorders, 5th Edition (DSM-V) (2013) or the
National Institute on Aging-Alzheimer’s Association
(NIA-AA) criteria of ‘MCI due to AD’ (Albert et al., 2011)
or ‘prodromal AD’ (Dubois et al., 2010) will no doubt be
explored in the future for their potential usefulness in the
clinical context. What the newer criteria have in common is
that current knowledge is used to not only define the criteria
for MCI or mild neurocognitive disorder but also to make a
statement in relation to the most likely underlying pathol-
ogy as to why the patient is experiencing MCI. As such,
these criteria, if validated for the clinical environment, will
help to make the heterogeneity of the term MCI more trans-
parent and therefore give better guidance for management
and prognosis. Receiving a diagnosis of MCI means auto-
matically being at a statistically increased risk of developing
a dementia syndrome later on, however, due to the aetio-
logical heterogeneity of the condition, different outcomes
are possible. Broadly speaking, patients might progress to
a dementia syndrome with passage of time or rather pres-
ent quite stable cognitive impairment or even revert back to
normal cognition (Gauthier et al., 2006). However, in popu-
lations visiting the memory clinic, most patients with MCI
will deteriorate eventually due to referral related enrichment
with neurodegenerative or cerebrovascular pathologies. In
439
440 Dementia
clinical settings, such as memory clinics, various patholo-
gies have been reported in autopsy studies of progressive
MCI (Bennett et al., 2005; see Chapters 41 and 42 for more
details).
Obviously, the individual clinical presentation, medi-
cal history and available evidence on the underlying cause
will determine how the diagnosis should be disclosed to
the patient and family and what prognostic advice is to be
given. MCI as a diagnosis often has a different meaning for
a patient from a family with familial AD as compared to
someone who has no family history of cognitive impair-
ment. Many specialists inform the patient and next of kin
about the many unknown elements surrounding the MCI
‘label’ and the fact that research in this area is still a work
in progress (Petersen, 2007) and this openness is usually
appreciated. Where available and appropriate, the question
of prognosis might make it relevant to educate patients and
family members about the potential usefulness of biomark-
ers, which can help with estimating the risk for clinical dete-
rioration. Structural magnetic resonance imaging (MRI) is
recommended when considering a clinical diagnosis of MCI
and can assist with estimating the underlying pathologies
contributing to the clinical presentation as well as the risk
for clinical deterioration in the near future. However, more
standardization and international guidelines are needed for
the clinical context (Petersen et al., 2001; Jack et al., 2009;
Jack et al., 2010; Jack et al., 2011; Petersen, 2011). Functional
imaging, such as fludeoxyglucose or more recently,
carbon-11-labelled Pittsburgh compound B or florbetapir
positron emission tomography (PET) can give an indica-
tion as to what extent AD pathology is present and might
impact on prognosis (Small et al., 2008; Johnson et al., 2013;
Villemagne et al., 2013). Another biomarker of relevance is
low cerebrospinal fluid (CSF) Aβ42, which has been shown
to have some predictive potential for future progression
towards dementia; however, a routine lumbar puncture as
part of diagnostic and management procedures for MCI is
currently not recommended for many countries (Mattsson
et al., 2009; Petersen, 2009; see Chapter 42 for more infor-
mation on biomarkers and MCI).
Educating the patient and family in detail about the rel-
evance of clinical symptoms, assessment process and results
of tests, for example, showing and explaining the relevant
imaging scans, is usually helpful since it validates the con-
cerns of the patient and family and frames the symptoms
of MCI in a medical context. This should include the expla-
nation that a thorough search for ‘reversible’ causes of the
symptoms was part of the investigations and did not reveal
any relevant potential causes. All this should help fam-
ily members to accept the medical diagnosis and therefore
alleviate anger, denial and guilt (Austrom and Lu, 2009).
This is especially crucial in patients where the observed
impairment fluctuates and the next of kin wonders whether
the patient is ‘putting the symptoms on’. In patients where
the clinical findings strongly suggest a pre-dementia syn-
drome, the possible emergence of psychological stress and
depression should not only be raised with the patient but
also with the next of kin who might have already moved
into a carer role without necessarily having processed this
gradual change consciously. It has been shown that family
members of patients with MCI already experience feelings
of loss and carer burden typically observed in carers of peo-
ple with AD (Artero et al., 2001; Garand et al., 2005; Lu and
Haase, 2009) and twice the general population risk depres-
sion (Guerriero et al., 2004). However, it is important to use
the term ‘carer’ carefully when communicating with MCI
patients and their families. Since the essence of the diag-
nostic category of MCI is that the level of independence of
the patient does not justify a diagnosis of dementia or major
neurocognitive disorder, the term ‘carer’ could be confusing
in this context. A more neutral term like ‘family member’ or
‘friend’ is preferable (Austrom and Lu, 2009). This does not
contradict recent findings showing that patients with MCI
do experience some impairment in very complex activities
of daily living (ADLs) (Perneczky et al., 2006) with family
members needing to provide ‘caregiving’ for more complex
ADLs (McIlvane et al., 2008).
Ethical concerns have been raised about disclosing the
‘label’ MCI to patients and family members. These concerns
include opening the door to distress, helplessness and hope-
lessness, with potential catastrophic outcomes like suicide
(Werner and Korczyn, 2008) in light of the unavailability of
effective treatment and looming AD. There is controversy
about whether patients with MCI already experience lim-
ited awareness of their symptoms, but, overall lack of insight
is considered less common than in AD patients (Vogel et al.,
2004; Kalbe et al., 2005). However, in the majority of cases,
the patient and family member already know that some-
thing is wrong and therefore the diagnosis does not surprise
them with ‘bad news’ but confirms symptoms observed,
often for many months. In this context, the term ‘mild’ in
MCI might be seen as trivializing symptoms, which causes
great concern. It is helpful to prevent this sentiment by
explaining that ‘mild’ is used in comparison to severe cog-
nitive impairment such as dementia or major neurocog-
nitive disorder, but not in relation to the individual, often
upsetting experience. Some clinicians, therefore, prefer to
describe the specific clinical findings without using the tem
MCI. On the other hand, similar to the disclosure process
of a dementia diagnosis, it should not be overlooked that
patients also have the right ‘not to know’ and, therefore, it is
important to adjust the level of detail of information given
accordingly.
43.3 PHARMACOLOGICAL AND
NON-PHARMACOLOGICAL
APPROACHES
No pharmacological approaches have yet shown significant
improvement of symptoms or delay of progression in MCI
and consequently there are currently no approved medi-
cations specifically for the treatment of MCI (Russ and

Morling, 2012). Randomized controlled trials (RCTs) with
negative results for the primary outcome have been con-
ducted with cholinesterase inhibitors, vitamin E, piracetam,
rofecoxib, ginkgo biloba and testosterone supplementa-
tion (Salloway et al., 2004; Petersen et al., 2005; Thal et al.,
2005; Jelic et al., 2006; Feldman et al., 2007; DeKosky et al.,
2008; Emmelot-Vonk et al., 2008; Winblad et al., 2008; Snitz
et al., 2009). However, there is some debate on whether the
RCT with donepezil and vitamin E showed some promis-
ing results by demonstrating a reduced risk for the first 12
months in the donepezil group, which grew even after 24
months for apolipoprotein E (ApoE) ε4–positive patients.
Off-label use of cholinesterase inhibitors continues to be
discussed in the literature (Diniz et al., 2009) and often in
combination with memantine, seems to be used by many
clinicians. A survey in the United States showed that one
quarter of patients with MCI received anti-AD medications
(Weinstein et al., 2009). A more recent 48-week RCT with
donepezil in MCI showed small but significant changes
on the Alzheimer’s Disease Assessment Scale-Cognitive
Subscale (ADAS-Cog), but no significant changes in the
primary outcome ­measure of global function (Doody et al.,
2009) was observed. RCTs with galantamine were overall
negative, but again showed interesting results, with a non-
significant reduction of progression rates and a reduced rate
of progression of brain atrophy in the galantamine group.
However, there was also an increased mortality rate reported
in ­galantamine-treated participants (Gold et al., 2004) and
a recent Cochrane review indicated that patients with MCI
might be at greater risk of experiencing an increase of
adverse effects when treated with cholinesterase inhibitors
(Russ et al., 2012). A small trial with memantine in patients
with age-associated memory impairment (AAMI) was
negative in relation to measures of memory performance
(Ferris et al., 2007). Pharmacological trial experiences
to date highlight the ongoing challenges in choosing the
most appropriate methodology and d ­ iagnostic criteria for
MCI (Knopman, 2009) and targeted trials with individuals
who qualify for the ­narrow diagnosis of ­prodromal AD via
routine use of biomarkers might improve the trial results
record in the future (see also Chapter 42).
There is increasing evidence that good general medical
management is particularly important for patients with
MCI. This includes adhering to current recommendation to
prevent and manage hypertension, heart disease, diabetes
and stroke, especially, in cases where vascular risk factors
or cerebrovascular changes are present (Langa and Levine,
2014).
In the absence of effective pharmacological treatment,
considering non-pharmacological approaches for an indi-
vidualized management plan becomes crucial. Reducing
modifiable risk factors for dementia and AD and enhanc-
ing potential protective factors are of particular interest
here as evidence is mounting that this approach could
delay the onset of dementia and AD not only in cognitively
healthy middle aged and older populations as a dementia
risk reduction strategy (Norton et al., 2014; Smith and
Managing the patient with mild cognitive impairment 441
Yaffe, 2014; Astey et al., 2015) but also in individuals
with SMC and MCI (Lautenschlager et al., 2014; see also
Chapter 55).
Evidence is still limited, and findings are not consis-
tent, but increasing evidence suggests that especially cog-
nitive and physical activity are activities, which should
also be encouraged in individuals with SMC and MCI
(Lautenschlager et al., 2014). Several theories have been
put forward to explain how cognitive activity could ben-
efit cognition in old age and, therefore, potentially help
patients with MCI. These theories include ‘use it or lose
it’, ‘environmental enrichment’, ‘the cognitive reserve
hypothesis’ and the ‘scaffolding theory of cognitive aging’
approach (Fratiglioni et al., 2004; Salthouse, 2006; Stern,
2006; Park and Reuter-Lorenz, 2009). Often cognitive
activity is grouped into further subtypes, such as cogni-
tive stimulation, cognitive training and cognitive rehabili-
tation, and significant benefits for participants with MCI
have been reported with all three subtypes, however, only
few investigated whether these benefits translated into
clinical and functional improvement (Kurz et al., 2011).
A recent Cochrane review highlighted non-consistent find-
ings dependent on whether the control group was passive
or active which called for high-quality trials (Martin et al.,
2011), but especially more recent studies have reported
positive findings (Hampstead et al., 2014).
As with cognitive activity, there are promising find-
ings for the outcome cognition such as exposing non-
demented older adults to regular ideally moderate physical
activity of at least 150 minutes per week (Sofi et al., 2010;
Lautenschlager et al., 2012; Norton et al., 2014). As with
cognitive activity, RCTs in SMC and MCI are still sparse
with often inconsistent findings (Lautenschlager et al.,
2013), but a recent RCT with 170 subjective memory
complainers and MCI patients aged 50 and above found
significant differences between the intervention and con-
trol groups (Lautenschlager, 2008; Cox et al., 2013). The
24-week intervention was individually tailored and home-
based, focusing on walking, but allowing combinations
with other forms of physical activity depending on pref-
erence and medical history. Participants in the interven-
tion group were asked to exercise for at least 150 minutes
per week. To enhance adherence, a modified behavioural
intervention based on social cognitive theory (Cox et al.,
2003) was implemented via workshop, manual, newslet-
ters and regular phone calls. Participants were reassessed
after 24 weeks, 12 and 18 months and the primary out-
come measure, the ADAS-Cog showed significant differ-
ences between the groups at all three time points. While
this encouraging finding needs to be confirmed in larger
RCTs, it demonstrates that patients with MCI can be moti-
vated to participate in a physical activity programme and
cognitively benefit from it. Currently, several international
groups are trying to combine potentially successful inter-
ventions in very large multicentre trials with individuals
at risk of dementia, aiming to maximize the protective
effect. To date a number of trials reported benefits in
442 Dementia
neuropsychological outcomes, including attention, execu-
tive functions and memory. Evidence is increasing that
next to aerobic exercise additional resistance training as
well as physical activity with cognitive components such as
tai chi, can be of benefit (Lam et al., 2011; Nagamatsu et al.,
2012). More research needs to be done to elicit specific
information on the optimal combination of types of physi-
cal activity, their duration and intensity, as well as how to
best motivate individuals with SMC and MCI to modify
their behaviour. Despite these limitations in knowledge,
recent reviews on MCI promote the importance to encour-
age patients with MCI to consider regular cognitive and
physical activity (Knopman and Petersen, 2014).
Other potentially protective factors include social activi-
ties (Karp et al., 2006) and a healthy diet with a focus on
specifically a ‘Mediterranean diet’ (Bhat, 2009). This seems
logical since a healthy diet positively affects the vascular risk
factors mentioned above. Nutrients such as fruit, vegetables,
fish, nuts, cereals and olive oil have been identified as poten-
tially lowering the risk of dementia (Scarmeas et al., 2006).
The effect of these nutrients is largely attributed to antioxi-
dants and polyunsaturated fatty acids; however, more trials
are needed (Bhat, 2009; Fotuhi et al., 2009).
Only recently evidence is emerging that offering a multi-
domain approach where several of these protective factors
are combined can lead in older adults at risk of cognitive
decline and dementia to cognitive benefits (Ngandu et al.,
2015). Long-term follow-up of these studies will help to
determine whether these approaches can also impact
dementia incidence.
43.4 PRACTICAL CONSIDERATIONS
AND CONCLUSIONS
The above findings and clinical experience suggests that
after disclosure of the diagnosis of MCI to the patient and
family, individually suitable management strategies should
be considered. Box 43.1 gives some guidance on relevant
topics, which could be raised during a discussion about
management options.
An increasing body of evidence emphasizes neuro-
psychiatric symptoms (Edwards et al., 2009; Simard
et al., 2009) as well as sleep disturbance in MCI (Beaulieu-
Bonneau and Hudon, 2009). Between 35% and 75% of
patients with MCI experience neuropsychiatric symptoms
with the most common being depression, apathy, anxiety
and irritability. These patients have been reported to have a
higher risk of progression to AD than those without these
symptoms (Apostolova and Cummings, 2008; Edwards
et al., 2009). Patients with MCI should be screened for
symptoms of depression and treated if pharmacological
treatment is indicated. Due to cognitive impairment, the
antidepressant should be chosen carefully, avoiding anti-
cholinergic medication. Clinicians should screen for and
treat neuropsychiatric symptoms in patients with MCI
BOX 43.1: Important topics to consider in
the management of MCI
Disclosure of diagnosis
Information on assessment results
Individualized information on prognosis
Pharmacological management options
Non-phamarmacological approaches
Information on research trials in the area
Monitoring health and vascular risk factors
Neuropsychiatric symptoms
Discuss ADLs (including driving)
Planning the future (e.g. finances, travelling, etc.)
Information on AD treatment in case of progression
‘Carer’ burden
Information on useful contacts (e.g. Alzheimer
association)
Regular follow-up appointments
and using standard instruments like the Neuropsychiatric
Inventory can be useful (also see Chapter 42).
After considering pharmacological and non-pharmacological
strategies, a regular follow-up visit with using standardized
instruments is the best approach for ­identifying cogni-
tive decline as early as possible. This approach can help to
reassure patients and family members, that, while there is
limited effective treatment for MCI, significant progression
of symptoms will not be overlooked and therefore, anti-
dementia treatment can be started as soon as it has been
proved helpful. Furthermore, management of potential
impairment of complex ADLs should be discussed, cover-
ing important areas such as work, finances, caring for sig-
nificant others, driving, etc. Recent findings demonstrate
that patients with MCI perform worse on driving tests
than cognitively healthy older adults (Frittelli et al., 2009;
Wadley et al., 2009) and deteriorated in their financial skills
when progressing towards dementia (Triebel et al., 2009).
Also, medical decision-making capacity can deteriorate
with progression of symptoms (Okonkwo et al., 2008) of
dementia. Additional individual counselling for patient
and family might be helpful (Ellison, 2008) if high levels
of distress are detected and especially, if next of kin start
experiencing carer burden.
To summarize, the best possible management of patients
with MCI is of increasing importance in light of the rising
uptake of the diagnosis in clinical settings. The manage-
ment approach needs to be individualized depending on the
medical history, results of assessments and investigations
as well as the personal situation of the patient and family
involved. If available, a multidisciplinary team approach
might be best to address the complex needs of the patient
and family (Ellison, 2008). The approach should not be
nihilistic. A proactive management plan with regular fol-
low-up visits is crucial to help patients and family members
cope in this difficult period of uncertainty.

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 3
Part    

Alzheimer’s Disease: Clinical aspects

44 Risk factors for Alzheimer’s disease 447

Patricia A. Boyle and Robert S. Wilson
45 The natural history of Alzheimer’s disease 453
Jody Corey-Bloom and Michael S. Rafii
46 The neuropathology of Alzheimer’s disease 470
Colin L. Masters
47 Neurochemistry of Alzheimer’s disease 486
Paul T. Francis
48 The central role of Aβ amyloid and tau in the pathogenesis of Alzheimer’s disease 492
Craig W. Ritchie and Colin L. Masters
49 Inflammation in Alzheimer’s disease 508
Clive Holmes
50 Genetics of Alzheimer’s disease 519
Margie Smith
51 Blood and cerebrospinal fluid biomarkers for Alzheimer’s disease 528
Simone Lista, Henrik Zetterberg, Sid E. O’Bryant, Kaj Blennow and Harald Hampel
52 Established treatments for Alzheimer’s disease 539
Alexander Kurz and Nicola T. Lautenschlager
53 Drug treatments in development for Alzheimer’s disease 554
Paul Yates and Michael Woodward
54 Vitamins and complementary therapies used to treat Alzheimer’s disease 587
Dennis Chang, Genevieve Z. Steiner, Dilip Ghosh and Alan Bensoussan
55 Prevention of Alzheimer’s disease and Alzheimer’s dementia 598
Tom C. Russ, Karen Ritchie and Craig W. Ritchie
56 Trial designs 613
Serge Gauthier

Risk factors for Alzheimer’s disease
PATRICIA A. BOYLE AND ROBERT S. WILSON
44.1 INTRODUCTION
Alzheimer’s disease (AD) is one of the top 10 leading
causes of death for which there is no cure or disease
modifying treatment, making it one of the most feared
conditions of ageing (Alzheimer’s Association, 2015). By
the time a clinical diagnosis of AD is made, the pathologi-
cal hallmarks of the disease are widespread in the brain,
making it very difficult to minimize damage and alter
disease progression. Prevention of AD, therefore, ranks
among the most significant public health challenges of the
twenty-first century. Identification of risk factors for AD
is important and will facilitate novel strategies to prevent
or delay onset of disease.
44.2 RISK FACTORS FOR AD
In this chapter, we review the major factors associated with
the risk of AD, with an emphasis on those supported by
data from prospective studies of incident disease. Although
much of the initial information regarding risk factors came
from studies conducted on persons with prevalent disease,
such studies are susceptible to bias because they involve
only a limited, non-random fraction of persons with AD.
Further, because disease prevalence is highly related to sur-
vival, population-based studies of prevalent disease can lead
to the identification of factors that are associated with sur-
vival after the onset of the disease rather than actual risk of
the disease. Studies conducted on incident disease, in which
risk factors are identified prior to disease onset, are better
positioned for identifying true risk factors. Considerable
data from such studies are now available and several factors
have been identified, including genetic, experiential and
medical factors, with some increasing and others decreas-
ing risk and many of which are modifiable.
44
Additionally, in this chapter, we discuss the possible
neurobiological mechanisms by which various risk fac-
tors influence the development of AD, with the caveat that
not all risk factors have been well-studied in this regard.
Moreover, the relationships among risk factors, common
age-related neuropathologies, such as the pathology of
AD, and cognitive impairment are complex. We focus on
three primary ways in which risk factors can be associ-
ated with AD: (1) they can initiate pathological processes
that lead to cognitive impairment and AD, (2) they can
modify or alter the relation of pathology to cognition and
(3) they can be related to the clinical expression of AD
but unrelated to its pathology. We discuss neurobiological
mechanisms whenever possible because an understand-
ing of how risk factors lead to AD is essential to develop
strategies for disease prevention and/or delaying onset of
dementia. Thus, we present findings from clinical–patho-
logic studies and focus in particular on the role of AD
pathological hallmarks (i.e. amyloid plaques and neurofi-
brillary tangles) and cerebral infarcts, the most common
causes of cognitive impairment in old age.
44.3 GENETIC RISK FACTORS
44.3.1 APOLIPOPROTEIN E ε4 ALLELE
Amyloid precursor protein, the presenilins and apolipo-
protein E: Several studies have examined the role of genetic
factors as determinants of AD and mutations in three
genes are now known to cause AD (i.e. amyloid precursor
protein, presenilin 1 and presenilin 2 – see Chapter 50).
Notably, however, these mutations account for only about
1% of AD cases, particularly early onset of AD. In contrast
to mutations, several polymorphisms are associated with an
increased risk of AD, but the apolipoprotein E gene is the
only consistently replicated risk factor for the most common
expression of AD, that which begins after 65 years of age.
447
448 Dementia
Persons with one or more copies of the ε4 allele have about
a two- to three-fold greater risk of developing AD com-
pared with those without the ε4 allele (Evans et al., 1997a;
Jellinger, 2006; Murrell et al., 2006) and some data suggest
that this association may be stronger among whites than
African Americans. AD pathology plays an important role
in the association of the ε4 allele with AD risk; ε4 is associ-
ated with the accumulation of AD pathology and findings
suggest that the ε4 allele works through amyloid deposition
and subsequent tangle formation to cause cognitive impair-
ment (Bennett et al., 2003, 2005a). However, the ε4 allele
also increases the likelihood of cerebral infarcts, which also
contributes to AD (Schneider et al., 2005). Altogether, these
findings suggest that the ε4 allele leads to accumulation of
AD pathology but also interacts with other risk factors to
cause cognitive impairment and AD.
44.3.2 APOLIPOPROTEIN E ε2 ALLELE
In contrast to the ε4 allele, which increases the risk of AD,
the presence of the ε2 allele is associated with a reduced risk
of AD (Wilson et al., 2002c; Jellinger, 2006). Although data
are limited because ε2 allele is uncommon, persons with
ε2 allele have about a 40% lower risk of AD compared with
those without the allele (Farrer et al., 1997). Although vari-
ous mechanisms have been proposed, clinical–pathologic
findings suggest that the ApoE genotype affects the risk of
AD primarily by affecting the accumulation of AD pathol-
ogy (Bennett et al., 2003, 2005a).
Other genetic variants: recent studies have identified sev-
eral other genetic variants including complement receptor 1
(CR1) and phosphatidylinositol-binding clathrin assembly
protein (PICALM) associated with AD risk (Chibnik et al.,
2011). These may also work via their effect on AD pathology,
particularly amyloid, but additional studies are needed to
fully elucidate mechanisms.
44.4 EXPERIENTIAL FACTORS
44.4.1 AGE
Old age is often touted as the strongest risk factor for AD.
Indeed, AD is fairly rare among younger persons, with
about 200,000 persons under the age of 65 currently affected
in the United States, but the risk of AD increases dramati-
cally after the age of 65 (Alzheimer’s Association, 2015).
Currently, in the United States, about 5.1 million persons
over the age of 65 have AD and the increase in risk rises con-
siderably with each decade of increase in age, with nearly
half of those over the age of 85 affected (Barnes et al., 2003;
Alzheimer’s Association, 2015). Importantly, however, age
is not the actual cause of AD, but rather a proxy for other
causes as yet unknown in the disease processes that lead to
the development of AD.
44.4.2 FEMALE SEX
Female sex is often considered a risk factor for AD, as the dis-
ease is more common among women than men, particularly
in those over the age of 80 (Alzheimer’s Association, 2015).
This sex difference appears to be applicable to increased
longevity among women. Overall, studies of persons under
85 years of age do not suggest strong sex differences in AD
incidence and the situation after the age of 85 is uncertain
because of the paucity of men in this age group. It has been
hypothesized that women may be more vulnerable to AD
due to hormonal changes that follow menopause, but this
remains unclear. One clinical–pathologic study suggested
that AD pathology was more likely to be expressed as a clin-
ical dementia syndrome in women than in men and these
findings may be due to possible sex differences in amyloid
precursor protein processing (Barnes et al., 2005).
44.4.3 EDUCATION
Many studies have shown that the risk of AD is reduced
among persons with higher levels of education (Evans et al.,
1997b; Karp et al., 2004; Caamano-Isorna et al., 2006).
Notably, however, a review study concluded that education
is not related to the rate of cognitive decline (Wilson et al.,
2009b), the primary clinical manifestation of AD, suggest-
ing that the association of education with AD is largely due
to its robust association with the level of cognitive function.
Nevertheless, it has been hypothesized that education con-
tributes to neural reserve by somehow reducing the adverse
clinical impact of mild to moderate pathologic burden.
Consistent with this idea, clinical–pathologic studies have
shown that education reduces the association of AD patho-
logic burden, particularly amyloid, with the level of cogni-
tion proximate to death (Bennett et al., 2005b).
44.4.4 RACE/ETHNICITY
African Americans and Hispanics may have a substantially
increased risk of AD compared with non-Hispanic whites
(Tang et al., 2001; Evans et al., 2003); however, it is difficult
to interpret from research conducted earlier, because race
and ethnicity are entangled with socio-economic and cul-
tural variables that strongly influence cognitive test perfor-
mance and there are disparities in risk factors and clinical
presentations of disease (Barnes et al., 2014). Thus, the avail-
able data on the association of race/ethnicity and AD should
be interpreted with caution.
44.4.5 DEPRESSIVE SYMPTOMS AND
LONELINESS
Data from several studies support a connection between
depressive symptoms and the risk of AD (Wilson et al.,
2002, 2003; Andersen et al., 2005), with one prospective
study reporting that the risk increased by about 20% for
each depressive symptom endorsed (Wilson et al., 2002a).

In addition, a related psychological construct, referred to,
as loneliness (i.e. the subjective sense of connectedness to
others) also is related to AD risk, even after controlling
depressive symptoms (Wilson et al., 2007c). Although,
some have suggested that depressive symptoms and
loneliness are a consequence of incipient dementia or its
underlying pathology rather than a true risk factor, these
psychological factors do not change considerably with
advancing age and are not strongly related to AD pathol-
ogy or other common dementia-related pathologies (i.e.
infarcts) (Wilson et al., 2003, 2008, 2015). Depressive
symptoms and loneliness, therefore, are not merely early
symptoms of the disease and are likely to work via some
other mechanism to affect AD risk.
44.4.6 NEUROTICISM
The personality trait referred to as neuroticism (i.e. prone-
ness to psychological distress) is associated with an increased
risk of AD, such that, in one study a person with a high level
of neuroticism was more than twice as likely to develop
AD compared to someone with a low level (Wilson et al.,
2006). Notably, however, distress proneness is unrelated to
measures of Alzheimer’s pathology and does not modify the
association of cognition with common neuropathologies
(Wilson et al., 2005, 2007A). These results suggest that, as in
the case of depressive symptoms and loneliness, neurobio-
logical mechanisms other than AD pathology must be the
underlying cause for the association of this personality trait
with dementia. Chronic stress has been associated with a
spectrum of neurobiological changes in brain regions criti-
cal for memory and may damage selected neural systems in
such a way that less dementia-related pathology is needed
to produce clinical dementia, but additional research is
warranted.
44.4.7 CONSCIENTIOUSNESS AND
PURPOSE IN LIFE
The personality trait of conscientiousness (i.e. the ten-
dency to be hard-working and focused) has been shown to
be associated with a considerable reduction in the risk of
AD, such that in one study, a person with a high score was
89% was less likely to develop AD compared to someone
with a low score (Wilson et al., 2007e). Similarly, a related
construct referred to as purpose in life (i.e. the tendency
to derive a sense of meaning in life and be intentional and
goal-focused) is associated with a substantially reduced
risk of AD (Boyle et al., 2010). Both conscientiousness and
purpose in life are unrelated to AD pathology but modify
the association of AD pathology with the level of cogni-
tion proximate to death (Wilson et al., 2002d, 2007e).
This ­suggests that conscientiousness and purpose in life
provide a buffer against AD and help maintain cogni-
tive function even in the face of accumulating disease
pathology.
Risk factors for Alzheimer’s disease 449
44.4.8 COGNITIVE ACTIVITY
Considerable evidence suggests that cognitive activity and
cognitive experiences in life are associated with a reduced
risk of AD in old age (Hall et al., 2000; Wilson et al., 2002b;
Boyle et al., 2012). In one study, a cognitively inactive per-
son was 2.6 times more likely to develop AD than a cogni-
tively active person (Wilson et al., 2007d). Again, cognitive
activity is not related to AD pathology or infarcts (Wilson
et al., 2007d, 2013), suggesting that it must work via another
mechanism to help maintain function even in the face of
accumulating disease pathology.
44.4.9 SOCIAL ENGAGEMENT AND
SOCIAL NETWORKS
Several studies have examined the association of social
engagement and AD (Fratiglioni et al., 2000; Barnes et al.,
2004) and findings generally suggest that people with an
extensive social network have a decreased risk of developing
AD. Relatively, little is known about the potential neuro-
biological basis of this association, although one clinical–
pathologic study reported that large social networks reduced
the impact of AD pathology on the level of cognitive func-
tion in older persons (Bennett et al., 2006). We suspect that
cognitive processing skills that allow people to develop and
maintain large social networks help provide some form of
neural reserve, such that socially connected persons can tol-
erate greater amounts of AD pathology prior to developing
clinical AD, but more research is necessary in this area.
44.4.10 PHYSICAL ACTIVITY
Physical activity is associated with a reduced risk of AD in
some but not all prospective research conducted supports
this (Podewils et al., 2005; Scarmeas et al., 2009; Buchman
et al., 2012). The mechanisms linking physical activity to
AD are not well-understood, but physical activity contrib-
utes to cardiovascular health and may partially reduce the
risk of AD via vascular mechanisms. However, physical
activity also has been related to decreased production of
AD pathology in transgenic animal models and additional
research needs to be conducted to establish the neurobiol-
ogy underlying the association of physical activity and AD.
44.4.11 VITAMIN INTAKE AND DIET
Several population-based studies have examined the asso-
ciation between vitamin intake, particularly E, C and other
antioxidants and diet with the risk of AD, but results are
mixed (Kawas, 2006; Morris, 2009). Perhaps, more com-
pelling evidence suggests that high saturated or trans-fatty
acids increase the risk of AD and high polyunsaturated
or monounsaturated fatty acids decrease risk (Morris and
Tagney, 2014). Towards that end, recent data suggests that
Mediterranean-style diets, which generally include olive
oil as the primary fat, high fish consumption and moderate
450 Dementia
consumption of wine with meals, as well as diets aimed to
combat hypertension, which include low consumption of
saturated fat and sweets and relatively higher consumption
of dairy, are associated with a reduced risk of AD (Morris
et al., 2015). Vitamins and diet are generally thought to
work via their antioxidant effects in the brain, in addition
to potential vascular benefits, but clinical–pathologic data
are greatly needed. Moreover, data on vitamins and diet are
difficult to interpret, partially because vitamin users and
careful eaters tend to differ in important ways compared
to those who do not use vitamins in their diet and precise
measurement of vitamin intake is very difficult to ascertain
in large-scale trials.
44.5 MEDICAL RISK FACTORS
44.5.1 CEREBROVASCULAR DISEASE/
STROKE
Although cerebrovascular disease is often considered a
pathologically distinct entity (i.e. vascular dementia) or a
contributing cause of dementia (i.e. mixed dementia), cere-
brovascular disease itself is associated with a substantially
increased risk of AD (Honig et al., 2003). Consistent with
these findings, clinical–pathologic data suggest that cerebral
infarcts work additively with AD pathology and indepen-
dently contribute to likelihood of clinical AD (Arvanitakis
et al., 2006). Additional research is needed to further clar-
ify exactly how cerebrovascular disease and AD pathology
work together to increase the risk of AD.
44.5.2 OTHER VASCULAR FACTORS
High blood pressure, diabetes, heart disease and hypercho-
lesterolemia are associated with an increased risk of AD
(Kivipelto et al., 2005; Arvanitakis et al., 2006). Blood pres-
sure rates in AD is the most well-studied and high blood
pressure in midlife is predictive of an increased risk of AD,
but the role of late-life blood pressure in relation to AD is
less clear. Diabetes also has been consistently associated
with an increased risk of AD and cholesterol studies give
mixed results. The mechanisms underlying these associa-
tions are likely to be complex. For example, as noted above
in connection to stroke, vascular risk factors are associated
with the development of cerebrovascular disease and likely
to increase AD risk via their association with cerebrovas-
cular disease. Notably, however, clinical–pathologic studies
have reported mixed findings with regard to the association
of vascular risk factors with pathologic changes in the brain;
for example, diabetes has been inconsistently related to AD
pathology (Arvanitakis et al., 2006). Further, it is likely that
the associations of vascular factors with AD are multifacto-
rial, such that, both vascular factors add to and interact with
each other and potentially other risk factors (e.g. ApoE) to
cause AD.
44.5.3 OBESITY AND THE METABOLIC
SYNDROME
Obesity and the metabolic syndrome (based on several com-
mon disorders including obesity, hypertriglyceridemia, low
high-density lipoprotein levels, hypertension and hypergly-
caemia) appear to be associated with the risk of AD (Yaffe
et al., 2004; Kivipelto et al., 2005). The mechanisms under-
lying these associations are unclear, but it is well established
that obesity has numerous adverse health effects and both
obesity and the metabolic syndrome are associated with
other vascular risk factors and an increased risk of cerebro-
vascular disease. These conditions may increase the risk of
AD via their association with cerebrovascular disease or via
another pathologic process, but clinical–pathologic data are
needed to elucidate these mechanisms.
44.5.4 OLFACTORY DYSFUNCTION
Prospective studies have shown that olfactory impairment
(e.g. difficulty identifying familiar odours) is associated with
the development of AD and its precursor, mild cognitive
impairment (Wilson et al., 2007b, 2007f, 2009a). Clinical–
pathologic studies have shown that impaired odour recogni-
tion is robustly related to level of AD pathologic changes in the
brain, particularly, density of neurofibrillary tangles in central
olfactory regions (Wilson et al., 2007b) and this association is
seen even in older people without apparent cognitive dysfunc-
tion and after using a controlling apparatus for other behav-
ioural and genetic risk factors (Wilson et al., 2009), suggesting
that olfactory dysfunction is an early sign of impending AD.
44.5.5 INFLAMMATORY MARKERS
Increasing evidence suggests that inflammation may play an
important role in the pathogenesis of AD and findings from
some prospective studies suggest that the level of systemic
markers of inflammation, particularly C-reactive protein
and interleukin-6 are associated with an increased risk of AD
(Barnes et al., 2014). Several potential mechanisms form the
underlying causes for the association between inflammation
and AD. Inflammation can occur as a consequence of neuro-
degeneration or, alternatively, it may be a causal part of a cas-
cade of events that lead to the accumulation of AD pathology,
particularly, amyloid deposition. Inflammation is also associ-
ated with vascular disease and may be related to dementia via
cerebrovascular disease. Additional research is needed to fur-
ther clarify the role of inflammation in the development of AD.
44.6 CONCLUSION
Using data from prospective studies of incident disease, sev-
eral factors associated with the risk of AD have been iden-
tified, including genetic, experiential and medical factors,
many of which are modifiable (particularly, experiential

factors). The relationships among risk factors, common
age-related neuropathologies and cognitive impairment are
complex and in many cases unclear. However, studies have
shown that some risk factors work directly via their influence
on the accumulation of AD and other common age-related
pathologies (i.e. infarcts) and others modify the association
of cognition with pathology, such that they ­benefit cogni-
tion in the face of accumulating neuropathology. Risk fac-
tors that work via these mechanisms offer specific targets for
future interventions to prevent, delay, or reduce the burden
posed by AD and warrant particular focus in behavioural
intervention and pharmacological studies.
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The natural history of Alzheimer’s disease
JODY COREY-BLOOM AND MICHAEL S. RAFII
45.1 INTRODUCTION
Even if new disease-modifying treatments are developed,
Alzheimer’s disease (AD) will continue to be an enormous
public health problem. Knowledge of the clinical features
and natural history of AD will facilitate planning in response
to the increased demands of medical and social resources.
In addition, this information will enable clinicians to pro-
vide patients and families with a more reliable prediction
of the course of the disease for treatment options, as well
as financial and family planning. Furthermore, monitor-
ing the stages of AD is important in recruiting patients for
clinical studies at definable levels of severity and for under-
standing the expected course of decline related to putative
treatment effects.
45.2 CLINICAL FEATURES
The diverse spectrum of symptoms of AD reflects dys-
function of widespread regions of the cerebral cortex.
Symptoms begin insidiously, making it difficult to date
the onset of cognitive and functional decline precisely.
Progression is generally gradual, yet can be interleaved
with occasional plateaus; however, reliable measurement
of clinical disease progression in AD is difficult because
of variability between and within subjects. Converging
evidence from longitudinal studies of clinically normal
elderly and familial AD cohorts strongly suggests that the
AD pathophysiological process begins decades before the
manifestation of clinical dementia. Hypothetical models
have been proposed in which biomarkers of AD become
increasingly abnormal in an ordered manner as the disease
progresses and symptoms emerge (Jack et al., 2010). The
field of AD has, therefore, steadily marched earlier in the
disease continuum, evaluating diagnostic and therapeutic
45
methods in prodromal form of AD and, recently, in pre-
clinical AD. Nonetheless, a firm understanding of the
clinical manifestations and natural progression of AD
dementia are required to approach patients practically,
thoughtfully and comprehensively.
Memory loss is the cardinal and commonest present-
ing complaint in AD. Initially, the patient has difficulty
­recalling new information such as names or details of con-
versation, while remote memories are relatively preserved.
The pattern of memory impairment in AD is quite distinc-
tive. Declarative memory (facts [semantic] and events [epi-
sodic]), which depends on medial temporal structures such
as the entorhinal cortex and hippocampus, is profoundly
affected in AD, while subcortical systems supporting pro-
cedural memory are relatively spared until quite late in the
disease (Carlesimo et al., 1992).
Semantic and episodic memory are both profoundly
impaired in early AD. Within episodic memory, there
is a distinction between immediate recall (e.g. mental
rehearsal of a phone number), memory for recent events
(within the past 2 weeks) and memory of remote events.
Memory for recent events, served by the hippocampus
and entorhinal cortex in the medial temporal lobe, is
prominently impaired in early AD. In contrast, immedi-
ate memory (encoded in the prefrontal cortices) is spared
early on, as are memories that are consolidated for long
periods (years), which can be recalled in the absence of
hippocampal functioning (Zola-Morgan et al., 1986).
The most precise way to describe the early memory defi-
cit in AD is therefore an anterograde episodic amnesia.
The symptomatic manifestations of this type of memory
failure include: forgetting important dates or events, ask-
ing for the same information over and over again, relying
heavily on memory aides, trouble following a familiar rec-
ipe or keeping track of monthly bills, trouble remember-
ing the rules of a favourite game, forgetting where things
are or how they got there, losing objects and being unable
to go back the steps to find them again. With progression,
453
454 Dementia
the memory loss worsens to include remote memory
(Wilson et al., 1983; Sullivan et al., 1986; Cummings and
Cole, 2002).
Early in AD, judgement and abstraction are often
impaired, suggesting involvement of the frontal lobes.
Social comportment and interpersonal skills are often strik-
ingly preserved and may remain relatively intact long after
memory and insight are lost. The ability to conduct one’s
self in brief social interactions despite significant underly-
ing impairment, however, is often superficial and can be
identified by the astute clinician as somewhat of a façade.
Language is frequently normal in the early stages of AD,
although, reduced conversational output (logopaenia) may
be noted. When asked to generate word lists in 1 minute,
patients with AD dementia perform significantly worse on a
category fluency test (e.g. lists of animals) than on a letter flu-
ency test (e.g. lists of words beginning with F). This reflects
the specific deficit in semantic memory (Canning et al.,
2004). As dementia progresses, many patients become more
recognizably aphasic. Initially, this manifests as dysnomia
and mild loss of fluency with paraphasic errors and relative
preservation of repetition, a pattern resembling transcorti-
cal sensory aphasia (Cummings et al., 1985; Cummings and
Cole, 2002). At a later stage, language is obviously dysfluent
and repetition impaired; terminally, a state of near-mutism
may occur (Murdoch et al., 1987).
Visuospatial impairment in AD results in symptoms
such as misplacing objects or getting lost and difficulty
with tasks such as recognizing and drawing complex figures
(Brouwers et al.,1984; Kavcic and Duffy, 2003). Difficulty
with calculation (affecting skills such as handling money),
apraxia and agnosia are further problems that develop in
AD. Apraxia may impair activities such as operating appli-
ances or dressing; as might be expected, more complex
skills tend to break down first, while highly overlearned
motor tasks (e.g. playing a musical instrument, using tools)
may be retained until, relatively, later years (Rapcsak et al.,
1989; Helmes and Ostbye, 2002). Agnosia develops in any-
time between the middle to late stages of AD and includes
features such as failing to recognize family members.
Behavioural or psychiatric symptoms occur f­requently
in AD (see Chapters 7 and 8). Over and above, a gen-
eral decline of activity and anhedonia in virtually all
AD patients, depressive symptoms occur in about 25%,
although severe depression is uncommon (Cummings et al.,
1987; Rapcsak et al., 1989; Rosen and Zubenko, 1991; Becker
et al., 1994; Cummings and Cole, 2002; Helmes and Ostbye,
2002; Starkstein et al., 2008; Snowden et al., 2015). The fre-
quency of significantly depressed mood in patients with AD
ranged from 0% to 87% in 30 studies reviewed by Wragg
and Jeste (1989) with higher rates reported from acute care
facilities than in studies conducted on outpatient research
sites. While many AD patients have depressive symptoms,
most do not display enough features to meet Diagnostic
and Statistical Manual of Mental Disorders, Fourth Edition
(DSM-IV) criteria for major depressive disorders. The fact
that vegetative symptoms, such as sleep disturbance, weight
gain, loss of libido, lack of interest and reduced motor ­activity
are common to both AD and depression, may account for
the high rate of ‘depression’ found in some studies (Lazarus
et al., 1987; Becker et al., 1994; Jost and Grossberg, 1996). In
patients with severe dementia, there is an apparent paucity
of depressive symptoms. A likely explanation is that certain
features of depression (guilt, hopelessness, anxiety) are less
discernible in subjects with severe dementia. But, symptoms
such as crying and diminished sleep can be expressed even
at later stages of AD.
Psychosis is frequent in people with AD (Schneider et al.,
2004). One observational study of 329 patients who did not
have psychosis at initial evaluation demonstrated a cumu-
lative incidence of hallucinations and delusions of 20% in
1 year, 36% in 2 years and 50% in 3 years (Paulsen et al.,
2000). The prevalence of psychotic symptoms in AD, the
relationship of hallucinations and delusions to the severity of
cognitive impairment and the influence of psychosis on the
rate of cognitive decline are controversial. Other estimates
of the prevalence of psychotic symptoms in AD range from
10% to 73%, with most in the range of 28%–38% (Wragg and
Jeste, 1989; Mega et al., 1999). Delusions have been reported
in 13%–75% of AD patients and hallucinations, more com-
monly visual than auditory, in 3%–50% (Mayeux et al.,
1985; Cummings et al., 1987; Reisberg et al., 1987; Drevets
and Rubin, 1989; Reisberg et al., 1989; Becker et al., 1994;
Jost and Grossberg, 1996; Cook et al., 2003). This substantial
variation in frequencies is probably due to different method-
ologic approaches, especially in defining delusions and hal-
lucinations and due to differences in the range of severity of
AD in each series. Although psychotic symptoms may occur
throughout the course of AD, they have their highest fre-
quency at a moderate level of dementia (Drevets and Rubin,
1989). The manifestation of psychosis in dementia can result
in significant distress for patients with AD, as well as for
caregivers (Steele et al., 1990). These symptoms constitute
the primary reason for transfer of patients with dementia
from general hospitals to psychiatric hospitals and for their
institutionalization (Hebert et al., 2001).
In addition to depression and psychotic symptoms, AD
patients show a wide range of behavioural abnormalities
including agitation, wandering, sleep disturbances and dis-
inhibition (Becker et al., 1994; Jost and Grossberg, 1996;
Lyketsos et al., 2002). These often impose a significant burden
on caregivers and may precipitate nursing home placement.
In contrast to psychotic symptoms, behavioural disturbances
are more clearly associated with the degree of dementia. For
example, a study of 127 AD patients found that the overall
number of behavioural problems increased significantly with
worsening cognitive function (Teri et al., 1988). Agitation
includes physical aggression, verbal a­ggression and non-
aggressive behaviours. Physically non-aggressive behaviours,
such as motor restlessness and pacing, are the most common
forms of agitation in outpatients with AD. However, physi-
cal aggression is the most distressing behaviour to custo-
dians and occurs in about 20% of patients (Reisberg et al.,
1987; Burns et al., 1990; Hooker et al., 2002). Various factors

appear to be important predictors of aggressive behaviour,
including premorbid history of aggression, a troubled pre-
morbid relationship between the caregiver and patient and a
greater number of social and medical problems. Wandering
behaviour affects 3%–26% of AD outpatients. Insomnia and
sleep disturbances are inconstant features of AD and sexual
disinhibition is reported in less than 10% of patients (Burns
et al., 1990; Becker et al., 1994). Thus, behavioural symptoms
are a pervasive and poorly understood concomitant symp-
tom of cognitive deterioration in AD.
The incidence of seizures in patients with AD is greater
than that expected in the elderly population, with an inci-
dence rate of 484 per 100,000 person-years (95% confidence
interval [CI] = 287–784) (Irizarry et al., 2012). Independent
risk factors for new-onset seizures in AD include younger
age, greater degree of cognitive impairment and history of
antipsychotic usage.
Excluding mental status testing, the neurologic exami-
nation is usually normal in AD and the presence of sig-
nificant or lateralizing abnormalities often suggests other
diagnoses. However, primitive reflexes (snout, glabellar,
grasp), impaired graphesthaesia and an abnormal response
to double simultaneous stimulation (face-hand test) are
frequently encountered in AD (Galasko et al., 1990; Becker
et al., 1994). Variable features, including extrapyramidal
signs (EPS – rigidity and bradykinesia), gait disturbances
and myoclonus may occasionally be seen early in the course
of AD and increase in prevalence with the severity of AD
(Stern et al., 1987). The frequency of EPS in patients with
AD was as low as 12% to 14% in some series (Galasko et al.,
1990; Burns et al., 1991; Becker et al., 1994) and as high
as 28%–92% in others (Mayeux et al., 1985; Molsa et al.,
1986; Bakchine et al., 1989; Lopez et al., 2000), depending
on the severity of dementia in patients who were studied.
In intermediate or advanced stages of dementia, patients
often develop non-specific impairment of gait and balance,
leading to an increased risk of falls. Myoclonus develops
late in the course of AD and longitudinal studies report an
increase in its frequency during follow-up (Mayeux et al.,
1985; Tschampa et al., 2001). Its prevalence in AD has varied
from 0% to 68%, although the usual reported rate is about
10% (Hauser et al., 1986).
A minority of AD cases do not present the classic fashion
with progressive amnestic dementia. One variant of AD is
posterior cortical atrophy (PCA) (see Chapter 77). This syn-
drome manifests with progressive cortical visual impair-
ment. Patients are often first evaluated by optometrists or
ophthalmologists for visual complaints such as difficulty in
reading and driving. Detailed neurologic evaluation may
elicit elements of the Balint syndrome: simultanagnosia (the
inability to integrate a visual scene despite adequate acuity
to resolve individual elements), optic ataxia (the inability to
reach accurately under visual guidance) and ocular apraxia
(the inability to gaze directly and accurately at a new tar-
get, frequently leading to difficulty in reading). Other fea-
tures include visual agnosia, prosopagnosia and visual field
neglect. Less common are visual hallucinations and frank
The natural history of Alzheimer’s disease 455
visual field defects. This constellation of findings implicates
the dorsal visual stream in the lateral occipital and parieto-
occipital regions (Aharon-Peretz et al., 1999).
Another variant of AD is the so-called Lewy body vari-
ant (LBV) of AD (see Chapters 61 through 63) with promi-
nent deficits in visuospatial function relative to amnesia
(Katzman et al., 1995; Hansen, 1997; Connor et al., 1998).
Compared to patients with AD alone, those with LBV have
a greater frequency of extrapyramidal manifestations and
subcortical deficits, somewhat better recall selected mem-
ory tasks and a significantly lower frequency of neocortical
neurofibrillary tangles at autopsy.
As neuronal degeneration progresses in AD, all symp-
toms worsen and eventually patients become uncommuni-
cative and unable to care for themselves, walk, or maintain
continence. They require total care, including feeding and
are often institutionalized. During end-stage AD, death
usually results from the complications of being bed-bound,
such as aspiration pneumonia, urinary tract infections, sep-
sis or pulmonary embolism (Molsa et al., 1986).
45.3 CLINICAL UTILITY OF ASSESSING
CHANGE
The course of AD and the combination of symptoms that
manifest in each patient are markedly heterogeneous; how-
ever, there are several direct clinical applications of track-
ing change. First, in early cases of AD, where impairment
is mild, documenting progression helps to confirm or
establish the diagnosis. Clearly, progressive cognitive dete-
rioration is incompatible with normal ageing, depression,
delirium, or a static encephalopathy. The clinical follow-up
of patients who are initially classified as having AD greatly
increases diagnostic accuracy.
Second, progression to a greater degree than expected
may prompt the physician to look for a superimposed factor
that may be treatable, such as hypothyroidism, intercurrent
infection, medication toxicity or depression. Improvement
or stabilization of psychometric scores indicates a favour-
able response to treating a remediable factor contributing
to dementia.
Third, defining the anticipated course of AD in detail
enables clinicians to provide patients and families with real-
istic expectations regarding the disease and aids in making
decisions for day care or institutionalization.
Longitudinal cognitive change may be fruitfully applied
to several problems in clinical research. Change over time
on mental status scores may be used to construct models
of the clinical course of ‘typical’ AD. This methodological
approach has ramifications, such as testing whether genetic/
environmental factors or experimental treatment influences
the rate of progression of dementia.
Attempts to refine the natural history of AD have uti-
lized two basic methods: global staging systems and serial
changes on psychometric test scores.
456 Dementia
45.3.1 MEASURING CHANGE WITH
GLOBAL STAGING SYSTEMS
Staging systems for AD comprise information on intellec-
tual, social and community functioning obtained by narra-
tion of history rather than formal rating scales. Two widely
used schemes are the Washington University’s Clinical
Dementia Rating (CDR) (Hughes et al., 1982; Morris, 1997)
and the Global Deterioration Scale (GDS) (Reisberg et al.,
1982, 1986), which divides AD into a succession of stages.
These scales reflect an overall indirect evaluation of cog-
nition, primarily obtained from caregivers, rather than a
direct assessment of the patient, but are able to assess the
influence of cognitive loss on the ability to conduct every-
day activities. They provide information about clinically
­meaningful function and behaviour and are less affected
by ‘floor’ and ‘ceiling’ effects commonly associated with
­psychometric tests.
The CDR incorporates information from patients and
informants concerning 6 areas of mental function: memory,
orientation, judgment and problem-solving, community
affairs, home and hobbies and personal care. Each area is
scored as 0 = normal, 0.5 = questionable, 1 = mild, 2 = mod-
erate, or 3 = severe impairment and integrated to obtain an
overall stage of dementia, using similar definitions of 0, 0.5
and 1 to 3. Inter-rater reliability is high, with a correlation of
0.91 and the CDR has been standardized for multicentre use
(Morris et al., 1997). Since the CDR includes cognitive items
and activities of daily living (ADL), it is not surprising that
it correlates well with the cognitive Blessed Information-
Memory-Concentration (BIMC) scale (r = 0.55) and with the
ADL-based Blessed Dementia Scale (BDS) (r = 0.53) (Berg et
al., 1988). These authors followed a cohort of 43 initially mild
AD patients (CDR 1) for 90 months. Over 67% of patients
progressed to CDR 3 (severe dementia) in 50 months and
over 80% in 66 months. Many patients in this CDR 1 group
reached end points: 50% of patients were institutionalized in
40 months and 80% in 60 months. Thirty per cent of patients
died in 40 months and 40% in 72 months. Although, the
CDR is a useful staging instrument and has become widely
accepted in the clinical setting as a reliable and valid global
assessment measure for AD, movement from one stage to the
next may take several years (Storandt et al., 2002). Focus has,
therefore, shifted to the CDR sum of boxes score (CDR-SB),
which sums the ratings for the six cognitive and functional
domains and permits more sensitive measurement of annual
or short-term rate of change in AD. Using data from 792
participants enrolled in longitudinal studies at an academic
AD research centre, one recent study (Williams et al., 2013)
found that the annual rate of change on CDR-SB scores was
1.43 (standard error [SE = 0.05]) in the CDR 0.5 sample and
1.91 (SE = 0.07) in the CDR 1 sample. Two other studies have
demonstrated annualized rates of change on the CDR-SB of
1.0–1.13 and 2.28 in the Consortium to Establish a Registry
for Alzheimer’s Disease (CERAD) registry database (Rossetti
et al., 2010) and Cache County Dementia Progression Study
(Tschanz et al., 2011), respectively.
The GDS divides AD into a succession of major clinically
distinguishable stages (further subdivided into 16) ranging
from normal cognition (GDS 1) to severe dementia (GDS 7)
(Reisberg et al., 1982). Criteria for many of the stages combine
history (initially of memory decline, later of functional impair-
ment, progressing to loss of self-care, language and gait), and
mental status examination. Stages defined by this integration
of history, ADL and cognition should show high correlations
with mental state screening tests: indeed, the GDS correlates
well with the Mini-Mental State Examination (MMSE) (r =
0.9, p < .001) and the BIMC (r = 0.8, p < .001) (Reisberg et al.,
1989). GDS stages 1 and 2 correspond to CDR 0 representing
normal ageing, and GDS 3 is equivalent to CDR 0.5. In a lon-
gitudinal study, only 5% of GDS 2 subjects became demented
over 3–4 years, whereas 15% of GDS 3 subjects progressed to
more advanced stages of dementia (Reisberg et al., 1986).
The GDS has similar virtues and drawbacks in compari-
son to the CDR, namely, difficulty in defining a natural his-
tory over periods shorter than a year or two. The primary
use of these staging systems may be research in progress and
in following patients observed longitudinally over extended
periods, since the transitions from one stage to the next
occur over relatively long intervals.
45.3.2 MEASURING CHANGE BY RATE OF
DECLINE ON COGNITIVE TESTS
As a more flexible longitudinal index of brain function, some
studies have measured the annual rate of change (ARC) of
mental status test scores in AD. Longitudinal data exist for
ARC on five mental status tests in common use: the BIMC
test, the MMSE, the Dementia Rating Scale (DRS), the
Cambridge Cognitive Examination (CAMCOG) (Roth et al.,
1986) and the Alzheimer’s Disease Assessment Scale (ADAS)
(Rosen et al., 1984). Unfortunately, although these rates of
decline are available, their generalizability is uncertain.
Katzman et al. (1988) compared four groups of subjects
with AD on the BIMC, with follow-up over 1 year (Reisberg
et al., 1989). These cohorts differed substantially with regard
to age, education, sex, severity of dementia and place of resi-
dence and included community-dwelling and institution-
alized subjects seen in private practice or public hospital
settings. The mean rate of change on the BIMC did not differ
significantly among the four groups for subjects who ini-
tially made 24 or fewer errors (out of a possible 33). In those
patients, the ARC on the BIMC was 4.4 errors per year and
did not vary with age, education or place of residence. Among
demented subjects with an initial BIMC score of more than
24 errors, the rate of change was lower, presumably, because
the test had reached a floor. A similar overall rate of pro-
gression for the BIMC was found in three further studies in
community-dwelling AD patients (Thal et al., 1988; Ortof
and Crystal, 1989; Salmon et al., 1990). Significant variation
in the mean ARC on the BIMC has been observed, however,
by other investigators. For example, Lucca et al. (1993) noted
a change of only 2.6 (± 4.9) points on the BIMC over 1 year

in a group of 56 patients with AD comprising outpatients
and inpatients at geriatric institutions. Using data from the
California Alzheimer’s Disease Diagnostic and Treatment
Centers, we observed an annual rate of change of 2.8 points
on the BIMC (Corey-Bloom et al., 1993a).
For the MMSE, a number of studies have reported a mean
ARC in AD ranging from 1.8 to 4.2 points. Of these studies,
the one with the lowest ARC entered patients at a very mild
stage of AD (Becker et al., 1988). Studies with the highest
ARC had entered severely impaired subjects (Yesavage et al.,
1988; Burns et al., 1991), while the remaining studies showed
an intermediate ARC (about 2.5 points per year) in patients
with an intermediate initial level of impairment (Salmon et
al., 1990; Teri et al., 1990; Corey-Bloom et al., 1993b; Aguero-
Torres et al., 1998; Swanwick et al., 1998; Thal et al., 2000;
Winblad et al., 2001). This illustrates that rate of change of
the MMSE is affected by the severity of cognitive impairment
even before the test reaches a floor. The MMSE tests a wide
range of cognitive skills and individuals may be expected to
decline at varying rates and over different cognitive tasks dur-
ing the progression of AD. For example, patients lose points
on the orientation, recall and construction items before lan-
guage or praxis becomes abnormal. The degree of variability
of ARC for the BIMC (reflected by the standard deviations in
ARC studies) is significantly smaller than that of the MMSE
(Schneider, 1992), suggesting that the BIMC has less noise
controls and may be more reliable as a change measure.
Few studies of longitudinal cognitive change in AD have
used extended follow-up periods. In a study distinguished by
7 years of follow-up, Aguero-Torres et al. (1998) found a mean
ARC of 2.8 points on the MMSE during their first period
of evaluation (entry to 3 years) and 3.0 points thereafter
(3–7 years). Salmon et al. (1990) compared the BIMC, MMSE
and DRS in 55 community-dwelling patients with AD over
2 years. Each subject’s scores on the three tests were highly
correlated when entered and after 1 and 2 years later. During
the study period, patients lost a mean of 3.2 points on the
BIMC, 2.8 points on the MMSE and 11.4 points on the DRS
per year. In general, the group declined to a greater degree
on all three scales in the second year than in the first, but
this was statistically significant only for the DRS. For indi-
viduals, however, the ARC of mental status scores in the first
year did not predict the next year’s rate of decline. Unlike the
BIMC and the MMSE, the ARC of the DRS did not decrease
with advanced dementia, indicating that the DRS has a wider
range for detecting change than these other tests.
Two somewhat longer instruments, similar to the DRS,
have been used for serial assessment: the CAMCOG and
the ADAS. The CAMCOG is the cognitive component of
the Cambridge Mental Disorders of the Elderly Examination
(CAMDEX), an instrument designed for assessing demen-
tia. It has sections testing memory, language, praxis, orienta-
tion, attention, calculation, abstraction and perception, with
a maximum total score of 107. In a survey of 110 patients,
spanning a wide spectrum of severity of AD, Burns et al.
found a significant decline over 1 year in the overall score
(12.3 points) and in virtually every abstraction were close to
The natural history of Alzheimer’s disease 457
‘floor’ on initial evaluation and declined further over 1 year.
The initial mean MMSE for this group was 10 (± 5.9), lower
than in studies cited above and changed by an average of 3.5
points (Burns et al., 1991). In a study of 95 less-demented
subjects (mean MMSE of 19.6 ± 3.8), Swanwick et al. (1998)
reported an annual decline on the CAMCOG of 9.42 points
(± 9.52). However, as reflected by the large standard devia-
tion, the ARC was normally distributed with a high degree
of individual variability. Additionally, the rate of decline in
the first year did not predict subsequent ARC.
The ADAS includes a cognitive portion, with a maximum
of 70 points and a non-cognitive subscale scored out of 40.
Kramer-Ginsberg et al. (1988; R.C. Mohs, personal commu-
nication) found an average ARC on the ADAS of 9.3 points
in 60 AD patients. Yesavage et al. (1988) reported a similar
ARC on the ADAS of 8.3 points in 30 patients with AD and
additionally noted a high correlation between selected sub-
scales of the ADAS and the MMSE. In a larger group of 102
AD patients participating in the acetyl-l-carnitine (ALCAR)
clinical trial, Thal et al. (2000) reported an ARC of 7.5 points.
The Alzheimer’s Disease Assessment Scale-Cognitive sub-
scale (ADAS-cog) is currently the most common cognitive
outcome measurement used in randomized clinical treat-
ment trials for AD (Wolfson et al., 2002; Jones et al., 2009); a
recent meta-analysis model representing data from approxi-
mately 19,972 AD patients in 52 clinical trials reported a rate
of change of 5.5 points per year (Ito et al., 2010). The rates of
decline in clinical trials may be less than those seen in natural
history studies because of inherent selection biases. Clinical
trial volunteers, who tend to have better overall healthcare,
are selected to reduce co-morbidities and typically have
more involved caregivers than the general population.
Unfortunately, while mean ARC for each of these cogni-
tive scales was reasonably consistent between studies, the
standard deviations were fairly large, roughly equal to the
means, indicating substantial individual variability. Some
patients’ scores did not decline and even improved over 1 to
2 years of follow-up. This variability has several possible
explanations. First, AD may not progress uniformly, since
patients with early dementia may enter a ‘plateau’ phase with
relatively slow deterioration. Second, performance on these
cognitive tests probably does not decline in a linear fashion.
Third, test–retest variability is influenced by patients’ mood,
attention and motivation and many other factors that have
an impact on day-to-day mental performance, adding a fur-
ther element of uncertainty to ARC calculations. A fourth
possibility is that biological and clinical factors may modify
the rate of progression of AD. These include demographic
factors such as age of onset of the disease, gender and edu-
cation; co-morbid disease such as cerebral vascular disease,
diabetes and hypertension; historical features such as lipid-
lowering agents, vitamin and non-steroidal anti-inflam-
matory drug use; genetic factors such as apolipoprotein E
status and clinical features such as psychosis and EPS.
Perhaps the most widely used cognitive screening instru-
ment is the Montreal Cognitive Assessment (MOCA)
(Nasreddine et al., 2005). The MOCA is superior to the MMSE
458 Dementia
in its sensitivity and specificity for MCI and AD (Costa et al.,
2014; Dong et al., 2012). Longitudinal studies of the MOCA
have demonstrated its clinical utility in screening and follow
up of patients with MCI and AD dementia (Gluhm et al., 2013).
45.4 CLINICAL PREDICTORS OF RATE
OF PROGRESSION
As noted earlier, a number of factors have been identified
which appear to affect the rate of decline in AD; however,
this is a thorny issue since variables thought to have inde-
pendent prognostic significance may simply be markers of
the level of disease severity (Drachman et al., 1990).
For example, using a large well-characterized sample of
CERAD subjects, Morris et al. (1993) found that dementia
progression may be non-linear, that rate-of-change determi-
nations were less reliable when the observation period was
1 year or less and that rate of progression in AD was deter-
mined by the severity of cognitive impairment: the less severe
the dementia, the slower the rate of decline. Similarly, Teri
et al. (1995), using a community-based sample of 156 patients
diagnosed with probable AD followed for up to 5 years, found
that average rate of decline in cognitive function, measured
by the MMSE and Mattis DRS, became more rapid as the dis-
ease progressed. This was confirmed by Storandt et al. (2002)
who, in a large cohort of mildly demented subjects, found
that initial dementia severity was the most significant predic-
tor of annual rate of progression on composite psychometric
testing, with increasingly steeper slopes as severity increased.
In addition, these authors found that the rates of decline were
highly variable from person to person and between groups
as well. Most recently, rate of AD progression on the ADAS-
cog has been shown to increase with baseline severity in data
from 817 patients in the Alzheimer’s Disease Neuroimaging
Initiative (ADNI) database (Ito et al., 2011).
Several studies investigating age at onset as a predic-
tor of deterioration, have reported a significant association
between earlier age at onset and greater rate of cognitive or
functional worsening (Lucca et al., 1993; Jacobs et al., 1994;
Teri et al., 1995; Mungas et al., 2001; Backman et al., 2003).
This is not supported by two large prospective studies of
AD subjects attending memory clinics (Bowler et al., 1998;
Swanwick et al., 1998).
Gender was not seen as an influence on cognitive decline
in several studies of AD (Reisberg et al., 1986; Drachman
et al., 1990; Burns et al., 1991; Mortimer et al., 1992; Jacobs
et al., 1994; Swanwick et al., 1998; Storandt et al., 2002).
However, this was not the case for others who reported
slower (Heston et al., 1981; Lucca et al., 1993; Aguero-Torres
et al., 1998) and faster (Swanwick et al., 1998) rates of pro-
gression in men as compared to women.
Level of education has also been examined as a predic-
tor of decline in several studies (Filley et al., 1985; Berg
et al., 1988; Katzman et al., 1988; Drachman et al., 1990;
Teri et al., 1995; Storandt et al., 2002). The cognitive reserve
hypothesis suggests that higher education delays the onset
of ­accelerated decline but that, once it begins, it is more
rapid in persons with higher education. This is supported
by Hall et al. (2007) who examined the Buschke Selective
Reminding Test (SRT) in the Bronx Aging Study and fur-
ther supported by Musicco et al. (2009), who reported faster
cognitive progression in more educated mild-to-moderate
AD subjects with a mean education of 8 (±4.4) years.
The apolipoprotein E (APOE) ε4 allele is associated with
both a high likelihood of developing AD and an earlier age
of onset; nonetheless, there have been conflicting results with
regard to the influence of APOE genotype on the course of cog-
nitive decline in AD. Gomez-Isla et al. (1996), in a prospective
longitudinal study of 359 AD patients, found that the APOE ε4
allele was not associated with any change in rate of progression
of dementia. Likewise, several others have reported that rate of
decline in AD did not vary significantly across APOE geno-
type on various cognitive assessments (Growdon et al., 1996;
Kurz et al., 1996). Furthermore, Frisoni et al. (1995) reported
a slower rate of progression with increasing ε4 gene dose in a
retrospective examination of 62 sporadic AD patients. These
latter findings were similar to those of Stern et al. who noted a
slower rate of decline on the modified MMSE among patients
with ApoE ε4 alleles compared to patients with other geno-
types (Stern et al., 1997). This is not supported, however, by
Craft et al. (1998) who reported an accelerated rate of decline
on the DRS in APOE ε4 homozygotes with probable AD and
Hirono et al. (2003), who reported a similar accelerated rate of
decline on the ADAS-cog, even after using controlling appara-
tus for age, gender, education, test interval and baseline scores.
The presence of at least one ε4 allele was associated with faster
cognitive decline in an incident population-based AD group;
also in two prevalent AD samples when adjusted for disease
severity (Cosentino et al., 2008). In a recent examination of
this subject, using the Religious Orders Study (ROS) and the
Memory and Aging Project (MAP), Yu et al. (2013) found
that presence of the ε4 allele, working primarily through AD
pathology, was associated with an earlier onset of terminal
decline and faster rates of cognitive decline before and after
its onset.
Concomitant cerebrovascular disease has not been
shown to increase rate of cognitive decline in AD signifi-
cantly (Lee et al., 2000; Storandt et al., 2002; Bhargava et
al., 2006; Lo et al., 2012). However, one longitudinal study
with autopsy follow-up of 50 patients with AD and strokes,
compared to 218 AD patients without strokes, showed a
slight increase in the rate of decline on MMSE scores in the
co-morbid stroke group for subjects over the age of eighty
(Mungas et al., 2001). In addition, several studies have now
reported that vascular factors, such as myocardial infarc-
tion, carotid atherosclerosis and hypertension affect the rate
of dementia progression after a diagnosis of AD (Mielke et
al., 2007; Helzner et al., 2009).
Although it has been suggested that patients who develop
EPS such as tremor, bradykinesia (slowness of movement),
rigid tone, or masked facies have a faster rate of decline, many
of these studies may have included patients on neuroleptics

and those with LBV and diffuse Lewy body disease (DLBD)
(Miller et al., 1991; Mortimer et al., 1992; Chui et al., 1994;
Stern et al., 1994; Portet et al., 2009). Furthermore, it is now
clear that there is a pathological subset of AD patients with
alpha-synuclein positive cortical Lewy Bodies in addition to
typical AD pathology (Fleisher and Olichney, 2005; Weisman
et al., 2007). A retrospective study by Lopez et al. (2000)
compared clinical characteristics of 185 autopsy-proven AD
and 60 autopsy-proven AD plus dementia with Lewy bodies
(DLB) subjects. These authors found no differences in rate of
cognitive decline between the two, although DLB subjects
developed EPS earlier. A recent meta-analysis of 18 stud-
ies, using the MMSE, also did not support the hypothesis
of a faster rate of cognitive decline in DLB compared to AD
(Breitve et al., 2014). However, a study of 56 patients with DLB
compared to 111 patients with AD, who were examined for up
to 5 years on end points of hospitalization, institutionaliza-
tion and death (Hanyu et al., 2009), found that DLB patients
had a significantly shorter time to clinical end points than
those with AD (median time; 40 months versus 52 months,
p < .0001). The proportion of hospitalizations (and death) was
significantly higher in DLB than in AD patients (30% versus
14%, p < .05), but differences with regard to nursing home
placement did not reach statistical significance (25% versus
17%). Rates of decline on the MMSE were equivalent for both
groups. Although, there is evidence that the addition of Lewy
bodies to AD pathology expedites clinical decline, it is not
clear that the EPS of typical AD, free from Lewy Body pathol-
ogy, predicts rapid decline.
Whether neuropsychiatric symptoms superimposed on
AD influence cognitive deterioration or not, has been exam-
ined by several authors. Initial reports suggested that AD
patients reached end points on a modified MMSE or BDS
score more rapidly when psychotic symptoms were present
(Mayeux et al., 1985; Drevets and Rubin, 1989; Stern et al.,
1990). However, these investigations did not match patients
according to their level of dementia. Controlling for severity
of AD, other studies were unable to replicate these findings
(Reisberg et al., 1986; Chen et al., 1991), although two more
have confirmed psychosis as a robust predictor of cogni-
tive decline (Chui et al., 1994; Stern et al., 1994). Lopez et
al. (1999) examined the effect of psychiatric symptoms and
medications on progression in 179 mild-to-moderate prob-
able AD patients, followed for a mean of 49.5 ± 27.4 months.
These authors found that the presence of psychiatric symp-
toms and the use of psychiatric medications were associated
with increased rate of functional (BDRS) but not cognitive
(MMSE) decline. One cross-sectional study reported that
AD patients with depression had more ADL impairment
than those without (Pearson et al., 1989), however, other
longitudinal studies found no effect of depression on the
rate of decline (Lopez et al., 1990; Storandt et al., 2002).
Recent data from the International Citicoline Trial on Acute
Stroke (ICTUS) study demonstrated that the rate of cogni-
tive decline in 1375 subjects with AD was not substantially
influenced by the presence of specific neuropsychiatric phe-
notypes (Canevelli et al., 2013).
The natural history of Alzheimer’s disease 459
Whether vitamin use, oestrogen, lipid-lowering agents,
or non-steroidal anti-inflammatory drugs (NSAIDs) affect
progression of AD, it has not been investigated. High dose
vitamin E appeared to slow disease progression in a dou-
ble-blind, placebo-controlled trial in patients with AD of
moderate severity (Sano et al., 1997). Reduction of serum
homocysteine with folate, B6 and B12 has shown no benefit
in slowing AD progression (Aisen et al., 2008). Likewise,
a recent meta-analysis of the effect of vitamin B supple-
mentation failed to show any significant cognitive (ADAS-
cog, MMSE), functional, behavioural or global benefit in
patients with AD (Li et al., 2014). An omega-3 fatty acid,
docosahexaenoic acid, was recently proved in a large pla-
cebo controlled, randomized clinical trial to not be effec-
tive in slowing cognitive decline in AD (Quinn et al., 2009).
Although, several observational studies have suggested that
oestrogen replacement therapy may have a beneficial effect
on cognitive performance in women with AD, many have
substantial methodologic problems (Haskell et al., 1997;
Yaffe et al., 1998). Furthermore, a study of the association
between serum oestradiol and oestrone levels in 120 hys-
terectomized women undergoing replacement found no
significant association between hormone levels and cogni-
tive functioning after either 2 or 12 months of treatment
(Thal et al., 2003). Additional evidence that oestrogen may
not be beneficial in AD comes from the Women’s Health
Initiative Memory Study (WHIMS), a randomized, double-
blind, placebo-controlled clinical trial of 4532 postmeno-
pausal women, comparing oestrogen and progesterone
versus placebo effects on incidence of dementia over 4 years.
The authors found that oestrogen plus progestin therapy
increased the risk of probable dementia in postmenopausal
women aged 65 years or above (Shumaker et al., 2003).
Several large cohort analyses have demonstrated decreased
prevalence of AD with use of various lipid-lowering agents
(Rockwood et al., 2002). A large multicentre placebo con-
trolled trial investigating the effect of simvastatin on pro-
gression of cognitive decline in AD failed to meet its end
points (Sano et al., 2011). Analysis of longitudinal changes
over 1 year revealed fewer declines among NSAID patients
than among non-NSAID patients on measures of verbal flu-
ency, spatial recognition and orientation, in a study consist-
ing of 210 patients with AD (Rich et al., 1995). On the other
hand, a randomized placebo-controlled trial of naproxen
and rofecoxib showed no effect on cognitive decline in
351 patients with mild-to-moderate AD (Aisen et al., 2003).
45.5 PREDICTING NURSING HOME
PLACEMENT IN AD
Most patients with AD reside in nursing homes or related
institutions late in the course of the illness. The interval
between the diagnosis of AD and the need for institutional
placement has practical and clinical importance, but is not
easy to predict. Behavioural symptoms such as agitation,
460 Dementia
wandering or aggression may pre-empt nursing home
placement, regardless of the level of cognitive impairment.
Other variables that greatly influence the decision for insti-
tutional placement of a demented patient may include social
support and caregiver burden. Many studies have evaluated
such predictors of nursing home placement. In a system-
atic review, Gaugler et al., (2009) examined 782 studies on
nursing home placement of dementia patients, performing
analysis on the 80 most relevant and high quality studies.
They found that the most consistent predictors of nursing
home admission in dementia patients included severity of
cognitive impairment, basic activity of daily living depen-
dencies, behavioural symptoms and depression. Caregivers
who reported greater emotional stress also increased risk
of placement in the nursing home. Demographic variables,
incontinence and use of available services did not predict
nursing home placement.
A large population based historical cohort study sug-
gests, unsurprisingly, that the mere presence of dementia
increases the overall risk of nursing home admission (Eaker
et al., 2002). In this study, the adjusted hazard ratio for insti-
tutionalization, compared to non-demented controls, was
5.44 (95% CI = 3.68–8.05) for AD cases and 5.08 (95% CI =
3.38–7.63) for non-AD dementia cases, independent of co-
morbid conditions.
As noted, several studies have examined predictors of
institutionalization in AD. And, as expected, the predic-
tive factors are complex and vary greatly among studies.
One investigation of 14 married men with AD found that
urinary or faecal incontinence, inability to speak coher-
ently and loss of bathing and grooming skills were major
determinants of institutionalization (Hutton et al., 1985).
1.0
0.8
Cumulative survival (%)
0.6
CDR = 1
0.4
0.2
0.0
0 2 4 6
Figure 45.1 Progression to nursing home placement in non-demented (Clinical Dementia Rating [CDR] of 0) and demented
(CDR 0.5 incipient, 0.5 dementia of the Alzheimer type and CDR 1) groups. (From Storandt, M. et al., Neurology, 59,
1034–1041, 2002.)
In a 5-year study of 92 patients who developed AD before
the age of 70, lower mental status scores or aphasia were
more common in those who were institutionalized (Hutton
et al., 1985; Heyman et al., 1987). In most instances, nursing
home placement occurred because the patients had become
almost completely helpless and required 24-hour supervi-
sion; for 10 patients the decision was prompted by death or
serious illness of their caregivers.
A prospective study of 101 initially community-dwelling
AD patients found that 12% with ‘mild AD’ were in nursing
homes after 1 year and 35% after 2 years (Knopman et al.,
1988). For ‘advanced AD’, the figures were 39% at 1 year and
62% at 2 years. Total activity of daily living (ADL) scores
were significantly related to institutionalization, while
incontinence, irritability, inability to walk, wandering,
hyperactivity and nocturnal behavioural problems were the
leading reasons for placement cited by caregivers.
A CERAD analysis, comprising 20 university medical
centres, found that the median time from enrolment as a
patient to nursing home placement was 3.1 years, with sig-
nificantly reduced times (2.1 years) for unmarried males
(Heyman et al., 1997). The major predictors of time to
admission were measures of dementia severity upon entry
into the study, including the degree of cognitive impair-
ment, functional disability and overall stage progression in
the disease. Age at entry and marital status (men only) also
predicted time of nursing home admission. Similar findings
with regard to marital status (Haupt and Kurz, 1993) and
rate of functional decline (Wattmo et al., 2011) have been
reported by others (Figure 45.1).
Finally, a large multiregional, prospective study
­distinguished by an extremely large number of patients
CDR = 0
CDR = 0.5
Incipient
CDR = 0.5
DAT
8 10 12 14 16 18 20 22
Years

(n = 3944), found that specific caregiver traits (including
age ≥ 80 years, low income, poor health and high perceived
burden as a result of caregiving) predicted earlier placement
for care recipients (Gaugler et al., 2003).
45.6 SURVIVAL IN AD
Length of survival in AD is highly variable, although an
excess mortality has consistently been reported (Katzman,
1976; Jorm et al., 1987; Aevarsson et al., 1998). Although,
mean survival after symptom onset may range from 2 to 16
years, the observed survival rate among AD population is
significantly less than the expected rate, based on life expec-
tancy tables (Walsh et al., 1990). Depending on the study,
survival at 5 years ranges from 10% to 40% in different AD
populations. The most favourable survival rates are seen in
mild cohorts followed up in outpatient settings, with low-
est survival rates reported in relatively severely demented
subjects from hospital series. The median duration of sur-
vival among CERAD patients from the time of study of
their entry in hospitals was 5.9 years (Heyman et al., 1996),
which compares favourably the 5.3 years reported by Walsh
et al. (1990), the 5.7 years noted by Molsa et al. (1986) and
the 5.8 years described by Jost and Grossberg (1995). Three
other studies found shorter median periods of survival of
3.4 years (Schoenberg et al., 1987), 3.5 years (Barclay et al.,
1985) and 4.3 years (Claus et al., 1998), possibly due to inclu-
sion of severe subjects.
The shortened survival of AD patients results from com-
plications due to severe mental decline. Malnutrition, dehy-
dration, pneumonia and other infections occur frequently
in the terminal stages when patients are bed-bound, incon-
tinent and unable to communicate with others or feed them-
selves. Compared to other elderly individuals, AD patients
are not especially predisposed to cancer, cerebrovascular or
cardiovascular disease (Molsa et al., 1986).
Unremarkably, the most consistent predictors of mor-
tality in AD patients are age, gender and dementia sever-
ity. Age was significantly associated with survival time in a
large sample of AD patients, drawn from California (Moritz
et al., 1997). Increasing age has also been related to shorter
survival in several additional studies (Hier et al., 1989;
Walsh et al., 1990; van Dijk et al., 1991; Heyman et al., 1996;
Reisberg et al., 1996; Aguero-Torres et al., 1998; Claus et al.,
1998; Gambassi et al., 1999; Ueki et al., 2001). Although two
reports have indicated that survival rates of patients with
early-onset AD are considerably less than those of late-onset
AD (Heyman et al., 1987; McGonigal et al., 1992), this find-
ing has not been confirmed by others (Walsh et al., 1990;
Bracco et al., 1994; Corder et al., 1995; Bowen et al., 1996;
Heyman et al., 1996).
Most investigators have reported shorter survival times
for men than women (Schoenberg et al., 1987; Berg et al.,
1988; Burns et al., 1991; van Dijk et al., 1991; Corder et al.,
1995; Jagger et al., 1995; Molsa et al., 1995; Stern et al., 1995;
The natural history of Alzheimer’s disease 461
Bowen et al., 1996; Heyman et al., 1996; Reisberg et al., 1996;
Moritz et al., 1997; Claus et al., 1998; Gambassi et al., 1999;
Lapane et al., 2001; Ueki et al., 2001), although this has not
been the case for all studies (Hier et al., 1989; Walsh et al.,
1990; Becker et al., 1994). Furthermore, it has been sug-
gested that predictors may differ according to gender. For
example, Moritz et al. (1997) found that, among men, but
not women, survival times were negatively associated with
selected neurological symptoms, particularly, aphasia and
apraxia. Among women, but not men, a history of cardio-
vascular conditions was associated with poorer survival.
Lapane et al. (2001), on the other hand, found that the most
important predictors of mortality for men were severity of
dementia and the occurrence of delirium. For women, death
was associated with impairment of ADLs, presence of pres-
sure sores, malnutrition and co-morbidity.
Patients with severe dementia at the beginning of the
study have shorter survival durations (Walsh et al., 1990;
Burns et al., 1991; Evans et al., 1991; Jagger et al., 1995;
Heyman et al., 1996; Moritz et al., 1997; Claus et al., 1998;
Ueki et al., 2001; Storandt et al., 2002) (Figure 45.2). In addi-
tion, functional disability decreases survival time in AD
(Martin et al., 1987; Bianchetti et al., 1995; Heyman et al.,
1996; Ueki et al., 2001).
Additional variables that may influence survival time
in patients with AD have not been well established, includ-
ing level of education (Becker et al., 1994; Stern et al., 1995;
Geerlings et al., 1997), medical co-morbidity (Moritz et al.,
1997; Aguero-Torres et al., 1998) and psychiatric or behav-
ioural symptoms (Barclay et al., 1985; Molsa et al., 1986;
Walsh et al., 1990; Stern et al., 1994; Samson et al., 1996);
however, exercise, diet and statin therapy have all been asso-
ciated with lower risk of AD mortality in several studies
(Scarmeas et al., 2007; Scarmeas et al., 2011; Williams, 2015).
Survival in AD appeared to be unrelated to ApoE ε4 gene
dosage in one study (Corder et al., 1995). However, Tilvis
et al. (1998) noted increased mortality in elderly demented
patients with the ε4 allele, a finding supported, at least for
men, in a study consisting of 92 autopsy-confirmed AD
cases (Dal Forno et al., 2002). On the other hand, Stern et al.
(1997) found that the presence of at least one ε4 allele was
associated with a less aggressive form of AD and a decreased
risk of mortality in 99 patients with probable AD followed
for up to 6 years.
EPS appeared to be an important predictor of mortality
in a population-based study of 198 patients with probable
early-onset AD (Samson et al., 1996). EPS at entry were also
associated with a higher relative risk of death in 236 patients
with mild AD followed up semi-annually (Stern et al., 1994).
A study of 379 AD patients found similar heightened mor-
tality due to EPS and demonstrated that individuals with
EPS were 3 times more likely to have Lewy bodies (LBs) at
autopsy (Haan et al., 2002) (Figure 45.3). Both EPS and LBs
were associated with an earlier age of death. This was not
the case for a study by Lopez et al. (2000) who reported no
differences between AD and AD+LB (LBV) with regard to
survival.
462 Dementia

1.0

CDR = 0
0.8

Cumulative survival (%)

0.6
CDR = 0.5
CDR = 1 Incipient
0.4

0.2

0.0
CDR = 0.5
DAT

0 2 4 6 8 10 12 14 16 18 20 22
Years

Figure 45.2 Progression to the end point of death in non-demented (CDR of 0) and demented (CDR 0.5 incipient, 0.5
dementia of the Alzheimer type and CDR 1) groups. (From Storandt, M. et al., Neurology, 59, 1034–1041, 2002.)

1.00

0.90

0.80

0.70

0.60
Neither
Survival function

EPSs
LBs
0.50 Both

0.40

0.30

0.20

0.10

0
52 55 60 62 64 66 68 70 72 74 76 78 80 82 84 86 88 90 92 94 96 102
Age at death, years

Figure 45.3 Survival differences by the presence of extrapyramidal signs (EPSs) and Lewy bodies (LBs) from a life table
analysis. (From Haan, M.N. et al., Archives of Neurology, 59, 588–593, 2002.)

45.7 CONCLUSIONS
Despite an abundance of observations about the natural
history of AD, the variability of its clinical features and
rate of progression has not been explained and the valid-
ity of ‘subtypes’ of AD has not yet been proved. The most
consistent predictor of rapid deterioration and death in AD
patients appears to be the degree of cognitive and functional
disability. Because of the relatively low prevalence of clini-
cal features such as EPS, depression and psychosis at early
stages of the disease, larger studies conducted carefully con-
trolling the potential confounding effect of dementia sever-
ity are needed to clarify their effect on prognosis.
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The neuropathology of Alzheimer’s disease
COLIN L. MASTERS
46.1 INTRODUCTION
In 2015, the centenary of the death of Aloysius Alzheimer
(1864–1915) was celebrated. Although Alzheimer highlighted
the two key histological lesions, amyloid plaques and neurofi-
brillary tangles (NFTs) (Alzheimer, 1907), it is only in the last
30 years that developments in molecular biology, molecular
genetics, immunohistochemistry, image analysis and protein
chemistry have transformed our understanding of the patho-
genesis of Alzheimer’s disease (AD). For laboratory-based
diagnostic pathologists, brain immunohistochemistry and
cerebrospinal fluid (CSF) immunoassays in particular have
become an essential part of the diagnostic armoury.
46.2 PATHOLOGIC CHANGES OUTSIDE
THE CENTRAL NERVOUS SYSTEM
(CNS)
General post-mortem examination does not reveal any
specific abnormalities outside the nervous system. Patients
with AD usually die from terminal respiratory illness,
and bronchopneumonia is most often the cause of death.
Ongoing investigations have, however, revealed that subtle
biochemical abnormalities may not be restricted to the brain.
AD may, like a systemic illness, cause secondary changes in
the CSF and peripheral blood that reflect neuronal metabo-
lism of the amyloid β (Aβ) and tau proteins. As the disease
progresses, the total biochemical pools of Aβ and tau
increase within the brain, CSF and blood, even though the
Aβ levels in CSF and blood decrease as the disease develops
(Ritchie et al., 2003; Bates et al., 2009; Craig-Shapiro et al.,
2009; Fagan et al., 2009).
That sensory outposts associated with the brain under-
going degeneration has been suspected for some time.
The optic nerve (Hinton et al., 1986) and retinal ganglion
470
46
cells (Blanks et al., 1989) show degenerative changes and
the anterior olfactory nucleus develops NFTs (Esiri and
Wilcock, 1984). Aβ deposits have been reported in the
retinal pigment epithelial layer, detectable with fluorescent
β-sheet ligands. Abnormalities in the processes of olfactory
neurones in the nasal mucosa have been reported (Talamo
et al., 1989) and tau-reactive filaments, absent from con-
trols, have been described in the olfactory mucosa in biopsy
specimens of patients with probable AD (Tabaton et al.,
1991a). Deposition of Aβ in the periphery of the lens may
also be linked to AD (Goldstein et al., 2003), although more
studies are required to confirm this association.
46.3 MACROSCOPIC
NEUROPATHOLOGIC
CHANGES
The naked-eye appearances of the brain range from
unremarkable to grossly abnormal. The leptomeninges
may be thickened, particularly over the convexity, and may
show orange-brown areas of various sizes, indicating old,
circumscribed subarachnoid haemorrhage, which most
often result from amyloid congophilic angiopathy (ACA).
The cranial nerves are normal and the large cerebral vessels
in uncomplicated cases of AD have not been damaged more
by atherosclerosis than expected for the patient’s age. Brain
weight is quite often reduced, sometimes below 1000 g. Since
brain weight normally depends on the patient’s age, sex and
constitution, the degree of atrophy should be considered in
the light of these factors. A discrepancy between the findings
of neuroimaging and neuropathology is not unusual: cere-
bral atrophy reported on computed tomography (CT) scans
or magnetic resonance imaging (MRI) may not always be
confirmed at post-mortem examination. Agonal changes
of haemodynamics, post-mortem delay and the effects
of fixation on the brain may be partly responsible for this

discrepancy. The normal ratio of 8:1 of total brain weight to
that of the brainstem and cerebellum may decrease, indicat-
ing loss of tissue from the cerebral hemispheres. The atrophy
is usually diffuse and symmetrical, although the frontopa-
rietal region and the temporal lobes may be more severely
affected than the rest of the brain (Figure 46.1). Moderate-
to-severe atrophy is easy to discern: the sulci are widened
and the gyri are narrowed both on the outside and on coro-
nal slices. The latter also reveal enlarged lateral ventricles
with rounded angles and additional space between the hip-
pocampi and the wall of the temporal horns. Decrease in
the thickness of neocortical ribbon, apart from extreme
cases of atrophy, is difficult, and may prove deceptive, to
assess on naked-eye appearances. A quantitative study,
however, revealed a decrease of neocortical areas of all lobes
in AD, whereas in patients over the age of 80, only the tem-
poral cortex was atrophied (Hubbard and Anderson, 1981,
1985). Reduction in cortical area may result from a decrease
in the length rather than in the width of cortex, indicating
loss of columns of cells and fibres perpendicular to the pial
surface. A correlation appears to exist between the length,
but not the thickness, of the cortical ribbon and dementia
score (Duyckaerts et al., 1985). Apart from occasional small,
orange-coloured old haemorrhages in the cortex, suggestive
of ACA, uncomplicated AD usually is not associated with
any other focal lesions. There is a growing awareness that the
topographic dispersion of the lesions of AD are related to an
underlying functional property of the higher nervous sys-
tem. The brain’s ‘default network’ may explain why certain
areas are more affected by atrophy and Aβ amyloid deposi-
tion (Buckner et al., 2009; Dickerson et al., 2009). In turn,
the evolution of Aβ amyloid deposition at the macroscopic
Figure 46.1 On the left, a coronal slice of the brain of a
patient with severe Alzheimer’s disease showing atrophy:
The lateral ventricle is enlarged with rounding of its angle
and there is additional space between the hippocampus
and the inferior horn of the lateral ventricle. Several gyri
are narrowed and the lateral fissure is widened. On the
right, a slice of the right hemibrain of a normal subject.
The neuropathology of Alzheimer’s disease 471
scale is now able to be visualised by positron emission
tomography (PET)-Aβ tracers or measured by CSF Aβ levels
as the disease begins and progresses (Rowe et al., 2007; Jack
et al., 2009; Villemagne et al., 2013) (see Chapter 12). These
new techniques and assays may be reporting on different
aggregation states of Aβ (Matveev et al., 2014).
46.4 HISTOLOGY, ULTRASTRUCTURE,
IMMUNOCYTOCHEMISTRY AND
MORPHOMETRY
The neurohistological features of AD are complex and vari-
able. The two hallmark lesions, Aβ amyloid plaques and
NFTs (Figure 46.2) are complemented by granulovacuolar
degeneration, Hirano bodies, neuronal and synaptic loss,
abnormalities of neuronal processes and synapses, astro-
cytic and microglial response, and vascular changes. The
white matter may also be affected (Esiri et al., 1997).
46.4.1 AMYLOID PLAQUES
The amyloid or neuritic plaque (‘senile’ plaque) is one of
the major lesions found in the AD brain, first described by
Blocq and Marinesco (1892). These structures, ranging in
size from 50 to 200 µm (Terry, 1985), can be readily demon-
strated in frozen and paraffin-embedded sections by silver
impregnation methods (Figure 46.3) and immunocyto-
chemistry. The lesion consists of an Aβ amyloid core with
a corona of argyrophilic axonal and dendritic processes,
Aβ amyloid fibrils, glial cell processes and microglial cells.
Neuritic processes in the periphery of the plaque are fre-
quently dystrophic and contain paired helical filaments,
which are composed largely of ubiquinated and phosphory-
lated tau protein (Gonatas et al., 1967; Hanger et al., 1991).
Divry (1927) demonstrated that the core of the AD plaque
contained a congophilic amyloid substance, which gave
an apple green colour under polarised light. The amyloid
plaque is composed of 5–10 nm filaments made up of a 38-
to 43-amino acid (4 kDa) peptide (Masters et al., 1985), now
referred to as Aβ peptide, derived from neurones by proteo-
lytic cleavage of the amyloid precursor protein (APP) (Kang
et al., 1987).
Three types of plaque have been identified in conven-
tional silver staining preparations: ‘primitive’ or ‘early’,
‘classical’ or ‘mature’, and ‘burnt out’ or ‘compact’. On the
basis of light and electron microscopic studies, a three-
stage evolution of the plaque has been proposed. The first
stage is the ‘primitive’ plaque, composed of a small num-
ber of distorted neurites, largely presynaptic in origin
with few amyloid fibres, astrocytic processes and the occa-
sional microglial cell. The second stage is the ‘classical’ or
‘mature’ plaque with a dense amyloid core with a halo of
dystrophic neurites, astrocytic processes and cell bodies
and the occasional microglial cell. The final stage in this
472 Dementia
Figure 46.2 Neurofibrillary tangles and neurotic amyloid plaques in the neocortex. Modified Bielschowsky silver impregnation.
Figure 46.3 An argyrophilic amyloid plaque in the
neocortex showing a neurotic ring with an amyloid core
formation. Modified Bielschowsky silver impregnation.
sequence is the ‘burnt out’ plaque consisting of a dense core
of amyloid (Terry et al., 1981; Esiri and Morris, 1997). The
relationship between dystrophic neurites, neurofibrillary
degeneration and Aβ amyloid deposition is not fully under-
stood (Adalbert et al., 2009), but the neurites and tangles
appear to be downstream of Aβ accumulation. These three
stages of plaque development have not been confirmed in
experimental transgenic mice and therefore the temporal
relationships suggested above remain speculative: it may yet
transpire that the three types of plaques are independent of
each other.
Studies using antibodies raised against Aβ peptide
reveal a much more widespread deposition of amyloid than
is visualized by traditional staining methods (Majocha
et al., 1988; Gentleman et al., 1989; Armstrong et al., 1996)
(Figures 46.4 through 46.8). Aβ immunoreactivity has been
detected throughout the CNS including the neocortex, hip-
pocampus, thalamus, amygdala, caudate nucleus, putamen,
nucleus basalis of Meynert (nbM), midbrain, pons, medulla
oblongata, the cerebellar cortex and spinal cord (Joachim
et al., 1989; Ogomori et al., 1989). These deposits take a vari-
ety of forms and include subpial, vascular, dyshoric, punc-
tate or granular, diffuse, stellar, ring-with-core and compact
deposits (Ogomori et al., 1989). A laminar pattern of Aβ
deposits in the neocortex has been described with concen-
trations in layers II, III and V (Majocha et al., 1988).
As noted, the Aβ peptide is a 38–43 residue cleavage
product of a larger precursor protein, the APP (Kang et al.,
1987). Although most cells have the potential to produce
APP, neurones and platelets express APP to high levels.
Moreover, neurones process APP with β-secretase (BACE)
to a greater extent than most other cell types, which in turn
leads to the formation of full Aβ sequences. The theory that
Aβ deposition is an early event in AD pathogenesis has been
given support by the presence of extracellular Aβ in diffuse
plaques not associated with any neuritic change or astro-
cytic involvement (Yamaguchi et al., 1991). More condensed
Aβ is, however, associated with a neuritic change, reactive
astrocytosis and microglial infiltration and phagocytosis.
Most species of Aβ have been detected by immunohisto-
chemistry using antibodies that recognize epitopes within

Figure 46.4 An amyloid plaque with a dense core and
corona. Amyloid β (Aβ) immunohistochemistry.
Figure 46.5 Aβ- protein deposits in the temporal lobe of
a patient with Alzheimer’s disease. Several deposit mor-
phologies can be seen. Aβ immunohistochemistry.
the full-length Aβ(1–42) or a truncated Aβ(1–40). The pre-
dominant species in sporadic AD is Aβ42(43) and this is
found in plaques of all morphological types. Diffuse plaques
contain mainly Aβ42(43) (Mann et al., 1996a, 1996b).
A number of other proteins co-localize with Aβ includ-
ing apolipoprotein E (ApoE), a widely distributed protein
involved in the transport of cholesterol. There are three
common isoforms of ApoE, which are encoded by three
alleles, ε2, ε3 and ε4, and there is a strong association
between the presence of the ε4 allele and the age of onset of
The neuropathology of Alzheimer’s disease 473
Figure 46.6 A high-power electron micrograph reveal-
ing (Aβ) fibrils (A) of a plaque. (Courtesy of Dr I. Janota,
Institute of Psychiatry, London.)
(a)
(b)
Figure 46.7 Congophilic angiopathy. Blood vessels
stained with Congo red showing birefringence under
polarised light (a) and β immunohistochemistry (b).
AD. ApoE has been shown to bind to Aβ and a high propor-
tion of Aβ and ApoE deposits tend to be co-localized. Thus,
both diffuse and compact Aβ plaques may be immunola-
belled by anti-Aβ and anti-ApoE antibodies (Cairns et al.,
1997b). The presence of one or more ε4 alleles leads to both
474 Dementia
Figure 46.8 A high-power electron micrograph showing Aβ fibrils (A) surrounding a blood vessel: dysphoric angiopathy.
(Courtesy of Dr I. Janota, Institute of Psychiatry, London.)
an earlier-onset and a more severe Aβ amyloidosis (Roses,
1994; Agosta et al., 2009). The relationship between Aβ and
ApoE is still imperfectly understood, as ApoE knockout
mice have an increased amount of Aβ deposition on a trans-
genic APP background.
The plaques are also immunohistochemically positive for
a number of neuroactive substances. Acetylcholinesterase,
a marker of the cholinergic system, can be demonstrated
within and around the neuritic elements of the corona.
Many of these elements derive from cholinergic neurones in
the basal forebrain, particularly the nbM, the diagonal band
of Broca and the medial septal nuclei. Several other neu-
rotransmitters have been demonstrated in the plaque. These
include substance P, neuropeptide Y, neurotensin, cholecys-
tokinin, 5-hydroxytryptamine (5HT) and catecholamine
(Walker et al., 1988; Hauw et al., 1991). Ubiquitin, a protein
acting as a signal for degradation of abnormal proteins, is
also present in intracellular neurites and NFTs (Perry et al.,
1987). The protease inhibitor α1-antichymotrypsin has
been localized to the plaque using immunohistochemical
methods (Walker et al., 1988). Serum amyloid P compo-
nent (SAP) is a glycoprotein complex produced in the liver,
distributed in serum and has been detected in diffuse and
consolidated Aβ deposits, NFTs and neuritic degeneration.
The plaques are more numerous in associative regions of
neocortex than in sensory areas and are also largest in those
laminae characterised by large pyramidal neurones (Rogers
and Morrison, 1985). Accumulations of Aβ peptide are
found in the neocortex of non-demented elderly individu-
als without any neurofibrillary change, suggesting that Aβ
deposition precedes neurofibrillary changes. However, NFT
formation has been reported in areas devoid of Aβ (Braak
et al., 1986; Duyckaerts et al., 1988; Delaère et al., 1990;
Armstrong et al., 1993), indicating that factors in addition
to Aβ may be required to cause aggregation of tau. Tangle-
bearing neurones generally project into areas with Aβ depo-
sition, suggesting some form of retrograde transport of the
toxic elements that are associated with Aβ.
46.4.2 NEUROFIBRILLARY TANGLES
The second histological hallmark of AD is the NFT. These
are not specific to AD, since they occur in other neurode-
generative disorders, including Down’s syndrome, posten-
cephalitic parkinsonism, dementia pugilistica, amyotrophic
lateral sclerosis–parkinsonism–dementia complex of Guam,
subacute sclerosing panencephalitis, dementia with tangles
with and without calcification, and in myotonic dystrophy
(Kiuchi et al., 1991). Globose NFTs also develop in progres-
sive supranuclear palsy and sporadic motor neurone dis-
ease, but their morphology and ultrastructure differ from
those seen in AD. Current controversy surrounds the con-
cept of primary age-related tauopathy (PART) and whether
this occurs in the absence of co-morbidity with other dis-
eases such as AD (Crary et al., 2014).
In AD, NFTs are common in the medial temporal struc-
tures, in the hippocampus, amygdala and parahippocam-
pal gyrus, and also occur throughout the neocortex and the
deep grey matter including the lentiform nucleus, the nbM,
the thalamus, the mamillary bodies, substantia nigra, locus
caeruleus, periaqueductal grey matter, the raphé nuclei of
the brainstem and the pedunculopontine nucleus.
NFTs are intracellular inclusions composed of ubiqui-
nated and phosphorylated tau. Their configuration is
determined in part by the shape of neurones in which they
develop. NFTs are flame shaped in pyramidal neurones,
while in the neurones of the brainstem they assume more
complex, globose forms. They can be easily discerned in

histological sections stained with haematoxylin and eosin,
silver impregnation techniques or with Congo red, which
renders them birefringent under polarised light. They can
be best demonstrated by immunocytochemistry using anti-
bodies against tau and ubiquitin (Figure 46.9).
Electron microscopy reveals the fine structural details
(Figure 46.10). NFTs are mainly composed of paired heli-
cal filaments (Kidd, 1963), which in turn are formed by two
­fi laments wound around each other. Each filament has a
diameter of 10 nm with crossover points every 80 nm, result-
ing in the typical periodicity of a double helix. A negative
staining technique has demonstrated that each filament is
composed of four protofilaments with a diameter of 3–5 nm
(Wisniewski et al., 1984). NFTs also contain straight fila-
ments with an average diameter of 15 nm. These straight and
the paired helical filaments may form hybrid filaments, dis-
playing both morphologies, share surface epitopes and have
identically shaped structural units. These common features
indicate that paired helical and straight filaments are related
and they represent only somewhat different assemblies of
the same basic molecular unit (Crowther, 1991).
A major component of the NFT is a microtubule-­
associated protein called tau, which is involved in microtu-
bule assembly and stabilization. In the adult human brain
there are six isoforms of tau and all of these are hyper-
phosphorylated in AD (Hanger et al., 1991; Goedert et al.,
1992). Antibodies that recognize specific phosphorylation-­
dependent epitopes may be used to identify the three sites
of tau aggregation: the NFT, dystrophic neurites of plaques
and neuropil threads. Phosphorylation-dependent antibod-
ies may also be used to distinguish the tauopathy in AD
from other neurological disorders (Cairns et al., 1997a).
Other neuronal inclusions that have confused neuropa-
thologists until recently have been elucidated as contain-
ing the TAR DNA-binding (TDP)-43 protein (Arai et al.,
2009). This type of neuronal inclusion is prominent in the
frontotemporal lobar atrophies of the non-Pick type, amyo-
trophic lateral sclerosis (ALS), and also in selected areas of
the AD-affected brain. Its significance in AD is the subject
of intense scrutiny.
Figure 46.9 A neuritic plaque (P) and neurofibrillary tan-
gles (T) demonstrated by anti-tau immunohistochemistry.
The neuropathology of Alzheimer’s disease 475
Figure 46.10 A high-power electron micrograph reveal-
ing paired helical filaments of a neurofibrillary tangle.
(Courtesy of the late Professor L.W. Duchen, Institute of
Psychiatry, London.)
Biochemically, NFTs are composed of phosphorylated
isoforms of tau (Goedert et al., 1988), and monoclonal anti-
bodies can be used to quantify NFTs (Harrington et al.,
1991). They also contain ubiquitin and anti-ubiquitin anti-
bodies giving strongly positive reaction with NFTs (Mori
et al., 1987; Perry et al., 1987).
While NFTs are intracytoplasmic neuronal inclusions,
they may become extracellular after the neurone that con-
tained them has vanished. These extraneuronal NFTs are
most often seen in the hippocampus and entorhinal cortex
in advanced disease, and both their antigenic properties
and ultrastructural features differ from their intraneuronal
counterparts (Tabaton et al., 1991b). They are chiefly com-
posed of straight, not paired, helical filaments and react dif-
ferently with antibodies to tau and ubiquitin. A small subset
of extraneuronal tangles gives positive reactions with anti-
bodies to both tau and Aβ protein. The degradation of the
NFT (the transition from intracellular to extracellular form)
is a series of distinct stages involving complex molecular
events that alter both the antigenicity and configuration of
the tangle (Bondareff et al., 1990). It is the insolubility of
NFTs that is most likely to be responsible for the occurrence
of extraneuronal forms (Terry, 1990). The extraneuronal
NFTs may be enveloped by glial processes and eventually be
internalized as part of their degradative cycle.
46.4.3 GRANULOVACUOLAR
DEGENERATION
Granulovacuolar degeneration was first described by
Simchowicz (1911) in the hippocampal neurones of senile
dementia patients (Figure 46.11). Granulovacuoles are
abnormal cytoplasmic structures: one or more vacuoles of
3.5 mm in diameter each containing a single granule. The
electron microscope shows a dense granular core, embedded
476 Dementia
Figure 46.11 Granulovacuolar degeneration (arrows) and
Hirano bodies (arrowheads) in the pyramidal cell layer of
the hippocampus. Haematoxylin and eosin.
in a translucent matrix. This granular component gives a
positive reaction with antibodies to tubulin (Price et al.,
1985), to phosphorylated epitopes of the heavy neurofila-
ment peptide (Kahn et al., 1985), to tau (Dickson et al., 1987)
and, in some neurones, to ubiquitin (Leigh et al., 1989).
A detailed immunocytochemical study has demonstrated
that most epitopes of the tau molecule are sequestered in
granulovacuoles and this tau protein is antigenically similar
to that found in paired helical filaments. Granulovacuoles
are now considered to be special autophagosomes that are
formed by the sequestration of electron-dense material by
a two-layered membrane. Granulovacuoles are virtually
restricted to the pyramidal neurones of the hippocampus
and in severe AD cases, the neuronal cytoplasm is replete
with these abnormal structures. They also occur, much less
often, in a variety of diseases, including progressive supra-
nuclear palsy, amyotrophic lateral sclerosis–parkinsonism–
dementia complex of Guam and tuberous sclerosis.
46.4.4 HIRANO BODIES
These abnormal structures were first described by Hirano
(1965). They are most commonly seen in and among the
pyramidal cells of the hippocampus. Hirano bodies occur
in normal subjects and their frequency increases with age.
However, AD patients have significantly more Hirano bod-
ies than age-matched controls. They also occur in various
neurological diseases, including Pick’s disease, motor neu-
rone disease and kuru, and in animals infected with kuru
and scrapie (Gibson and Tomlinson, 1977). Hirano bodies
stand out in sections stained with haematoxylin and eosin
as bright pink, homogeneous structures that are circular in
cross section with a diameter up to 25 µm, and rectangu-
lar or spindle shaped up to 30 µm in length in longitudinal
sections. Ultrastructurally, they are composed of a complex,
crystalline array of interlacing filaments forming a lattice-
like or ‘herringbone’ configuration (Tomonaga, 1974). It
has been reported that they stain positively with antibodies
to actin (Goldman, 1983) and immunostaining for tau
(Galloway et al., 1987).
46.4.5 NEURONAL LOSS
Neuronal loss is far more difficult to assess than the his-
tological abnormalities previously described, although the
decrease of particular neuronal populations is more readily
accepted than in normal ageing (Terry, 1990). While well-
defined, neuronal groups, like the locus ceruleus, are easier
to count, the cerebral cortex presents considerable technical
problems. Nevertheless, it has been established that there
is a significant decrease of 36%–46% in the concentration
of large neurones, particularly from layers III and V of the
neocortex (Terry et al., 1981). The loss of the large corti-
cal neurones is age dependent: the column of these cells is
reduced in patients under 80 years of age, but appears to be
normal for age in older subjects (Hubbard and Anderson,
1985). This neuronal loss, however, does not affect the
neocortex evenly; it appears to be restricted to the fron-
tal and temporal lobes, whereas the parietal and occipital
regions are less involved (Mountjoy et al., 1983). The hip-
pocampus is even more severely affected: neuronal fall out
reaches an average of 47% (Ball, 1977) and the number of
pyramidal neurones is reduced by 40% in area H1 (Mann
et al., 1985). This loss appears to correlate with the num-
ber of tangle-bearing cells, while the end plate and area H2
are less affected. There is also a substantial decrease of neu-
rones in the cholinergic nbM (Whitehouse et al., 1981), in
the cholinergic pedunculopontine nucleus (Jellinger, 1988),
in the noradrenergic locus ceruleus (Tomlinson et al., 1981;
Marcyniuk et al., 1986) and in the serotonergic raphé nuclei
in the brainstem (Yamamoto and Hirano, 1985).
46.4.6 ABNORMALITIES OF NEURONAL
PROCESSES AND SYNAPSES
Neuropil threads or ‘curly’ fibres and dystrophic neurites have
been well documented in silver impregnated preparations
developed by Gallyas (1971), but they attracted attention when
it was realized that their occurrence was associated with the
severity of dementia (Braak et al., 1986). Neuropil threads or
curly fibres are slender, short structures found in the neuropil
of the cortex. Dystrophic neurites, some of which contribute to
the formation of plaques, also appear as somewhat contorted,
thread-like structures in these preparations. These abnormal
neurites are likely to be a heterogeneous population of den-
drites and axons (Tourtellotte and Van Hoesen, 1991). Their
ultrastructural and immunocytochemical features are strik-
ingly similar to those of NFTs, indicating that they also origi-
nate from the altered neuronal cytoskeleton. Neuropil threads
immunostain with antibodies to tau (Kowall and Kosik, 1987;
Probst et al., 1989) and to ubiquitin (Joachim et al., 1987).
Electron microscopy has revealed that they are often in den-
drites and contain straight filaments of 14–16 nm in diameter
in addition to paired helical filaments (Tabaton et al., 1989;
Yamaguchi et al., 1990b). Moreover, they are often in the

dendrites of those nerve cells that contain NFTs in their cell
body (Braak and Braak, 1988). There is increasing evidence
that their distribution is more closely associated with NFTs
than with plaques. Considerable decrease of synapses also
occurs and this loss is likely to contribute to the development
of the disease (Davis et al., 1987). Moreover, immunocyto-
chemical quantification of synaptophysin, a protein localized
in presynaptic terminals, revealed an average decrease of 50%
in the density of the granular neuropil immunoreaction in
the parietal, temporal and midfrontal cortex (Masliah et al.,
1989). In the electron microscope, some presynaptic terminals
were distended and contained altered synaptic organelles,
including swollen vesicles and dense bodies, similar to those
seen in dystrophic neurites. These latter structures gave posi-
tive staining with antibodies to synaptophysin and immu-
noreactivity was mainly localized to the outer membranes of
synaptic vesicles and dense bodies. This finding lends further
support to the view that progressive synaptic derangements
occur in the neocortex of AD (Masliah et al., 1991).
46.4.7 GLIAL CHANGES
Astrocytes can be readily observed immunohistochemi-
cally by using an antibody to glial fibrillary acidic protein
(GFAP; see Figure 46.12). Both NFTs and plaques are more
prevalent in the pyramidal cell-rich layers II, III and V than
in other laminae (Mann et al., 1985; Majocha et al., 1988;
Braak et al., 1989), and both have been associated with pat-
terns of gliosis in AD (Itagakai et al., 1989; Cairns et al.,
Figure 46.12 Astrocyte cell bodies and processes
encircling a plaque. Glial fibrillary acidic protein
immunohistochemistry.
The neuropathology of Alzheimer’s disease 477
1992), where perivascular gliosis is prominent throughout
the cerebrum. In AD, extensive gliosis has a laminar pat-
tern in the neocortex, but there does not appear to be an
AD-specific pattern of subcortical gliosis. In addition to
NFTs, plaques and dystrophic neurites, reactive astrocyto-
sis is associated with degenerating neurones in AD. In the
pathogenesis of the plaque Aβ deposition appears to be an
early event preceding gliosis (Yamaguchi et al., 1990a).
The presence of major histocompatibility complex
(MHC) class II antigens on reactive microglia in association
with plaques in AD is indicative of an immune response,
although the significance of such expression on the cell
surfaces of reactive microglial cells is uncertain. Reactive
microglial cells have been found in association with dif-
fuse Aβ deposits and, more frequently, with compact cores
of plaques (Itagakai et al., 1989). Leucocyte common anti-
gen and complement receptors – including the cell adhe-
sion molecules, the β-2 integrins – have been localised on
microglial cells around plaques. These data are consistent
with a phagocytic role for microglia and provide evidence
for an innate immune response of brain tissue in AD.
46.4.8 VASCULAR ABNORMALITIES
When stained with the dye Congo red, cerebral blood ves-
sels containing amyloid appear apple green under polarized
light. Pantelakis (1954) called this deposition congophilic
angiopathy (see Figure 46.8). These changes affect lepto-
meningeal and cortical arterioles, and occasionally intra-
cortical capillaries and venules. The parieto-occipital cortex
is usually more affected than that in the frontal and tem-
poral lobes and the change is most easily identified in the
striate cortex in the occipital lobe. The brainstem and cer-
ebellar cortex are less frequently affected. The occurrence
of ACA in conjunction with AD is quite common (Keage
et al., 2009).
Vascular amyloid is the same protein as the Aβ amyloid
found in plaques. Although vascular amyloid is frequently
present in AD, it may be absent even when there are abundant
plaques and parenchymal deposits. Occasionally, Aβ appears
to extend from the vessel wall into the surrounding cerebral
tissue; this is referred to as dyshoric angiopathy (or the drusige
Entartung of Scholz). This is commonly seen in lamina III of
the striate cortex and adjacent occipital cortex, occasionally
in Ammon’s horn and in the cerebellum (Hauw et al., 1991).
At least three forms of autosomal dominant familial cere-
bral amyloid angiopathy have been identified at the molecu-
lar level. In the Dutch (Levy et al., 1990) and Icelandic forms,
patients suffer from recurrent cerebral haemorrhages that lead
to an early death (before 40 years of age in Icelandic patients,
and between 50 and 60 years in Dutch patients). The amyloid
fibrils in patients with the Icelandic type are made up of cys-
tatin C, a degradation product of a larger protease inhibitor.
In the Dutch patients the amyloid fibrils are composed of the
same Aβ protein found in amyloid angiopathy in AD, Down’s
syndrome and sporadic amyloid angiopathy. In British and
Danish pedigrees, another form of diffuse cerebrovascular
478 Dementia
amyloidosis has elucidated the Worster-Drought syndrome
(Masters and Beyreuther, 2001) in which another novel amy-
loidogenic peptide aggregates in the brain.
46.4.9 WHITE MATTER CHANGES
Although the degenerative process in AD primarily affects
the grey matter, the white matter may not be spared. CT
scans may show areas of hypodensity. The precise patholog-
ical substrate remains controversial. Since amyloid angiop-
athy is often part of AD, it is possible that the white matter
changes result mainly from vascular causes. Symmetrical,
incomplete infarctions of the white matter histologically
correspond to partial loss of myelin sheaths, axons and oli-
godendrocytes. These changes are accompanied by mild
astrocytosis and macrophage response, while there is hya-
line fibrosis of small vessels. Cavitating infarctions do not
develop and this white matter damage, which occurs in the
absence of hypertensive vascular degeneration, is thought
to be caused by hypoperfusion (Brun and Englund, 1986).
However, severe loss of cortical neurones may also contrib-
ute to fibre loss and consequent pallor of white matter.
46.5 FAMILIAL AUTOSOMAL
DOMINANTLY INHERITED AD
(FAD)
AD is a disease primarily of old age and it is difficult to deter-
mine the proportion of genetic cases as many family members
will die before expressing the disease. Familial forms of AD
with multiple affected individuals are rare and account for
probably fewer than 5% of AD cases. Mutations in the APP
gene and two related genes, presenilin-1 (PS1) and preseni-
lin-2 (PS2), account for the majority of early-onset autosomal
dominant cases of familial AD (Lamb, 1997) (see Chapter
50). Although clinical features may differ between fami-
lies, the neuropathological features are not markedly differ-
ent between FAD and early-onset sporadic cases. However,
prominent cerebellar plaques and Aβ deposition have been
reported in familial cases (Iseki et al., 1990; Struble et al., 1991;
Fukutani et al., 1996, 1997). Computerized methods of image
analysis have been used to more accurately define the patho-
logical phenotype of AD. Using these techniques, differences
in Aβ load have been reported. Mann et al. (1996a, 1996b)
have shown that both APP and presenilin (PS) mutations lead
to measurable increases in Aβ load. More recent studies using
PET-amyloid ligands show a very distinctive accentuation of
Aβ amyloid in the striatum (Villemagne et al., 2009).
In those cases with an early onset, below 65 years of age,
the duration of illness tends to be shorter, and the density
of NFTs and plaques is often greater than in sporadic, late-
onset patients. Cortical and brainstem Lewy bodies may
coexist with AD in APP (Lantos et al., 1992) and PS muta-
tion patients (Figure 46.13). It is now known that the Lewy
body and dystrophic neurites of Parkinson’s disease and
Figure 46.13 Lewy bodies (L) and dystrophic neurites
(N) in the midbrain of a patient who died with famil-
ial Alzheimer’s disease with the amyloid precursor
protein 717 valine–isoleucine mutation. α-Synuclein
immunohistochemistry.
dementia with Lewy bodies contain the protein α-synuclein
(Spillantini et al., 1997). Familial and sporadic forms of AD
may also be found in combination with cerebrovascular dis-
ease. Rare sporadic cases of AD have been found in com-
bination with other neurodegenerative disorders including
Pick’s disease, Creutzfeldt–Jakob disease, motor neurone
disease and progressive supranuclear palsy.
46.6 PATHOGENESIS
While the cause of AD is now clearly defined as the cere-
bral deposition of Aβ amyloid, the pathogenesis of AD is
not fully understood. Although many risk factors have been
proposed, the evidence for most of these is weak except for
age, family history and ApoE genotype (Alafuzoff et al.,
2009; Chen et al., 2009). A genetic contribution to the aeti-
ology of AD has received strong support in recent years and
it is likely that more genes (such as BIN1, CLU, ABCA7,
CRI, PICALM, MS4A6A, CD33, MS4A4E, CD2AP from the
Alzgene top results, April 2015) will be associated with the
disease. In the more common non-familial, sporadic cases,
and in discordant monozygotic twins, environmental fac-
tors may be important in the aetiology.
The discovery of mutations in the APP and PS genes, all of
which lead to overproduction of Aβ or preferential production
of a long 42-amino acid form of Aβ, has confirmed the cen-
tral role of APP and Aβ deposition in the pathogenesis of AD
(Lamb, 1997). Deposition of Aβ appears to be an early event in
both AD and Down’s syndrome and precedes the development
of plaques, NFTs, microgliosis and astrocytosis (Rozemuller
et al., 1989; Woltjer et al., 2009). The amyloid deposits char-
acteristic of AD, 42- to 43-amino acid Aβ fragments, are the
abnormal proteolytic cleavage products of APP. Aβ has both
toxic (Yanker et al., 1989) and trophic effects on neurones in
culture, which may relate to plaque and NFT formation.

Metal ions such as aluminium, iron, copper and zinc
have been implicated as an environmental toxic agent in the
pathogenesis of AD. Accumulations of aluminosilicates and
iron in the central region of the core of plaques and within
neurones containing NFTs have been reported (Candy
et al., 1986). Another environmental factor implicated in Aβ
deposition is head trauma. Although Roberts et al. (1991)
showed that in a series of patients suffering sustained head
injury, there were extensive deposits of Aβ in the neocortex,
longer-term follow-up studies have failed to confirm any
association (Chen et al., 2009).
Although varying amounts of Aβ with a range of morphol-
ogies may be found in cognitively normal elderly individuals,
it is quantitatively much more severe and cytoarchitectoni-
cally defined in AD (Majocha et al., 1988; Cairns et al., 1991).
The importance of overexpression of APP and its abnormal
cleavage product, Aβ, in the pathogenesis of AD has been
demonstrated by transgenic mouse models (Borchelt et al.,
1998). Transgenic mice expressing the full-length human APP
develop Aβ deposits similar in morphology to those found in
AD, but as noted above, differing somewhat in their human
‘subtype’ counterparts. These animal models will be useful for
testing anti-amyloid drugs (Morrissette et al., 2009).
46.7 NEUROPATHOLOGY AND
CLINICAL FINDINGS
Alzheimer first suggested a correlation between the presence
of NFTs, plaques and dementia in 1906. Roth et al. (1966) and
Wilcock and Esiri (1982) demonstrated that elderly patients’
mental test scores correlated with the neuropathological
lesions characteristic of AD. Many other neuropathological
(Nelson et al., 2009) and neurochemical changes (Zubenko
et al., 1991) have been associated with AD and the accuracy
of clinical diagnosis ranges from 43% to 87% (Boller et al.,
1989; Jellinger et al., 1990) and, in one sample of 26 cases,
100% (Morris et al., 1988). Conversely, inaccuracy in the ante-­
mortem diagnosis of AD is common, and for this reason, post-
mortem examination remains an essential component of AD
research. An accurate differential diagnosis is made difficult
by the problems of distinguishing between mild dementia
and the cognitive changes of ‘normal ageing’. Mild cognitive
impairment is the earliest clinically recognizable form of AD,
which is now being evaluated with in vivo neuroimaging of
Aβ load using PET radioliogands (Villemagne et al., 2013).
Although not all studies have produced positive findings,
there is general agreement that cases with earlier onset,
shorter duration of illness and greater cognitive impair-
ment have more cortical plaques, whereas late-onset cases
that take a milder course tend to show less cortical change
(Bowen et al., 1979; Hansen et al., 1988). High correlations
were observed between cognitive performance and plaque
counts in brain biopsies from dementing patients exam-
ined earlier in the course of illness (Mann et al., 1986, 1988;
Neary et al., 1986). Plaques and NFTs were detected in 38
The neuropathology of Alzheimer’s disease 479
(75%) of 51 unselected non-demented patients who died
between the ages of 55 and 64 years (Ulrich, 1985). These
lesions were consistently found in the entorhinal cortex, the
hippocampus, or both, suggesting that this region is a site
of origin of the lesions. A morphometric analysis of cere-
bral slices by de la Monte (1989) showed that patients with
‘preclinical’ AD had shrinkage of white matter comparable
to that found in AD, yet the cortical areas were normal,
suggesting that white matter degeneration is an intrinsic
component of AD. In clinical AD, there was global cerebral
atrophy of both cortex and white matter. Neuronal death
in patients with AD is closely associated with extensive
synapse loss in the neocortex and this has been correlated
with cognitive impairment (Terry et al., 1991). Measures of
the morphological substrates of brain function frequently
show an overlap between AD and control groups (Coleman
and Flood, 1987). There does not appear to be a consistent
relationship between the pattern of vascular amyloid and
the distribution of plaques. Neither is there a correlation
between vascular amyloid and dementia (Mountjoy et al.,
1982). More recent studies have confirmed that the Aβ
amyloid per se is probably not the best indicator of severity
of disease – rather, the soluble Aβ, which are a prelude to
plaque formation show a closer correlation with the degree
of neurodegeneration (Mclean et al., 1999). With the advent
of molecular imaging probes for Aβ, many of the above
issues will be resolved (Jack et al., 2009).
46.8 DIAGNOSTIC PROBLEMS AND
CRITERIA
Despite the fact that the neurohistological abnormalities of
AD have been established, the neuropathological diagnosis
is not always straightforward (Cruz-Sánchez et al., 1995).
There are several reasons to explain this problem. First, the
histopathology of AD is complex and the various abnormal-
ities described previously, when severe and extensive, enable
a diagnosis to be made. However, there are considerable
differences from case to case and this histological hetero-
geneity of disease presents the most formidable difficulties
for the neuropathologist. The severity and distribution of
any of the histological lesions may considerably vary and
are influenced by the age and genetic background of the
patient, among other factors. Quantitative morphometry
and neurochemistry have supported the view that AD is not
a uniformly diffuse disorder: morphological abnormalities
and neurochemical deficits tend to be more severe and more
extensive in younger patients. There may be subtle differ-
ences in the pathology of familial and sporadic cases, and
atypical cases exist both in the familial and sporadic forms.
Second, although there are several histological abnormali-
ties in AD, only Aβ deposition approaches a level of speci-
ficity, since many of these lesions occur in normal ageing
and in other diseases of the nervous system. Third, AD may
concurrently occur with other diseases, most commonly
480 Dementia
with vascular disease and more rarely with other neurode-
generative disorders.
For these reasons, it is important to establish a set of
neuropathological or neurochemical criteria. Although
several attempts have been made, no universally accepted
criteria exist for the neuropathological diagnosis of AD.
An attempt has been made to define AD in terms of hip-
pocampal pathology. Based on quantitative morphometry,
it was suggested that more than 20 tangle-bearing neurones
per mm3 and fewer than 5600 neurones per mm3 should
be diagnostic. This threshold, however, has proven too low
and would include 30% of mentally normal elderly people
(Anderson and Hubbard, 1985). A North American panel
of neuropathologists has recommended age-adjusted plaque
and tangle counts. In patients under 50, plaques and tangles
in excess of 2–5 per mm2 in the neocortex should secure the
diagnosis of AD. Between 60 and 65 years, there should be
more than 8 plaques per mm2, between 66 and 75 years more
than 10 and over the age of 75, more than 15. In the first two
age groups, some neurofibrillary tangles may be found, but
in the last group these may not be necessary for diagnosis
(Khachaturian, 1985). The value of these criteria has, how-
ever, been diminished by the statement that these figures
can be revised downwards by as much as 50% in the pres-
ence of positive clinical history of AD. A survey of the prac-
tical application of these criteria has revealed considerable
variations in the use of criteria and the methods of exami-
nation (Wisniewski et al., 1989). A European Multicentre
Study found that subjective assessment currently was more
reliable to compare cases from different laboratories, since
quantitative values are greatly influenced by the neurohisto-
logical technique employed (Duyckaerts et al., 1990).
The most widely used protocol for neuropathologi-
cal assessment is that developed by the Task Force of the
Consortium to Establish a Registry for AD (CERAD). This
takes clinical findings into consideration, and neuropatho-
logical criteria for ‘definite’, ‘probable’ and ‘possible’ AD
are proposed (Mirra et al., 1991). This system is based on
a semi-quantitative assessment of plaque scores. The pres-
ence or absence of tangles does not enter into the formal
assessment. The more recent National Institute on Aging
and Reagan Institute (NIA-RI) criteria require both semi-
quantitative measures of plaque and tangle distribution
and additional sampling (Hyman and Trojanowski, 1997).
A change from previous criteria is the opinion that any
Alzheimer lesions should be considered as pathological
even when they appear to be incidental. By acknowledging
that a spectrum of changes exists within AD, these criteria
may prove more successful than previous ones (Hyman and
Trojanowski, 1997).
In the final analysis, it is likely that a combination of
morphologic and biochemical assays will yield a set of cri-
teria through which a secure diagnosis of AD will be made.
Current indications are that blood, CSF and brain tissue
levels of Aβ (soluble, insoluble), tau, ApoE and BACE may
provide a more practical method for the diagnosis and ther-
apeutic monitoring of AD (McLean et al., 1999; Holsinger
et al., 2002, 2004; Bates et al., 2009; Craig-Shapiro et al.,
2009; Fagan et al., 2009; Woltjer et al., 2009).
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Neurochemistry of Alzheimer’s disease
PAUL T. FRANCIS
47.1 INTRODUCTION
The demonstration of deficits in choline acetyltransfer-
ase (ChAT) activity in patients dying with Alzheimer’s
disease (AD) (Bowen et al., 1976; Davies and Maloney,
1976), together with human anticholinergic drug studies
(Drachman and Leavitt, 1974) led to the eventual develop-
ment of cholinesterase inhibitors (ChEIs) for the symptom-
atic treatment of AD. Present neurochemical investigations
of this system attempt to understand how early the choliner-
gic deficit develops and the extent to which it occurs in mild
cognitive impairment (MCI). In addition, recognition of the
role of the glutamatergic system in learning and memory
has prompted study of biochemical markers of the major
excitatory neurotransmitter system. Anatomical studies
suggest interconnectivity between glutamatergic and cho-
linergic systems but their exact role in AD still requires
further elucidation. Just as cholinergic and glutamatergic
disruption may be additive in contributing to cognitive and
behavioural symptoms of dementia, so can pharmacologi-
cal replacement therapy be synergistic (Francis et al., 1993,
2010b; Francis, 2005).
The amyloid cascade hypothesis has undergone many
revisions but still provides a framework in which to under-
stand disease progression in AD (Hardy, 2006). It is widely
accepted that neurotransmitter deficits, neuronal and syn-
apse loss and subsequent decline are final consequences of
this cascade.
47.2 NEUROCHEMISTRY
From a neurochemical standpoint, acetylcholine (ACh),
glutamate, serotonin and noradrenaline are the major
transmitter systems affected in AD with relative sparing of
dopamine, γ-aminobutyric acid (GABA) and most peptides
486
47
(Francis et al., 1993, 2010b). This chapter examines both
cognitive and non-cognitive (behavioural) correlates of
neurotransmitter dysfunction, the latter also being consid-
ered to relate to structural and functional alterations in the
central nervous system (CNS). Such changes are important,
partially because carers find behavioural disturbances dif-
ficult to cope with and the presence of such behaviours in
AD patients often leads to institutionalization. This chap-
ter focuses on cholinergic and glutamatergic systems; for a
comprehensive review of neurotransmission in AD see Lai
et al. (2007).
47.2.1 ACETYLCHOLINE
Neuropathologically, loss of neurones from the nucleus of
Meynert (Ch4 cholinergic nucleus) is well documented in
AD, although, the extent of the loss reported varies from
moderate to severe and it has been suggested that in AD
cholinergic dysfunction exceeds neuronal degeneration
(Perry et al., 1992). This is consistent with studies of cholin-
ergic markers in biopsy samples from patients who had AD
for approximately 3 years, where reduction in functional
cholinergic measures, acetylcholine synthesis and choline
uptake exceeded the reduction in choline acetyltransferase
(ChAT) activity (Francis et al., 1985).
On the basis of the aforementioned evidence, neocortical
cholinergic innervation appears to be lost at an early stage
of the disease. Beach et al. (2000) reported neurofibrillary
tangles (NFTs) in entorhinal cortex and a 20%–30% loss of
ChAT activity in brains from patients in the earliest stages of
AD, namely Braak stages I and II and tangle formation in the
main cholinergic nucleus is present in MCI (Mesulam et al.,
2004). However, another study using the Clinical Dementia
Rating scale (CDR) suggests that the greatest reduction in
markers of the cholinergic system occurs between moderate
(CDR 2.0) and severe (CDR 5.0) disease with little change
between the non-demented patients and those in the mild
stages of dementia (CDR 0-2) (Davis et al., 1999). In contrast

to a study on MCI, the suggested AD prodromal reported
an increase in ChAT activity in some cortical regions
(DeKosky et al., 2002). The acknowledged problems of these
latter studies is that ChAT activity is not the rate-limiting
step of ACh synthesis and hence, there could be cholinergic
dysfunction before structural loss, possibly linked to aber-
rant sprouting. Changes in cholinergic neurones appear to
relate to aspects of cognitive function (Francis et al., 1985)
as well as non-cognitive behaviour (Minger et al., 2000;
Gauthier et al., 2002). It has also been suggested that ace-
tylcholine (Ach) is centrally involved in the process of con-
scious awareness (Perry et al., 1999) and that, the variety
of clinical symptoms associated with cholinergic dysfunc-
tion in AD and related disorders reflects disturbances in the
conscious processing of information.
Nicotinic and muscarinic (M2) ACh receptors, most
of which are considered to be located on cholinergic ter-
minals, are reduced in AD (Court et al., 2001; Lai et al.,
2001). Reductions in nicotinic receptors are confined to the
α4β2 subtype. The postsynaptic cholinergic system (usu-
ally present upon glutamatergic neurones) appears to be
less affected, which is a hopeful sign for therapeutic inter-
vention. Postsynaptic muscarinic M1 receptors (Perry et
al., 1990) are relatively preserved, although, there may be
a degree of functional uncoupling (Tsang et al., 2006). The
enzyme responsible for the breakdown of ACh acetylcho-
linesterase, is reduced, perhaps in part, due to a loss of cho-
linergic terminals, while butyrylcholinesterase activity (the
function of which is not yet fully understood and which is
present in extrasynaptic areas and plaques), increases (Perry
et al., 1978).
47.2.2 ACETYLCHOLINE AND COGNITION
A prediction of the cholinergic hypothesis is that, drugs
likely to potentiate this function should improve cognition
in AD patients. There are a number of treatment approaches
to the amelioration of the cholinergic deficit; however, the
use of acetylcholinesterase inhibitors (AChEIs) is the most
well-developed approach till date (Francis et al., 1999).
During the late 1980s and early 1990s, the first cholino-
mimetic compound, tacrine, underwent large-scale clinical
studies and the ChEI treatment benefits were established in
patients with probable AD. A so-called second-generation
of ChEIs has been developed including donepezil, rivastig-
mine and galantamine (Francis et al., 1999; Wilkinson et
al., 2004). Such compounds demonstrate a clinical effect
and magnitude of benefit of at least that reported for tacrine,
but with a more favourable clinical profile. Evidence has
emerged from clinical trials of ChEIs that such drugs
may improve the behavioural symptoms of AD patients.
Physostigmine, tacrine, rivastigmine and donepezil have
variously been reported in placebo-controlled trials to
decrease psychotic symptoms, agitation, apathy, anxiety,
disinhibition, pacing, aberrant motor behaviour (inability
to sit still) and lack of cooperation (Cummings et al., 2008).
In one study, muscarinic acetylcholine M2 receptor density
Neurochemistry of Alzheimer’s disease 487
was increased in the frontal cortex of AD patients with
delusions and in the temporal cortex of those with halluci-
nations and then compared with patients without psychotic
symptoms. This suggests a role of M2 receptors in the psy-
chosis of AD and may provide the rationale for treatment of
behaviourally disturbed AD patients with M2 antagonists
(Lai et al., 2001).
Related to these findings in AD, a study of rivastigmine
in patients with Parkinson’s disease dementia showed a
positive outcome (Emre et al., 2004); such patients have a
greater cholinergic deficit than AD patients (Perry et al.,
1994).
47.2.3 GLUTAMATE
Glutamate is the principal excitatory neurotransmitter of
the brain, being used at approximately two-thirds of syn-
apses and as a consequence, the majority of neurones and
glia have receptors for glutamate. An integral part of pro-
tein, energy and ammonia metabolism of all cells with a
high intracellular concentration, it has been difficult to dis-
tinguish the presynaptic transmitter pool of glutamate from
the metabolic pool (Francis et al., 1993). Considered to be
the main neurotransmitter of neocortical and hippocampal
pyramidal neurones, glutamate is thus involved in higher
mental functions such as cognition and memory (Francis
et al., 1993). An important mechanism by which glutamate
may contribute to learning and memory functions is via
long-term potentiation (LTP) at pyramidal neurone syn-
apses (Baudry and Lynch, 2001). LTP is a form of synaptic
strengthening following brief high-frequency stimulation.
Histological AD studies indicate loss of pyramidal neu-
rones and their synapses together with surrounding neu-
ropil (Esiri, 1991). Corticortical and corticofugal-projecting
pyramidal neurones are lost together with those of the ento-
rhinal and hippocampal CA1 region. Remaining neurones
are subject to NFT formation. Uptake of d-aspartate, a
putative marker of glutamatergic nerve endings, is reduced
in many cortical areas in AD brains (Procter et al., 1988).
Biochemical evidence suggests a presynaptic ‘double
blow’ as the activity of glutamatergic neurones is heavily
influenced by the cholinergic system, also dysfunctional
in AD patients. The clinical relevance of these changes is
emphasized because glutamatergic and cholinergic dys-
function are both strong correlates of cognitive decline in
AD. Glutamatergic (and cholinergic) cells die over a period
of years and in a very specific regional and neurochemi-
cally selective pattern (Francis et al., 2012). The selectiv-
ity is intriguing because cholinergic neurones of the basal
forebrain dies while those of the pons are spared; glutama-
tergic neurones of the frontal, temporal and parietal cor-
tex are lost while apparently similar neurones in the motor
and sensory cortex are unaffected. Factors that may lead to
necrosis or apoptosis in selected groups of neurones in AD
may include tangles, Aβ toxicity, microglia, free radical gen-
eration, excitotoxicity (too much and too little glutamater-
gic neurotransmission) and withdrawal of trophic factors.
488 Dementia
The strongest evidence suggests that most of glutamatergic
pyramidal neurones die as a consequence of the presence
of NFTs within the cytoplasm (Kowall and Beal, 1991).
However, this may only account for up to 50% of such cells.
Glutamate is synthesized in nerve terminals by one of
several possible enzymes. First, glutamine can be converted
to glutamate by the action of the mitochondrial enzyme
glutaminase (Procter et al., 1988); alternatively glutamate
can be produced by transamination from aspartate in
the cytosol. Direct measurement of glutaminase activity
was unaffected in AD (Procter et al., 1988). By contrast,
glutaminase-positive neurones were reduced in number
and subject to tangle formation (Kowall and Beal, 1991).
Several groups have shown reductions in the concentra-
tion of glutamate in AD tissue and lumbar CSF (Lowe et al.,
1990). Although, glutamate neurotransmission failure was
not extensive in these studies, glutamate concentration was
reduced by 14% in temporal lobe biopsy samples and by 86%
in the terminal zone of the perforant pathway at autopsy of
AD patients (Hyman et al., 1987).
More recent investigations have examined the status of
the vesicular glutamate transporters (VGLUT), VGLUT1
and VGLUT2 (Bellocchio et al., 2000). These proteins are
only present in the glutamatergic neurone terminals and
therefore, represent a useful marker of their number.
Studies indicate that there is a reduction in VGLUT1 (but
not VGLUT2) in parietal and occipital cortex in AD but
not in temporal cortex (Kirvell et al., 2006). Other studies
link this reduction to cognitive impairment (Kashani et al.,
2008).
Upon release into the synapse, approximately 95% of
glutamate is removed by glutamate transporter proteins
present upon glial cells named GLT, GLAST and EAAC
(Danbolt, 2001). Reductions in glutamate uptake in AD
cases have been reported in fresh (unfrozen) post-mortem
brains (Procter et al., 1994). Antibodies directed against
the individual glutamate transporters reveal conflicting
data. Reduced levels of GLT protein (but not its messen-
ger ribonucleic acid [mRNA]), with normal levels of both
GLAST and EAAC have been reported (Danbolt, 2001).
Even on assuming there was no reduction of transporter
protein, there is considerable evidence for oxidative dam-
age of proteins such as these glutamate transporters (Begni
et al., 2004). This might explain the functional deficit in
glutamate uptake identified above and is likely to lead to
elevations in synaptic concentrations of glutamate (Francis,
2009; Francis et al., 2012).
47.2.4 GLUTAMATE AND COGNITION
A role for glutamate and glutamate receptors in learning and
memory is widely recognized. For example, N-methyl-d-
aspartate (NMDA) antagonists impair learning and mem-
ory, while NMDA agonists and facilitators improve memory
(Francis et al., 1993). Likewise, AMPAkines (positive mod-
ulators of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-
propionic acid [AMPA] receptor function) facilitate learning
and memory (Lynch, 1998). Circumstantial evidence of the
involvement of glutamatergic pathways includes the well-
established role of structures such as, the hippocampus in
learning and memory. More specifically, lesions of certain
glutamatergic pathways impair learning and memory. In
addition, glutamate and glutamate receptors are involved
in mechanisms of synaptic plasticity (LTP and long-term
depression or LTD, of the synapse), which are considered to
underlie learning and memory (Baudry and Lynch, 2001).
Loss of synapses and pyramidal cell perikarya from the
neocortex of AD patients correlates with measures of cog-
nitive decline and is considered to be the best evidence of
a functional role of glutamatergic involvement in cognitive
dysfunction of AD patients (Francis et al., 1993).
47.2.5 THE GLUTAMATERGIC SYSTEM
AND AD PATHOLOGY
Excitotoxic cell death involves excess activation of receptors,
leading to raised intracellular Ca2+ and consequent acti-
vation of a cascade of enzymes, resulting in cell death by
necrosis or apoptosis (Lipton, 1999). During the 1980s
it was also suggested that endogenous glutamate could
accumulate and become excitotoxic, perhaps, as a result
of impaired clearance (as a consequence of disrupted
transporter function or indirectly in conditions of reduced
energy availability). There is some evidence that energy lev-
els may be reduced in AD due to perturbed mitochondrial
function (Francis et al., 1993) and considerable evidence
for oxidative damage of proteins including the glutamate
transporter (Keller et al., 1997). Others have cautioned that
there is no simple relationship between raised extracellular
glutamate concentrations and cell death in vivo. It remains
possible that changes in numbers of glutamate receptors or
changes in ion selectivity may lead to cell death over time.
For instance, the large numbers of calcium-permeable
AMPA receptors present on basal forebrain cholinergic
neurones may be linked to their loss in AD (Ikonomovic
and Armstrong, 1996).
The glutamatergic system is a significant target for
AD-related pathology in which tangles occur principally in
glutamatergic pyramidal neurones, these cells are lost and
much of the observed synaptic pathology will involve these
cells. Tangles, cell and synapse loss are the strongest cor-
relates of cognitive impairment in AD patients (Neary et
al., 1986; Terry et al., 1991). There is also an emerging role
of tangle formation within pyramidal neurones of specific
brain regions as a causative mechanism of agitation and
aggression in AD (Tekin et al., 2001; Guadagna et al., 2012).
47.2.6 INTERACTIONS BETWEEN
CHOLINERGIC AND
GLUTAMATERGIC SYSTEMS
It is important to remember that glutamatergic neurones of
the neocortex and hippocampus are influenced by acetyl-
choline through nicotinic and muscarinic receptors (Dijk

et al., 1995; Chessell and Humphrey, 1995). Terminals of
cholinergic neurones are found in all layers of the neo-
cortex, synapsing with pyramidal neurones in layers II/III
and V (Turrini et al., 2001). Both muscarinic and nicotinic
receptors activate pyramidal neurones and hence, facili-
tate glutamate release in rat model receptors (Chessell and
Humphrey, 1995; Dijk et al., 1995). Thus, under activity
of the cholinergic system, it is likely to have effects on the
activity of the glutamatergic system and conversely, it fol-
lows that treatment of patients with cholinomimetics which
is likely to increase glutamatergic function.
47.2.7 TREATMENT STRATEGIES BASED
ON FACILITATING GLUTAMATERGIC
NEUROTRANSMISSION
Cholinergic stimulation is one pathway to enhance gluta-
matergic function. Other treatment strategies that more
directly increase the activity of remaining glutamater-
gic neurones, without causing excitotoxicity, represent an
important target for the symptomatic treatment of AD and
may have a disease modifying effect. Several approaches
have been tried, including positive modulation of both
AMPA and NMDA receptors. AMPAkines, which are con-
sidered to work by increasing the sensitivity of these recep-
tors, have been in clinical trial for MCI but with modest
success (Johnson and Simmon, 2002).
Perhaps, the most surprising development is the suc-
cess of the un-competitive NMDA antagonist meman-
tine in clinical trials in moderate and severe AD patients
(Reisberg et al., 2003). One would normally consider that
such an approach – blockade of a receptor that would
normally be activated in learning and memory – would
be counter-intuitive. However, there is evidence that this
molecule acts like the endogenous NMDA antagonist,
magnesium ions, able to prevent background activation of
the NMDA receptor (‘noise’), while allowing activation of
this receptor for LTP formation (Francis et al., 2012). The
observed effects of memantine on agitation and aggression
may be explained by this mechanism; however, there is
preclinical evidence to suggest that this drug is capable of
altering the phosphorylation state of tau, the precursor to
tangle formation (Francis, 2009). There is also evidence of
a benefit of the addition of memantine to established treat-
ment with a ChEI in AD patients (Tariot et al., 2004). Since
ChEIs are likely to act in part by increasing glutamate
release (‘signal’) (Dijk et al., 1995; Francis et al., 2012), the
benefit may be hypothesized to come from the combina-
tion of a reduction in glutamate ‘noise’ (by memantine)
and an increase in discrete glutamate signals (donepezil)
(Francis et al., 2012).
47.2.8 SEROTONERGIC SYSTEMS IN AD
Extensive serotonergic denervation of the neocortex and
hippocampus has been reported in AD; however, the con-
tribution of such changes towards clinical symptoms is
Neurochemistry of Alzheimer’s disease 489
complex. Reduction of 5-HT as well as its metabolites (nota-
bly 5-hydroxyindolacetic acid, 5-HIAA) has been reported
in many studies of post-mortem AD brains and studies of
neurosurgical biopsy material (Francis et al., 2010a). There
is also evidence of plasticity in the serotonergic system as
the ratio 5-HIAA/5-HT is often found to increase in both
frontal and temporal cortex. With respect to serotonergic
receptors, the picture is equally complex with region specific
changes that relate to the presence of behavioural symptoms
with particular links to agitation.
Because of the widespread influence of the serotonergic
system on pathways important for cognition and behaviour,
together with the receptor diversity, this system has con-
siderable potential for pharmacological manipulation. The
rationale for targeting 5-HT2A receptors for some behav-
iours and 5-HT6 for cognition and behaviour is at the fore-
front of clinical studies (Ramirez et al., 2014).
47.3 CONCLUSION
The changes in cholinergic neurotransmission seen in the
brains of patients dying with AD provided the rationale
for the development of compounds aimed at symptomatic
relief. Treatment of AD patients with ChEIs has confirmed
the relevance of this finding. However, it has long been rec-
ognized that the major changes in AD are likely to involve
the abundant cortical glutamatergic pyramidal neurones.
Hence, there is a need for this change to be addressed. Since
increasing cholinergic function will also increase glutama-
tergic activity, there may be synergistic benefit from co-
administration of drugs that target both the cholinergic
system (ChEIs) and glutamatergic systems (memantine).
There is renewed effort to identify improved symptomatic
treatments to combine with ChEIs and memantine and
serotonergic agents are at the forefront of these efforts. As
disease modifying treatments become available, it is likely
that symptomatic therapy will continue to be required and
indeed there is evidence that such treatment may also slow-
down the disease progression.
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The central role of Aβ amyloid and tau in the
pathogenesis of Alzheimer’s disease
CRAIG W. RITCHIE AND COLIN L. MASTERS
48.1 INTRODUCTION
The details of the molecular neuropathology of Alzheimer’s
disease (AD), from the amyloid precursor protein (APP)
through to the production of amyloid Aβ, plaque formation,
neurodegeneration and to final neuronal death are discussed
in this chapter. This process, like Alexander’s Gordian
knot, has been scrutinized over the last four decades with
the ongoing hope that a decisive therapeutic incision is not
too distant. Points in the biochemical pathway that may be
amenable to therapeutic intervention are highlighted.
The theory that Aβ amyloid underlies the neurodegen-
erative changes in AD remains pre-eminent (Figure 48.1)
despite the emergence in recent years of alternative disease
pathways. It is clear that there are both proven and hypo-
thetical links between the alternate pathways (including
oxidative stress, altered innate immune reponses, elevation
of cortisol and impaired axonal transport) and Aβ protein.
Integral to the pivotal role of Aβ and AD is the presumed
neurotoxicity of Aβ, especially in its soluble/diffusible oligo-
meric forms, while the polymerized fibrillar forms in the
amyloid plaques may represent a toxic reservoir.
This Aβ peptide is the main constituent of the amyloid
plaque, one of the characteristic pathological features of
AD. It is also found in vessel walls as a congophilic amyloid
angiopathy (Glenner and Wong, 1984; Masters et al., 1985).
Neurofibrillary changes are also major features in the brains
of patients with AD. Tau protein, a microtubule-associated
protein, is ubiquinated, phosphorylated and accumulates as
neurofibrillary tangles (NFT) and dystrophic neurites (Kosik
et al., 1986; Wood et al., 1986). The actual link between Aβ
accumulation and tau-associated NFT remains unknown,
although NFT appear to be downstream of the events that
surround Aβ accumulation in the AD brain. The hyperphos-
phorylation of tau protein may occur after aggregation, in
492
48
which case it may be a secondary ­phenomenon. Oxidative
damage may also be the result of Aβ or tau aggregation.
There is increasing evidence that sporadic AD is primarily
the result of failure of clearance of Aβ over many decades. This
is in contrast to the autosomal dominant inherited forms of
AD, in which pathogenic mutations in critical genes in the
Aβ-biogenesis pathway cause an overproduction of Aβ from
the time of conception. These processes will be discussed in
more detail later in the chapter.
The biogenesis of Aβ from APP and putative mechanisms
for its neurotoxicity, together with genetic risk factors such
as apolipoprotein E (ApoE) that may interact with Aβ and
affect its clearance from the brain, is the focus of this chap-
ter. More detailed reviews on these subjects can be found
elsewhere (Masters et al., 2015).
48.2 Aβ AMYLOID ACCUMULATION
AND PLAQUE DEVELOPMENT
One of the two characteristic microscopic features of AD is
the accumulation of Aβ amyloid in plaques of varying mor-
phology. These are extracellular or perivascular congophilic
deposits of aggregated Aβ with a high content of β-pleated
sheet secondary structure. The amyloid plaque itself is the
end result of a process of Aβ oligomerisation, fibril formation,
aggregation and precipitation occurring in several stages, with
each stage potentially having a different impact on surround-
ing neurones. Initially it was postulated that a soluble species
of Aβ forms oligomers. Over time there developed a consen-
sus that it is the oligomeric form of Aβ that is the most syn-
aptotoxic (Naylor et al., 2008; Shankar and Walsh, 2009) and
neurotoxic (Mclean et al., 1999). Oligomers are formed from
monomeric Aβ through the formation of covalent dityrosine
bonds or other post-translational changes that are relativeley
 The central role of Aβ amyloid and tau in the pathogenesis of Alzheimer’s disease 493

Alzheimer’s disease

Neurodegeneration

NFT APC / ACA

Genetic
Aβ ApoE risk
factors
PS1,2

Environmental Pathogenetic
APP
risk mutations
factors

Figure 48.1 The amyloidocentric pathway that leads to Alzheimer’s disease proceeds from the proteolytic processing of
the amyloid β precursor protein (APP) into the Aβ amyloid. The amyloid forms visible plaques (amyloid plaque cores [APC];
amyloid congophilic angiopathy [ACA]). The relationship between Aβ and neurofibrillary tangle (NFT) formation remains
unclear. The mechanisms that underly the basic neurodegenerative changes in Alzheimer’s disease are also uncertain. This
pathway is subject to modulation by environmental and genetic factors at various points.

resistant to catabolism (Naylor et al., 2008). The formation
of oligomers is dependent upon the micro-environment in
which Aβ is released from the cell membrane (Smith et al.,
2007). These oligomers may aggregate into protofibrillar
structures, which may first be seen as precipitates in diffuse
amyloid plaques; this progresses with dystrophic neurite for-
mation both within the neuropil and around dense crystalloid
precipitates of amyloid cores. Following this, an intermediate
stage is reached, where the plaque increases in complexity
before a final stage of a non-neuritic ‘burned out’ or ‘end-stage
plaque’ is reached.
In autosomal dominantly inherited AD, processing of
APP creates a high ratio of Aβ42 (‘long’ Aβ of 42 amino
acids) to Aβ40 (‘short’ Aβ of 40 amino acids). These pro-
cesses are discussed later in this chapter. The more insoluble
long Aβ is the primary constituent of the amyloid plaque.
However, immunocytochemical techniques have demon-
strated that diffuse plaques contain not only Aβ42 but also
Aβ40 and, in a small proportion of plaques (most of which
have a dense amyloid core), Aβ(16–40/42) (the p3 fragment)
(Dickson, 1997). Perivascular amyloid identified in the
congophilic angiopathies predominantly consists of Aβ40
(Suzuki et al., 1994; Barelli et al., 1997).
Plaque morphology also varies as a function of topo-
graphic location. Smaller granular deposits are seen in
the deep grey matter nuclei, and linear streaks occur in
the molecular layer of the cerebellum. The morphology of
the amyloid plaque therefore varies depending upon both
location and stage of development.
Beyond a certain level, the number of amyloid plaques
at post-mortem does not correlate well with the severity
of clinical disease (McKee et al., 1991; Morris et al., 1991;
Terry et al., 1991; Berg et al., 1998). More recent studies
using positron emission tomography (PET)-Aβ molecular
imaging show how the Aβ burden correlates with cognitive
impairment and rates of decline (Villemagne et al., 2013,
Lim et al., 2015). At high levels, the rates of Aβ increase may
reach a plateau, explained in part by a process of growth
and resolution of plaques (Hyman and Tanzi, 1992). In
concert with traditional explanations of the disconnect
between plaque number and disease severity, there is now
a gathering consensus that the soluble/diffusible Aβ42 load
may be more closely related to clinical severity (McLean
et al., 1999), whether or not the Aβ42 exists as an oligomer
or complexed to other proteins (Lorenzo and Yanker, 1994;
Howlett et al., 1995). A major argument raised by opponents
of the amyloid theory is that individuals can have numerous
plaques but no clinical cognitive impairment. As we learn
more from PET-Aβ and cerebrospinal fluid-Aβ (CSF-Aβ)
measurements, this argument becomes less convincing.
Aβ may mediate clinical symptomatology predominantly
through synaptotoxicity and neurotoxicity, which precedes
frank neurodegeneration. Finally, Aβ accumulation and the
plaques are components within a very complex biological
494 Dementia

system that relies on numerous other pathological processes
before AD develops clinically. These processes are mediated
by other biological, genetic and environmental risk factors.
It may be that to trigger AD from the physiological produc-
tion of monomeric Aβ requires the ‘perfect storm’ combin-
ing several biological (e.g. neuroinflammation, oxidated
stress and genetic vulnerability) and environmental (e.g.
cerebrovascular) risk factors – all of which are more likely
to accumulate and co-occur with advancing age.
48.3 GENETIC EVIDENCE FOR THE
ROLE OF Aβ IN AD
The most convincing support for the central role of Aβ and
APP in the pathogenesis of AD is that most of the known
fully penetrant autosomal dominant gene mutations that
cause early-onset AD lead to an increase of Aβ42 produc-
tion (Bateman et al., 2006; Mawuenyega et al., 2010) (see
Table 48.1). Mutations in the APP gene itself lead to the
development of aberrant APP that is preferentially pro-
cessed to produce an increase in the Aβ 42:40 ratio. More
recently, mutations near the β-secretase (BACE1) site have
been identified, which are protective (Jonsson et al., 2012).
All causative APP mutations identified to date occur in
proximity to the Aβ domain of the protein. Similarly, mul-
tiple mutations in the two presenilin (PS) genes have a dra-
matic effect on the Aβ 42:40 ratio (Szaruga et al., 2015).
48.4 AMYLOID PRECURSOR PROTEIN
The APP is a transmembrane protein that is found in most
cell types including neuronal and glial cells (Figure 48.2). It
is especially enriched in the alpha-granule of platelets. The
APP gene is located on chromosome 21 (Kang et al., 1987).
The pathogenic APP mutations account for less than 5% of
all cases of AD inherited in an autosomal dominant manner.
The precise physiological function of APP is unknown,
though no doubt is complex and possibly related to synaptic
plasticity, repair and regeneration. The structural domains
suggest that it may have a role in cell–cell (synapse) or cell–
matrix interactions (neurite stabilization). There is evidence
to suggest that APP is affected by metal ion binding, calcium
levels and heparin binding. APP has also been associated
with cell proliferation and neurite outgrowth in response to
nerve growth factor (Milward et al., 1992; Small et al., 1994;
Yankner, 1996). Other in vitro experiments have suggested
that a deficiency of APP renders cells more susceptible to a
variety of neurotoxic insults.
48.5 APP PROCESSING BY α-, β- AND
γ-SECRETASES
APP exists in three major isoforms of 695, 751 and 770 amino
acids. The 695-amino acid isoform (APP695) is predomi-
nantly expressed in neurones (Kang et al., 1987; Tanzi et al.,
1987). The APP751 and APP770 isoforms are predominantly
expressed in peripheral tissues and astrocytes (Golde et al.,
1990; Kang and Müller-Hill, 1990). APP is synthesised in the
endoplasmic reticulum and is then transported through the
Golgi apparatus to the cell surface. In its transmembrane ori-
entation (as shown in Figure 48.2) it undergoes proteolytic
cleavage to produce Aβ. The half-life of APP is short and is
processed by at least two pathways (α- and β-/γ-secretase
activities). In peripheral cells, α-secretase activity predomi-
nates, cleaving the Aβ domain of APP at position 16/17. This
leads to the production of soluble ectodomain protein sAPPα
(Evin et al., 1994). The soluble ectodomains of APP (both
sAPPα and sAPPβ) do not aggregate and do not participate

Table 48.1 Pathogenic mutations that cause Alzheimer’s disease

Mutations Mechanism of action Effect

APP gene dosage or aberrant regulation
Down’s Syndrome (trisomy 21) Upregulation of APP gene promoter Increased total Aβ
up to fivefold to sixfold
Pathogenic APP gene mutations
APP codons:
670/671 (‘Swedish’) Increase β-secretase cleavage Excess total Aβ production
692 and 693 (‘Dutch and Flemish’) Decrease α-secretase activity? Resultant increase in β- and γ-activity
with consequent increased total Aβ
715 (‘French’) Affects γ-secretase activity Increased amounts of Aβ p3 fragment
717 (‘London’) Altered γ-secretase activity Increased ratio of Aβ42:40
723 (‘Australian’) Affects γ-secretase activity Increased ratio of Aβ42:40

Pathogenic PS1, 2 gene mutations

More than 70 point or misense mutations Direct or indirect alteration of Increased ratio of Aβ42:40
and exon deletion γ-secretase
Abbreviation: APP, amyloid precursor protein.
 The central role of Aβ amyloid and tau in the pathogenesis of Alzheimer’s disease 495

Poly-T GPD HBD-2 CS-GAG

NPXY
APP

P CHO
Clathrin/Fe65
binding
KPI OX-2 Exon 15
Aβ G0 binding

HBD-1 ZnBD Membrane

(a) β α γ anchor
Secretase sites
Aβ

β-Secretase α-Secretase γ-Secretase

NH2 T E E I S E V K M D A E F R H D S G Y E V H H Q K L V F F A E D V G S N K G A I I G L M V G G V V I A T V I V I T L V ML K K K C O OH
1 10 20 30 40
I
G
Mutation NL GC MVF P

APP770 Codon 670/671 692 693 715 717 723

Swedish Flemish Dutch French London Australian
(b) 716
Florida

Figure 48.2 (a) The structural domains of APP are schematically shown. Within the large extracellular ectodomain
there are heparin-binding sites (HBD-1,2), metal-binding sites (ZnBD), growth-promoting domains (GPD), carbohydrate-­
attachment sites (CHO; CS-GAG), and alternatively spliced exons (KPI, OX2, Exon 15). The shorter cytoplasmic domain
has interacting motifs for G0 protein, clathrin (NPXY) and the Fe65 family of proteins. (b) The Aβ (juxtatransmembrane
and transmembrane) domains are shown in more detail. The β-, α- and γ- secretase sites are shown, with the major
­cleavage sites indicated by unbroken arrows. The critical pathogenic mutations are shown to be clustered near the
­secretase sites (see also Table 48.1).

in plaque formation. α-Secretase activity leaves in the mem-
brane a small carboxyl-terminal (C-terminal) fragment that
undergoes further processing. The α-secretase activity may
be sequence non-specific and act on several other trans-
membrane proteins. Furthermore, recent work has identi-
fied a disintegrin and metalloprotease (ADAM), as being a
potent effector of α-secretase activity (Lammich et al., 1999).
Increase of ADAM-10 expression and activity may theoreti-
cally be effective as a treatment for AD.
Aβ, therefore, exists in several forms depending on
the site of cleavage by α-, β- or γ-secretases. The length
of the Aβ fragment varies depending on the site of cleav-
age leading to a product between 38 and 43 amino acids
in length. The amino-terminal (N-terminal) 28 residues
are from the extracellular portion of APP, and the 11–15
C-terminal residues are derived from the transmembrane
domain. It is the Aβ42 which is considered to be the more
insoluble and toxic moiety and is a product of γ-secretase
cleavage of the APP molecule. β- and γ-secretase activity
involves cleavage of APP at sites corresponding to posi-
tions 1 (β-secretase) and 40 or 42 (γ-secretase) of the Aβ
fragment, releasing the insoluble amyloidogenic peptide
Aβ(1–40/42) commonly referred to as Aβ42. It is intrigu-
ing to note that in animal models, elevated levels of cortisol
are associated with preferential activity of the β-secretase
pathway (Green et al., 2006) as well as hippocampal atro-
phy and increased amyloid plaque development (Butters
et al., 2008) in patients with depression. The pharma-
cological inhibition of the enzyme 11β-hydroxysteroid
dehydrogenase (HSD) that converts inactive cortisone
to cortisol is attracting interest as a potential therapeutic
avenue (MacLullich et al., 2012). These biological observa-
tions provide a basis for the epidemiological and clinical
links between depression/stress and Alzheimer’s demen-
tia (Jorm, 2001; Huang et al., 2009).
Determination of the structure of γ-secretase could have
important therapeutic implications (De Strooper et al.,
1999; Struhl and Greenwald, 1999; Wolfe et al., 1999; Ye
et al., 1999; Iwatsubo 2004). The macromolecular complex
that constitutes γ-secretase activity is >400 kDa in mass
and contains at least three other molecules: Aph1, Pen2 and
nicastrin (Iwatsubo, 2004). Active development of inhibi-
tors of γ-secretase has progressed at a radical pace, but the
results of clinical trials have been disappointing. Further
work on dosage and pharmacodynamics are required
to achieve more suitable inhibition and modulation of
γ-secretase activity (Bai et al., 2015; De Strooper and Chávez
Gutiérrez, 2015).
496 Dementia
48.6 APP MUTATIONS AND Aβ
PRODUCTION
The various APP mutations inevitably produce increased
ratios of Aβ42 through a variety of mechanisms (Table 48.1).
The mutations at codons 670/671 (the ‘Swedish’ mutation),
increase β-secretase cleavage and lead to an overall excess
amyloid production (Cai et al., 1993). Mutations at codon
717 (the ‘London’ mutation), 715 (the ‘French’ mutation), 716
(the ‘Florida’ mutation) and 723 (the ‘Australian’ mutation)
act at the γ-secretase site, increasing the ratio of Aβ42:40
(Suzuki et al., 1994; Brooks et al., 1995; Eckman et al., 1997;
Ancolio et al., 1999; Kwok et al., 2000). Mutations at 692
and 693 (the ‘Dutch’ and ‘Flemish’ mutations) are either
associated with α-secretase activity, presumably leading to a
decrease in this pathway with a resultant increase in β- and
γ-activity (Haass et al., 1994) or yield a mutant Aβ peptide
with enhanced toxicity or propensity to aggregation. In
Down’s syndrome (trisomy 21), where there is an extra copy
of the APP gene, there is a similar increase in the overall
levels of Aβ42 (Teller et al., 1996).
It is necessary to elucidate the mechanisms that regu-
late the activity of the secretase enzymes involved in APP
metabolism, as a greater understanding of these processes
will aid the development of therapeutic interventions. One
factor that may predict which form of cleavage is utilized is
cell type, with glial cells and neurones (both differentiated
and undifferentiated) producing different isoforms of APP
(Haass et al., 1991; Baskin et al., 1992; Hung et al., 1992).
Exon 3
cleavage site
Exon 4
Exon 8
Exon 6
Exon 7
Exon 5
Figure 48.3 A model of the presenilin 1 molecule. The multiple mutations that cause early-onset Alzheimer’s disease are
seen to cluster in the transmembrane domains and in proximity to the normal ‘presenilinase’ cleavage site. The cytosolic
loop between transmembrane domains six and seven may play a critical role in γ-secretase activity.
Another factor that influences the cleavage pathway may
be the release of APP mediated by protein kinase C (PKC),
which leads to a predominance of the α-secretase path-
way (Caporaso et al., 1992; Gillespie et al., 1992; Sinha and
Lieberburg, 1992). Of interest, PKC-mediated α-secretase
activity may be induced by neurotransmitters and other
first-messenger ligands (Buxbaum et al., 1992; Lahiri
et al., 1992; Nitsch et al., 1992). If these first- and second-­
messenger pathways prove to directly influence the pro-
duction of Aβ42, then these systems could provide another
target for pharmacological intervention (Roh et al., 2012; Ju
et al., 2013)
48.7 PRESENILINS 1 AND 2
The presenilin 1 (PS1) gene is located on chromosome 14
and PS2 on chromosome 1. In the brain, PS1 is found in
both neurones and glia. It has a multipass transmembrane
orientation (Figure 48.3). PS2 expression in the pancreas
and muscle exceeds other sites including the brain (Rogaev,
1998). The PS molecules undergo cleavage by unidentified
mechanisms to yield N- and C-terminal fragments.
A link between PS mutations and Aβ production has
been confirmed as an increased ratio of Aβ42:40 is noted
in transfected cell lines and transgenic mice expressing
mutant forms of PS1 (Borchelt et al., 1996; Citron et al.,
1996; Duff et al., 1996; Lemere et al., 1996). Patients and
at-risk individuals with PS mutations have increased ratios
Exon 10
Alternative
(caspase)
Exon 9
Exon 12
Cytosol
`Presenilinase´
cleavage site
Lumen
Exon 11
PS-I residue change due to misense mutation
PS-I exon deletion mutations: ΔE4
ΔE9
ΔE10
 The central role of Aβ amyloid and tau in the pathogenesis of Alzheimer’s disease 497
of Aβ42:40 (Scheuner et al., 1996). PS1 may have an anti-
apoptotic activity (Roperch et al., 1998) and mutations in
PS1 may sensitise neuronal cells to apoptosis by disruption
of intracellular calcium levels (Keller et al., 1998).
In summary, most of the identified genotypes in auto-
somal dominant AD have, as their common denominator,
an increase in the production of Aβ42. This observation
suggests a direct causal relationship between Aβ42 and the
development of AD.
48.8 Aβ AND NEUROTOXICITY
Despite the above evidence that an increase in the propor-
tion of Aβ42 is a common end point for all the autosomal
dominant mutations that lead to AD, the exact mechanism
of underlying Aβ42 and neuronal degeneration remains
unclear (Table 48.2).
Aβ has been shown to be directly neurotoxic to hippo-
campal neurones that are particularly sensitive to oxidative
stress and are affected first in the spread of AD throughout
the cerebral cortex. While some authors have been unable
to demonstrate neurotoxicity of Aβ when it exists in an
immature, non-fibrillar, amorphous aggregate (Lorenzo
and Yanker, 1994), there is now an emerging consensus that
the smaller oligomeric aggregates of Aβ, in association with
factors such as metal ions, constitute the principal forms
of the toxic Aβ species. Aβ can potentiate the neuronal
insult of excitatory amino acids (Koh et al., 1990), oxida-
tive stress (Lockhart et al., 1994) and glucose deprivation
(Copani et al., 1991). This may explain why the cumulative
exposure of the ageing brain to other risk factors renders it
more vulnerable to the toxic effects of Aβ. Aβ has also been
shown in vitro to cause plasma membrane lipid peroxida-
tion, impairment of ion motive ATPases, glutamate uptake
and uncoupling of γ-protein-linked receptors (Behl et al.,
1994; Butterfield et al., 1994; Hensley et al., 1994; Mark et al.,
1996). These pathological processes may contribute to a loss
of intracellular calcium homeostasis that has been reported
in cultured neurones (Mattson et al., 1993). Aβ, when intro-
duced into neuronal cultures, leads to a gradual increase in
intracellular calcium, though this activity is not affected by
the addition of either calcium channel blockers or chelat-
ing agents (Lorenzo and Yanker, 1994; Whitson and Appel,
1995). Aβ may also impair redox activity in mitochon-
dria, leading to the production of free radicals (Shearman
et al., 1994). Cellular damage mediated by Aβ is inhibited
by vitamin E (Behl et al., 1992). This supports the above
Table 48.2 Aβ toxicity-proposed mechanisms
●● Generation of reactive oxygen species, metal
mediated
●● Physical disruption of cellular membrane
●● Receptor-mediated uptake and apoptotic signalling
●● Disturbance of intracellular calcium homeostasis
observation that a free-radical-based process, mediated by
Aβ, leads to neuronal damage and that this process, in vitro,
can be inhibited by antioxidants. The use of antioxidants
in the treatment of AD has been investigated clinically in
recent years and some clinical efficacy has been shown with
vitamin E (Sano et al., 1997) though a summation of the
evidence to date has concluded that this intervention may
well be too late in advanced disease or early dementia (Ames
and Ritchie, 2007). Moreover, preliminary trials with com-
pounds that target the redox-active metal-binding sites on
Aβ have yielded encouraging results (Ritchie et al., 2003;
Lannfelt et al., 2008).
48.9 Aβ INTERACTION WITH
APOLIPOPROTEIN E AND OTHER
RISK FACTOR GENES
48.9.1 APOLIPOPROTEIN E
ApoE isoforms represent a major genetic susceptibility fac-
tor for sporadic AD, affecting all people over the age of 60
years. It is the strongest of a multiple set of genetic risk fac-
tors that have the potential to modify any putative environ-
mental risk factor (Saunders et al., 1993; Huang et al., 2004).
The ApoE gene, located on chromosome 19, was the first
polymorphic gene to be associated with a complex disease
using positional cloning strategies. The ApoE gene products
vary depending upon the inherited pair of polymorphic
alleles. There are three allelic varieties ε2, ε3 and ε4. ApoE is
a glycoprotein of 299 amino acids that is a normal constitu-
ent of plasma and CSF lipoprotein particles. The physiologi-
cal function of the protein is to mediate cholesterol uptake,
storage, transport and metabolism. There is a binding site
for Aβ present near the C-terminus of the ApoE molecule
(Wisniewski et al., 1993). ApoE is a component of the very-
low-density lipoprotein (VLDL) and high-density lipo-
protein (HDL) complexes involved in cellular uptake and
metabolism of cholesterol (Mahley, 1988). ApoE is normally
upregulated and released from astrocytes following neuro-
nal injury and not only affects lipid metabolism following
this trauma but may also complex with VLDL to increase
neurite outgrowth and synaptogenesis. However, the dif-
ferent ApoE genotypes differentially affect this process.
Individuals carrying the ε4 allele have a decreased capac-
ity for compensatory neurite outgrowth and synaptogenesis
following neuronal injury (Poirier, 1994).
It has also been demonstrated that individuals with
at least one ε4 allele develop greater numbers of neuritic
plaques (Olichney et al., 1996) irrespective of whether or not
they have clinical AD (Rebeck et al., 1993; Schmechel et al.,
1993; Polvikoski et al., 1995). ApoE ε4 also complexes with
Aβ, whereas ApoE ε3 does not have the same affinity, thus
promoting protofibril formation, which, as has been alluded
to already, may be the immediate neurotoxic product in
AD. A model therefore exists that outlines the interaction
498 Dementia
between Aβ and ApoE, which explains why the latter exists
as one of many contributing genetic risk factors to the devel-
opment of AD. At the very least, it links the metabolism of
cholesterol into the Aβ-mediated pathway of AD causation.
Not only the genotype that an individual carries is rele-
vant as a risk factor for AD but also variations in ApoE levels
may also be an important factor in predicting disease onset.
The promoter of ApoE that regulates the synthesis of the lipo-
protein is polymorphic. The allelic variants at −491 (Bullido
et al., 1998), −427 (Artiga et al., 1998) and −219 (Lambert
et al., 1998) of the ApoE promoter region, when homozygous,
may be associated with increased risk of AD, and a combina-
tion of the adverse alleles of the promoter and coding regions
confer even greater risk of developing AD (Artiga et al., 1998).
Clinically, possession of the ε4 allele increases the risk of
developing AD at any particular age. In individuals who are
ε4 heterozygotes, there is an approximate doubling of risk
and for those who are homozygous for ε4 the risk is increased
by a factor of between six and eight (National Institute on
Aging/Alzheimer’s Association Working Group, 1996).
Possession of an ε4 allele may lead to an earlier age of onset
(Blacker et al., 1997; Burlinson et al., 1998) and there may be
an even greater risk of developing AD in females who carry
the ε4 allele (Poirier et al., 1993; Payami et al., 1994; Duara
et al., 1996). There are, however, conflicting reports regard-
ing the rate of decline associated with different genotypes.
More recent data obtained from longitudinal cohorts and
PET-Aβ molecular imaging clearly demonstrate the effect
of ApoE in the preclinical, prodromal and clinical phases
of Aβ (Lim et al., 2015). The ApoE ε2 allele may confer pro-
tection against the development of AD (Corder et al., 1994;
Myers et al., 1996).
The ε4 allele also confers additional risk of developing
AD in those patients who have suffered strokes (Slooter
et al., 1997), though other authors, in smaller studies, have
failed to replicate this finding (Burlinson et al., 1998). Other
cerebral insults such as head injuries have been associated
with increased Aβ deposition in patients who carry an ε4
allele (Nicoll et al., 1995). Determining the ApoE status of a
patient may be of value in aiding the diagnosis of AD where
there is already a high clinical suspicion of the condition.
Table 48.3 Top 10 genes associated with increased risk of Alzheimer’s dementia from AlzGene Project
Rank Gene
1 Apolipoprotein E
2 Bridging integrator (BIN) 1
3 Clusterin (Apolipoprotein J)
4 ATP-binding cassette sub-family A member (ABCA) 7
5 Complement component (3b/4b) receptor (CR1)
6 Phosphatidylinositol-binding clathrin assembly protein (PICALM)
7 Membrane-spanning 4-domains, subfamily A, member 6A (MS4A6A)
8 CD33
9 Membrane-spanning 4-domains, subfamily A, member 4E (MS4A4E)
10 CD2-associated protein (CD2AP)
Abbreviation: CI, confidence interval.
However, there may only be a marginal increase in diag-
nostic accuracy (American College of Medical Genetics/
American Society of Human Genetics Working Group on
Apolipoprotein E and Alzheimer’s Disease, 1995; National
Institute on Aging/Alzheimer’s Association Working
Group, 1996). In isolation, knowledge of the ApoE genotype
of any given individual lacks the sensitivity, specificity or
positive predictive value to be useful as a screening tool.
48.9.2 OTHER GENETIC RISK FACTORS
FOR AD
The AlzGene initiative has provided major insights into
genetic risks for AD. The project allows the knowledge
gained from numerous studies and meta-analysis to pro-
vide dynamic conclusions on risk across a range of poten-
tially relevant genes. From this, gene polymorphisms can be
ranked by their strength of association with AD (be that a
risk or protective) or by the p-value. It is the latter method
of ranking that is currently used. The current ‘top 10’
genes are summarized below (Table 48.3), which has been
extracted from the AlzGene website: http://www.alzgene
.org/TopResults.asp.
The relationship of the ‘top 5’ of these genes to Aβ and tau
pathology is summarized. ApoE and AD has been dealt with
in detail above. The bridging integrator 1 (BIN1) gene, also
known as amphiphysin 2, is primarily associated with AD
pathology through its role in tau modulation. It also has a role
in calcium homeostasis, apoptosis, endocytosis/­trafficking
and inflammation. Epigenetic modifications are important
for AD pathogenesis, and there are data that suggest the pos-
sible DNA methylation of the BIN1 promoter. Finally, given
the potential contributions of BIN1 to AD pathogenesis, tar-
geting BIN1 might present novel opportunities for AD ther-
apy (for a further review see Tan et al., 2013).
Clusterin or apolipoprotein J has also been associated
with AD risk for many years (see Li et al., 2014). Clusterin
is a chaperone protein and can inhibit the aggregation of
Aβ. However, it has also been shown to promote intra-
cellular pathways of Aβ metabolism that are neurotoxic
as well as promote the formation of neurotoxic, soluble
Odds ratio (CI) p-value
3.68 (3.3–4.12) <1−50
1.16 (1.13–1.2) <1.6−26
0.88 (0.86–0.9) <3.4−23
1.23 (1.18–1.28) <8.2−22
1.17 (1.14–1.21) <4.7−21
0.88 (0.86–0.9) <2.8−20
0.9 (0.88–0.93) <1.8−11
0.89 (0.86–0.93) <2.1−10
1.08 (1.05–1.11) <9.5−10
1.12 (1.08–1.16) <2.8−9
 The central role of Aβ amyloid and tau in the pathogenesis of Alzheimer’s disease 499
Aβ species. To this end the impact that clusterin, and
genetic and epigentic variants therein has on AD risk
remains uncertain with the biology of the protein to still
be full characterized. ATP-binding cassette sub-family
A member 7(ABCA7) is a member of the superfamily
of ATP-binding cassette (ABC) transporters. These pro-
teins transport various molecules across extracellular and
intracellular membranes. The function of this protein is
not yet known; however, the expression pattern suggests
a role in lipid homeostasis in cells of the immune system
and elsewhere (Reitz et al., 2013). With relevance to AD,
it has been demonstrated that ABCA7 is involved in APP
transport through the neuronal cell membrane (Chan et
al., 2008), as well as being involved in the phagocytosis
by macrophages of apoptotic cells (Tanaka et al., 2011).
Complement receptor 1 (CR1) is a gene involved in the
complement cascade that has been linked to AD pathol-
ogy. Its role is as a receptor protein for complement frag-
ments C3b and C4b especially in the circulatory system.
Activated complement is involved centrally in activation
and recruitment of microglia around fibrillar amyloid
plaques (Eikelenboom and Veerhuis, 1996), a process that
is further enhanced by Aβ (Haga et al., 1993). The cyto-
lytic effects of complement cascade in association with
Aβ have been recognized for over two decades (Rogers et
al., 1992), but the complex genetic association shown with
ApoE status (Thambisetty et al., 2013), evidence of meta-
bolic alterations associated with AD (Darborg et al., 2012)
and evidence that CR1 inhibition can reduce the classical
complement cascade (Davis et al., 2008) has stimulated
further interest in this area from both a mechanistic and
therapeutic perspective.
α2-MACROGLOBULIN (α2M),
48.9.3 
LOW-DENSITY LIPOPROTEIN
RECEPTOR-RELATED PROTEIN
(LRP1) AND INSULIN-DEGRADING
ENZYME
Over and above the genes listed above, there is an ongo-
ing interest in other genes and gene products related to Aβ
metabolism. While the ApoE gene was the first polymor-
phic marker to be identified as a genetic modifier of risk
for AD, other candidate genetic loci are being investigated,
including α2M, a protease inhibitor found in association
with amyloid plaques in AD. The gene for α2M is located on
chromosome 12, binds Aβ with high affinity and may influ-
ence fibril formation and the toxicity of Aβ in vitro (Hughes
et al., 1998). The activity of α2M has also been associated
with LRP1. Both α2M and LRP1 are upregulated following
neuronal injury (Lopes et al., 1994). Furthermore, α2M is
thought to mediate Aβ degradation via endocytosis through
LRP1 (Narita et al., 1997). As ApoE and APP are also ligands
of LRP1, it is postulated that different isoforms of ApoE and
α2M may interact differentially and competitively for this
system, affecting the clearance of Aβ.
Several investigators have now shown that, like ApoE,
different LRP1 genotypes are associated with the develop-
ment of AD (Kang et al., 1997; Hollenbach et al., 1998),
mediated possibly through an increase in Aβ burden. α2M
genotypes, unlike ApoE genotypes, have seemingly no
effect on the age of onset in AD (Liao et al., 1998). The odds
ratio for AD associated with the γ/γ α2M genotype was
shown to be 1.77 (1.16–2.70, p < 0.01) and in combination
with ApoE ε4 was 9.68 (3.91–24.0, p < 0.001). In the same
study, there was no increased risk of AD demonstrated in
heterozygotic individuals with γ\γ genotype, and stratifi-
cation of the sample based on the presence or absence of the
ApoE ε4 allele demonstrated a similar over-­representation
of the γ/γ genotype in both strata (Liao et al., 1998). This
finding was demonstrated in a population-based study.
This initial work suggests that the α2M γ/γ genotype may
increase the risk of developing AD, that this risk is inde-
pendent of the effects of ApoE ε4, and that the risks are
additive and substantial. The studies to date require fur-
ther replication and the effect requires demonstration in
different populations in a similar manner to studies defin-
ing the risks associated with ApoE ε4. If future studies do
conclude that α2M is an independent risk factor for AD,
then predictive testing considering both genes (and also
including genotyping of the ApoE promoter regions) could
be developed with much higher positive predictive values
than those demonstrated with ApoE testing alone. Whole
genome search strategies (Blacker et al., 2003; Ertekin-
Taner et al., 2004) have yielded other ‘hot spots’ of inter-
est, the most intriguing of which is that on chromosome
10, close to the insulin-degrading enzyme (IDE) locus.
Attempts to identify IDE as a risk factor have so far failed,
but it remains an ­attractive candidate for its ­demonstrated
role in ­promoting the clearance of Aβ from the brain
(Farris et al., 2004).
48.10 LINKING Aβ PRODUCTION AND
AGGREGATION TO THE OTHER
OBSERVED PATHOLOGIES IN AD
48.10.1 Aβ AND TAU
HYPERPHOSPHORYLATION
The two most well-defined pathological processes in AD
are the aggregation of tau protein and subsequent destabi-
lization of the cytoskeletal protein tubulin, and the aggre-
gation of Aβ to form amyloid plaques. While traditionally
there has been debate about which process is upstream from
the other and hence more ‘important’, less prosaic think-
ing would lead one to develop hypotheses about how these
two important lesions are linked. One such hypothesis rec-
ognizes the importance of the protein glycogen synthase
kinase 3 (GSK3) having a pivotal role in the pathological
events observed in AD (Hooper et al., 2008).
500 Dementia
GSK3 has a multiplicity of functions including roles in
maintaining microtubule stability, apoptosis and gene tran-
scription. Upregulation of the protein is associated with
induction of tau hyperphosphorylation (Lovestone et al.,
1994) an effect inhibited by insulin (Lesort et al., 1999). The
role of insulin to not only inhibit GSK3 but also promote the
expression of IDE, which is an Aβ protease as well as a pro-
moter of APP processing through the α-secretase pathway
has led to the proposition that AD could be labelled ‘Type 3
Diabetes’ (de la Monte and Wands, 2008).
Moreover, the GSK3α isoform has been shown to regu-
late APP processing leading to increased Aβ production
(Phiel et al., 2003), which in turn has been shown in neu-
rones to further increase GSK3β expression. Both the GSK3
isoforms are associated with tau hyperphosphorylation.
Althouth there are other theories associating tau and Aβ
protein in the genesis of the disease, GSK3 overexpression
and its interaction with insulin would appear likely linking
processes with much consistent evidence supporting this
theory.
48.10.2 Aβ AND MITOCHONDRIAL
DYSFUNCTION
Mitochondria are the energy source of the cell and any dis-
ruption of mitochondrial function will necessarily lead to
impaired neuronal function, defences, repair and integrity.
Again, the question is raised as to whether Aβ overproduc-
tion leads to mitochondrial damage or whether the latter
precedes the former.
An energy-deficient neurone will tend to favour less-
energy-dependent processes, where an alternate exists. In
this regard it has been demonstrated that BACE increases
its function in energy deprived neurones (Vassar et al.,
2009). Therefore – upstream mitochondrial damage may
lead to increased Aβ42 production. Downstream from
this though – mitochondrial membranes and multiple
mitochondrial processes are damaged by intracellular Aβ
(Reddy and Beal, 2008) and the C-truncated fragment of
APP can lead to further mitochondrial dysfunction through
disruption of translocase of outer m
­ itochondrial membrane
40 (TOMM40). It is also worth noting that the hyperphos-
phorylation of tau protein is more likley to occur in energy-
deficient cells (Rhein and Eckert, 2007).
48.10.3 Aβ AND NEUROINFLAMMATION
Finally, there has been a long-held hypothesis that glial acti-
vation is central to the pathology seen in AD (Meda et al.,
2001). Glial cells activate in response to inflammatory sig-
nalling from both peripheral and central sources (including
the amyloid plaque via process outlined above regarding the
role of complement). The response of glia to systemic inflam-
mation may explain the genesis of delirium in patients with
systemic infections and the apparent acceleration of decline
in Alzheimer’s dementia as a result of delirium (Fong et al.,
2009). When activated, glial cells overproduce the excito-
toxic neurotransmitter glutamate, and pro-inflammatory
cytokines also influence concentrations of zinc (Vasto et al.,
2007). While the glutamate is directly neurotoxic through
the N-methyl-d-aspartate (NMDA) receptor, the height-
ened levels of zinc may drive the oligomerization of Aβ lead-
ing to both acute (synaptotoxic) delirium-generating events
as well as – over time – neurotoxicity and neurodegenera-
tion leading to more entrenched and irreversible symptoms.
This observation may explain why PBT2 was shown to have
an acute effect in Phase 2 trials despite being developed pre-
dominantly as a disease-modifying agent (Lannfelt et al.,
2008). While the above highlights the negative consequencs
of glial activation, it is recognized that phagocytosis by glial
cells of Aβ at earlier stages of the disease process is benefi-
cial. Therefore there is a both positive (early) and negative
(later) effect of glial activation vis-a-vis the progression of
AD. This topic has been reviewed elsewhere (Gambuzza et
al., 2014) wherein the role of Toll-like receptors (proteins
intimately involved in the innate immune system) can be
activated to either induce Aβ uptake or (in later disease)
neuroinflammation.
48.11 A PHYSIOLOGICAL ROLE FOR Aβ
It is debated whether an invariably toxic protein or
single process explains the pathology of AD – rather it
may be the interaction of many (normally) physiologi-
cal processes whose interactions associated with genetic
and environmnetal risks associated with ageing become
pathological. In this light, Aβ may well perform an
important physiological role to act as an antioxidant and
a chaperone elevating metals towards biological inactiv-
ity embedded within the β-pleated sheet of the plaque.
When the system is in homeostatic equilibrium between
trace metal elevation, Aβ genesis and aggregation – there
is little if any synaptotoxicty, but when multiple systems
start to fail under the influence of genetic vulnerability
and in the context of ageing mediating accumulation of
risks, the normally benign systems tip into a pathological,
malignant cascade that evolution has not found a way (or
a need) to switch off.
Accordingly, to intervene beyond what is possible from a
preventative perspective, one must not throw the baby out
with the bathwater; interventions will need to be subtle and
no doubt used in combinations with other interventions
affecting other parts of the process.
48.12 INTERVENTIONS
Being able to determine the risk that a given individual
has of developing Alzheimer’s dementia late in life has
important clinical implications, as risk modification
 The central role of Aβ amyloid and tau in the pathogenesis of Alzheimer’s disease 501
strategies are most likely to be of greatest benefit when
disease processes are nascent or indolent. As proven
disease-modifying treatments for AD are still in early
­development, another benefit of defining a population
with AD but without dementia is to be able to define a
cohort for ­clinical trials of drugs or biological agents with
a ­postulated preventative or significant disease-modify-
ing action.
Current therapeutic interventions for AD operate far
downstream from the postulated initial toxicity of Aβ42.
Their efficacy is dependent upon augmenting the activ-
ity of surviving cholinergic neurones; the cholinesterase
inhibitors (donepezil, galantamine and rivastigmine)
have shown only modest effect on clinical progression of
AD and have no demonstrable disease-modifying effect
(Ritchie et al., 2004; see Chapter 52). To prevent neuronal
damage and clinical impairment, effective therapies must
either affect the pathological levels of production of Aβ42
from APP or mediate its toxicity or clearance. Therapeutic
paradigms may therefore (and this list is not exhaustive)
target inhibition of γ-secretase, or BACE1, or upregulate
the α-secretase pathway; influence the phosphorylation
state of the APP molecule; interdict metal–ions interac-
tion with Aβ and hence prevent oligomerization; scav-
enge free radicals; affect the postulated overactivation
of microglial cells in response to Aβ deposition and sys-
temic inflammatory signals; inhibit GSK3; stabilize or
protect TOMM40; improve insulin sensitivity; protect α-7
nicotinic receptors and do so as a combination of these
approaches.
These actions may, if the Aβ theory is correct, decrease
Aβ42 oligomerization and downstream toxic effects thereby
protecting both the synapse at the early stage of disease and
latterly the neurone itself.
48.13 CONCLUSIONS
This chapter highlights the complexity and intricacies of
the various systems that tie Aβ to the neuronal degenera-
tion of AD. One sword blow upon the Gordian knot will
not work, rather the interventions and untying should
represent a thoughtful, careful unpicking. Intensive
investigation of these biochemical systems has elucidated
several potential targets for rational therapeutic interven-
tion. The test of the Aβ theory will be in the examina-
tion of interventions that modulate the production and
accumulation of Aβ42, initially in mice before human tri-
als take place. In preparation for these trials, defining a
high-risk population based on genetic risk factors and the
observation of biological changes in patient’s precognitive
decline will continue with the hope that more effective
disease-modifying drugs will be available in the not too
distant future.
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Inflammation in Alzheimer’s disease
CLIVE HOLMES
49.1 INTRODUCTION
In the past, the role of neuroinflammation in Alzheimer’s
disease (AD) was considered to be a simple response to the
well-established neuropathological features (e.g. the neu-
ritic plaques or tangles) of the disease. However, emerg-
ing evidence now shows it is a major contributor to the
progression and development of the disease. Indeed, both
preclinical and clinical research support an early and sub-
stantial involvement of neuroinflammation in AD patho-
genesis that changes in character as the disease progresses.
The term ‘neuroinflammation’, in its broadest sense,
encompasses any inflammatory process, whether acute or
chronic, involving the nervous system. Depending on the
nature of the inflammatory process diverse cell types may
be involved. The central nervous system (CNS) resident
cells (microglia and astrocytes) are a major component of
this inflammatory response. However, in some circum-
stances, e.g. where the blood–brain barrier (BBB) is dam-
aged or in areas surrounding the vasculature of the brain,
other peripherally derived cells (neutrophils, lymphocytes,
plasma cells, macrophages and monocytes) may also be
involved. In AD, the key cellular players are thought to be
the CNS resident cells with its key mediators being cyto-
kine proteins. However, there is also a developing interest
in the potential role for peripherally derived cells and other
mediators of inflammation. Furthermore, there is increas-
ing recognition that neuroinflammatory processes in the
AD brain are markedly influenced by inflammation that
occurs outside the CNS. A greater understanding of the
central and peripheral inflammatory processes involved in
AD will undoubtedly enable the development of clinical
tools allowing the early detection of the disease but will,
most importantly, lead to new preventative strategies and
treatment approaches.
508
49
49.2 PRECLINICAL STUDIES
49.2.1 CNS RESIDENT CELLS
49.2.1.1 Microglia
Microglia are unique among the major cell types of the
CNS in that they are not derived from the neuroectoderm
(Chan, et al., 2007). These resident CNS cells were originally
derived from myeloid precursors and are representatives of
the early migration of monocytes from the periphery into
the brain (Ginhoux et al., 2010).
Microglia are ubiquitously distributed throughout the
brain and constantly survey their environment for the
presence of pathogens, protein aggregates and evidence of
neuronal cell death or synaptic damage. Detection of these
triggers is mediated by receptors that recognize pathogen-
associated molecular patterns (PAMPs), danger-associated
molecular patterns (DAMPs) and other cell surface recep-
tors including cluster of differentiation (CD) 33, CD36,
CD40 and toll-like (TL) receptors (e.g. TLR3, TLR4 and
TLR6) that drive the activation of these microglial cells
(Bianchi, 2007; Medzhitov, 2007; Kono and Rock, 2008;
Stewart et al., 2010).
Activation of microglia to these triggers is a complex
process and our understanding is largely based on mod-
els of activated macrophages outside the CNS. Here acti-
vated macrophages are considered to be of two broad
phenotypes. The first phenotype M1 or classical activation
is defined by the response of macrophages to challenge
by the cytokine interferon-γ, a cytokine usually associ-
ated with host defence to intracellular pathogens. M1 is
pro-inflammatory and is characterized by increases in
pro-inflammatory cytokines, including interleukin (IL)-1,
IL-6, IL-12 and tumour necrosis factor (TNF) α, and is
associated with tissue damage caused by increases in nitric

oxide and reactive oxygen species. The second major phe-
notype M2 or alternative activation phenotype is defined
by the response to the cytokine IL-4, a cytokine associ-
ated with the host defence to extracellular pathogens and
is associated with the upregulation of the mannose recep-
tor that binds to the surface of bacteria and fungi enabling
their phagocytosis. M2 is characterized by secretion of
anti-inflammatory cytokines IL-4, IL-10, IL-13 and trans-
forming growth factor (TGF)-β and is also associated with
tissue repair and remodelling. A third type of activation,
acquired deactivation (considered a subtype of M2), is
defined by the response to the cytokine IL-10, a cytokine
associated with the presence of apoptotic cells. Acquired
deactivation is associated with removal of apoptotic cells,
a strong immunosuppressive profile and by an increase in
the cytokine TGF-β (Colton, 2009; Boche et al., 2013).
Against this complex background is the finding that
microglial cells show enhanced sensitivity to inflammatory
stimuli with ageing with an upregulation of a range of cell
surface receptors and an exaggerated microglial response
to a second inflammatory stimulus. This phenomenon is
called priming and its exact causes are unknown. It might
be caused by microglial senescence or by prolonged expo-
sure to the aged neuronal environment including the pres-
ence of amyloid beta (Aβ) protein. The result is that in aged
animal or AD mouse models, priming results in microglial
cells show that a markedly increased production of pro-
inflammatory cytokines, enhanced phagocytic activity
and an increased production of reactive oxygen species by
microglia follow this second stimuli. Thus, priming results
in a microglial state that are once activated cut across the
simple classification of M1 or M2 state by having elements
of both (Perry et al., 2010; Perry and Holmes, 2014).
It is clear from the above description that the activation
of microglial cells can have both beneficial and detrimental
effects. Classical activation of microglia (e.g. following trau-
matic brain injury and stroke) is associated with persistent
microglial activation, neuronal damage and reduced phago-
cytic removal of Aβ and detrimental outcomes on disease pro-
gression. However, activation of the alternative pathway might
be considered to have potentially positive effects by increasing
phagocytosis of Aβ (Koshinaga et al., 2000; Gentleman et al.,
2004; Tajiri et al., 2013). Indeed, cellular studies have shown
that microglia bind to soluble Aβ oligomers and Aβ fibrils
through the cell surface CD33 receptors (Griciuc et al., 2013).
This results in activation of microglia with extracellular enzy-
matic degradation of soluble Aβ and the phagocytosis of Aβ
fibrils and degradation in the endolysosomal pathway. Indeed,
in late-onset AD, inefficient clearance of Aβ by microglia
because of defects in the alternative pathway is thought to lead
to the accumulation of Aβ. This inefficient clearance is thought
to be caused in part by downregulation of CD33 receptors. In
support of this hypothesis, peripheral macrophages isolated
from subjects carrying the single nucleotide polymorphism
(SNP) in CD33 and established as a risk factor for the develop-
ment of AD have been shown to have reduced Aβ phagocyto-
sis (Bradshaw et al., 2013).
Inflammation in Alzheimer’s disease 509
49.2.1.2 Astrocytes
Astrocytes, unlike microglial cells, are ectodermally
derived (Campbell and Williams, 1978). Their role in medi-
ating CNS inflammation has been relatively neglected.
They have an important role in innate immunity, including
cytokine production, complement and nitric oxide produc-
tion (Sofroniew and Vinters, 2010). In AD astrocytes, like
microglia, Aβ plaques are found in a hypertrophic reactive
state and they also have a role in the internalization and
degradation of fibrillar Aβ (Medeiros and LaFerla, 2013).
In addition, astrocytes have a role in clearance of soluble
Aβ from the parenchyma to cerebral blood vessels, a pro-
cess that requires the presence of apolipoprotein E (ApoE)
(Koistinaho et al., 2004). In addition, astrocytes are central
to the maintenance of synaptic transmission and because of
their close contact with neurones and cerebral blood vessels
(the neurovascular unit) they can also act to modify BBB
permeability (Farina et al., 2007).
49.2.2 SYSTEMIC INFLAMMATION
AND ITS EFFECTS ON CNS
INFLAMMATION
In the past, the parenchyma of the CNS was considered
an ‘immunologically privileged site’ because the BBB was
thought to prevent the entry, or exit, of many molecules,
including antibodies from the periphery and was largely
devoid of macrophages, neutrophils and lymphocytes. This
historical concept has led to research on CNS inflamma-
tion being viewed in isolation and independent of systemic
inflammation occurring outside the CNS. However, com-
munication of the presence of systemic inflammation to
the brain is clearly supported by the constellation of cen-
trally derived symptoms that occur in animals following an
acute systemic bacterial or viral infection. This syndrome
is known as ‘sickness behaviour’ and includes anorexia,
depression, somnolence, decreased social interaction,
decreased concentration and fever and is an evolutionary
conserved, homeostatic mechanism that allows the body to
adapt to an insult (Hart, 1988). The state of the BBB in AD is
still uncertain, and although controversial, it is possible that
there may, in limited circumstances, be some direct entry of
immune cells (monocytes, macrophages) from the periph-
ery into the brain. Thus, it is known that sepsis (Lee and
Slutsky, 2010) and persistent peripheral inflammatory stim-
uli may compromise the BBB because of a breakdown of
the intercellular tight junctions caused by lipopolysaccha-
ride (LPS) and peptidoglycans (Nau et al., 2010). However,
there are a number of other communication routes from the
periphery to the brain that occur despite the presence of an
intact BBB. These include the following:
1. Stimulation of peripheral nerves (e.g. the vagus) by
cytokines and prostaglandin that signal to the medulla
oblongata and are relayed to the hypothalamus
(Ek et al., 1998; Dantzer et al., 2000).
510 Dementia
2. Direct actions of LPS or pro-inflammatory cytokines
at brain areas lacking a BBB, e.g. the circumventricu-
lar organs (Blatteis et al., 1983).
3. Direct action of LPS or pro-inflammatory cytokines of
perivascular macrophages in the neurovascular unit of
the BBB (Matsumura and Kobayashi, 2004).
In animals, unless the peripheral inflammatory event is
extreme, sickness behaviour is a relatively benign and tran-
sient phenomenon (Perry, 2010). Damage limitation in the
brain is in part due to the wide number of regulatory mecha-
nisms that reduce the pro-inflammatory response to an acute
challenge within the brain. Thus, following a peripheral sig-
nal the pro-inflammatory response in the brain appears to be
suppressed by the increased production of a large variety of
proteins from microglial cells including anti-inflammatory
cytokines IL-10; TGF-β and other cytokine signalling protein
suppressors (Rivest, 2009). However, in circumstances where
microglial cells are primed the response of these cells to even
a very modest peripheral inflammatory event is very different.
Here, the presence of even modest peripheral inflammation
can switch the ­protective downregulated state to a damag-
ing phenotype with increased pro-inflammatory cytokine
productive and oxidative stress and neuronal damage (Perry
and Holmes, 2014). This hypothesis is supported by animal
studies showing an exaggerated inflammatory and oxidative
stress response to peripheral stimuli in aged mice (Godbout
and Johnson, 2009), increased concentrations of IL-1β in the
CNS and neuronal apoptosis in the ME7 prion mouse after
peripheral challenge with the bacterial mimic LPS or the viral
mimic polyinosinic–polycytidylic acid (Cunningham et al.,
2005, 2009; Field et al., 2010).
49.2.3 MOLECULAR MEDIATORS OF CNS
INFLAMMATION
Both astrocytes and microglial cells are sources of a variety of
molecules that orchestrate the inflammatory response. These
include cytokines, chemokines, nitric oxide, hydrogen perox-
ide, complement and antimicrobial peptides (AMPS).
Cytokines in the brain are produced largely by microglia
and astrocytes. There is increasing evidence from animal
studies to suggest that the development of AD is preceded
by a relative increase in the pro-inflammatory cytokine
response (M1), e.g. TNF-α, IL-6 and IL-1β, and a reduced
anti-inflammatory cytokine response (M2), e.g. IL-4, IL-10
and IL-13. Thus, both cellular and animal studies of amy-
loid precursor protein (APP) transgenic mice show that
pro-inflammatory cytokine expression increases with
increasing Aβ levels (Patel et al., 2005). Several other inter-
actions also suggest an M1-like activation state to exist in
early AD. For example, in neurone–microglia co-cultures,
the synergistic action of Aβ with either interferon-γ or
CD40 ligand triggers TNF-α secretion and production of
neurotoxic reactive oxygen species (Meda et al., 1995; Tan
et al., 1999, 2002). Additionally, the innate immune r­ eceptor
Toll-like r­eceptor 4 (TLR4) is responsible for increased
c­ oncentrations of TNF-α in mouse models of AD (Jin et al.,
2008). However, although a pro-inflammatory cytokine
­expression drive may drive the development of the disease,
once there is appreciable cell death, mouse models show
that the inflammatory response more closely resembles an
acquired deactivation state becoming more muted with
active apoptosis (Streit et al., 2004; Streit, 2006).
Consistent with the priming hypothesis, in a mouse APP/
presenilin (PS)1 model of AD where microglial are primed
by the presence of Aβ, the additional transgenic expression
of a second pro-inflammatory stimulus (IL-1β) leads to a
robust inflammatory state and a reduction of amyloid plaque
pathology (Ghosh et al., 2013). In another study, expression
of interferon-γ in the brain of another amyloid mouse
model showed the ability of this pro-inflammatory cytokine
to enhance clearance of amyloid plaques, with a widespread
increase in astrogliosis and microgliosis (Chakrabarty et
al., 2010a, 2010b). Additionally, these mice had decreased
concentrations of soluble Aβ and Aβ plaque burden, with-
out altered APP processing. Similar results were obtained
following the expression of the pro-inflammatory cytokines
IL-6 and TNF-α (Chakrabarty et al., 2010a, 2010b, 2011)
and conversely, the expression of the anti-inflammatory
cytokine IL-4 resulted in an exacerbation of Aβ deposition
(Chakrabarty et al., 2012).
In addition to their direct actions via surface receptors,
cytokines also stimulate inducible nitric oxide synthase
(iNOS) in microglia and astroglia cells, producing high
concentrations of nitric oxide that is toxic to neurones,
whereas genetic knockouts of iNOS are protective in mouse
models of AD (Nathan et al., 2005). Likewise, nicotinamide
adenine dinucleotide phosphate (NADPH) oxidase is highly
expressed by microglia and rapidly activated by inflamma-
tory stimuli such as Aβ, resulting in production of hydro-
gen peroxide, which further promotes microglia activation
(Jekabsone et al., 2006; Choi et al., 2012).
Chemokines have a role to play in microglial migration to
areas of neuroinflammation, thereby potentially enhancing
local inflammation in AD (Savarin-Vuaillat and Ransohoff,
2007). In AD, upregulation of the chemokines CCL2, CCR3,
CCL4 and CCR5 has been reported in reactive microglia
and astrocytes (Ishizuka et al., 1997; Xia et al., 1998). In
in vitro studies of human post-mortem tissue, Aβ has been
shown to lead to the generation of CXCL8 (also known as
IL8), CCL2, CCL3 in human macrophages and astrocytes
(Lue et al., 2001; Smits et al., 2002).
The complement system is a major constituent of the innate
immune system, mainly involved in the defence against
pathogens. Activation of the proteolytic complement cas-
cade results in opsonization and in lysis of microorganisms.
In the brain, the major cells that contribute to the produc-
tion of proteins of the complement system are microglia and,
to a lesser extent, astrocytes (Veerhuis et al., 2011). Activated
factors of the complement system are associated with Aβ
deposits (Strohmeyer et al., 2002) and a number of genetic
variants of complement are associated with the develop-
ment of AD providing strong evidence for the importance

of the complement system in disease pathogenesis (Harold
et al., 2009; Lambert et al., 2009).
AMPS are produced by a large number of cells includ-
ing microglia and other phagocytes and endothelial cells in
the defence against pathogens (Lupetti et al., 2003). AMPS
are small proteins, usually less than 50 amino acids long,
that interact with the outer membrane of pathogens lead-
ing to pore formation and the destabilization of the mem-
brane (Cudic and Otvos, 2002; Radek and Gallo, 2007).
Oligomerization of AMPS is a key to the targeting and per-
meabilization of membranes (Kourie and Shorthouse, 2000)
with non-oligomerized fibrils having little antimicrobial
properties. AMPS also trigger the upregulation of TNF-α
and CXCL8. A number of cerebral AMPS are known to exist
including neuro-AMP but it has recently been recognized
that Aβ1–42 is an AMP (Soscia et al., 2010). Thus, it has been
hypothesized that the development of Aβ deposits in AD
may be initiated by pathogens originating in the periphery
and entering the brain following altered BBB permeability
(Welling et al., 2015). Whether the signalling mechanisms
communicating the presence of systemic inflammation to
the brain are also associated with increased brain AMPS are
not known, but animal studies have shown that peripheral
infections in animal with an intact BBB are associated with
the deposition of amyloid (Krstic et al., 2012).
49.3 CLINICAL STUDIES
49.3.1 RISK FACTORS
49.3.1.1 The ageing inflammatory
environment
Ageing is the major risk factor for the development of AD.
One possible explanation for this is the observed change in
the regulation of inflammatory pathways as we age, a con-
cept known as inflammaging (Franceschi et al., 2007). Thus,
as we get older there is a low-grade chronic upregulation of
the pro-inflammatory response and a relative decline in
adaptive immunity and the anti-inflammatory cell response
(Franceschi et al., 2007). The reasons for inflammaging are
thought to be due to various factors that increase the imbal-
ance between pro-inflammatory and anti-inflammatory
networks.
Possibly the most important group of inflammaging
factors is exposure to an increased range of inflamma-
tory diseases or events with age. Thus, age can be seen as a
proxy for lifelong exposure to these inflammatory events.
These events include pro-inflammatory conditions such
as recurrent acute or chronic inflammatory diseases that
directly or indirectly affect the brain from the systemic
environment.
Two major conditions, traumatic brain injury and stroke,
cause direct CNS inflammation. Human studies have
shown that a pro-inflammatory state can persist for months
Inflammation in Alzheimer’s disease 511
or years following traumatic brain injury (Koshinaga
et al., 2000; Ramlackhansingh et al., 2011) and several stud-
ies have established traumatic brain injury as a risk factor
for development of AD (Sivanandam and Thakur, 2012).
Likewise, although different mechanisms are involved in
the pathogenesis of stroke, there is increasing evidence that
the pro-inflammatory response to the damage caused by the
stroke accounts for its progression (Feuerstein et al., 1998).
Again, stroke is a well-established risk factor for the devel-
opment of AD (Honig et al., 2003).
A range of inflammatory conditions outside the CNS
are also known to act as risk factors for the development
of AD. Delirium, a condition largely attributed to the pres-
ence of a variety of acute systemic infections, is associ-
ated with an increased risk of developing dementia. Thus,
the increased risk of developing dementia in cognitively
intact individuals following a delirium is substantial with
a cumulative incidence of 55% after a 1-year follow-up
(Rahkonen et al., 2000). In addition, the risk of develop-
ing AD appears increased following the development of
an acute infection in the absence of an obvious delirium.
Thus, in a retrospective general practitioner database the
presence of one or more infections over a 5-year follow-
up period increased the odds of developing AD by around
twofold with risk increasing with age (Dunn et al., 2005).
In addition to acute infections there is also increasing evi-
dence for a role for low-grade chronic peripheral infections
being associated with increased risk. Thus, periodontitis,
a condition caused by chronic infection with periodontal
bacteria has been identified as a potential risk factor for
the development of AD (Stein et al., 2007) with research
showing that both elevated levels of antibodies against
periodontal bacteria and raised peripheral TNF-α are
associated with the disease (Kamer et al., 2009). Likewise,
although not all studies have been consistent (Shiota et al.,
2011), the gut bacterium Helicobacter pylori has also been
identified as a possible risk factor for the development
of AD (Kountouras et al., 2006; Shiota et al., 2011). In
addition to infective agents, aseptic chronic inflamma-
tory conditions including atherosclerosis (Casserly and
Topol, 2004), diabetes (Donath and Shoelson, 2011) and
depressive illness (Andersen et al., 2005) have a robust
epidemiological basis for being proposed as risk factors in
the development of AD. For all of these risk factors, the
individual attributable risk is likely to be small (Launer
et al., 1999). However, the combined cumulative effects
over time might be considerable.
Importantly, there are a number of modifying factors
that can influence the onset of inflammaging. One impor-
tant modifying factor is age-related endocrine dyscrasia.
Thus, the loss of sex steroids and associated elevation of
gonadotrophins as we age is associated with an increase
in the pro-inflammatory state and the development of AD
pathology (Clark and Atwood, 2011; Butchart et al., 2013).
Likewise, lifestyle factors may also modify inflammaging
and delay the onset of AD, including exercise and calorific
restriction (Ngandu et al., 2015).
512 Dementia
49.3.1.2 Genetic factors
Following ageing, genetic inheritance is considered the sec-
ond most important risk factor for the development of AD.
In a small number of individuals, less than 0.1% of the
total AD population, mutations in one of three genes, pre-
senilin 1, presenilin 2 and APP, or a duplication of the APP
gene (Campion et al., 1999; Rovelet-Lecrux et al., 2006) is
directly responsible for the development of early-onset AD
by altering amyloid processing so that Aβ deposition is
greatly enhanced (Hardy, 2006). However, the majority of
the cases of AD are of late onset. Genome-wide association
studies (GWAS) have now established that, in addition to the
well-established genetic risk factor ApoE ε4, a large number
of less common genetic polymorphisms are also associated
with increased risk of developing late-onset AD. While these
new risk alleles have a much smaller individual effect on AD
susceptibility than ApoE ε4 there is good evidence to suggest
that, in combination, they have a substantial impact on AD
predisposition. Thus, estimates of the population-attribut-
able fractions for these individual new loci are smaller than
for ApoE ε4 (in the range 1%–8.1% c.f. 27.3%) but the cumu-
lative population-attributable fraction effect is 31.7% and is
therefore comparable (Lambert et al., 2013).
Of the genetic variants identified by GWAS the immune
and complement system/inflammatory response pathway is
the most substantial accounting for 11 of the 22 genes iden-
tified to date. Thus the first two large-scale GWAS (Harold
et al., 2009; Lambert et al., 2009) both identified poly-
morphisms in the genes encoding complement receptor 1
(CR1) and clusterin. CR1 has binding sites for complement
factors C3b and C4b. Like ApoE, clusterin is involved in
lipid transport, but it has also been hypothesized to influ-
ence receptor-mediated clearance of Aβ from the brain by
microglial endocytosis (Nuutinen et al., 2009). Two sub-
sequent studies (Hollingworth et al., 2011; Naj et al., 2011)
identified six additional genes (CD33, the MS4A6–MS4A4
cluster, ABCA7, CD2AP, BIN1 and EPHA1), the products
of which are all postulated to be involved in immune sys-
tem activation. A further large, two-stage meta-analysis of
AD (Lambert et al., 2013) has identified three further genes
involved in inflammatory processes including HLA-DRB5-
CDRB1, INPP5D and MEF2C.
More recently, a rare genetic variant involved in innate
immunity with an effect size comparable to ApoE ε4 has
also been identified. Thus, two independent data sets have
identified a rare missense mutation in triggering receptor
expressed on myeloid cells 2 (TREM2), which gives rise
to a threefold increase in the risk of AD (Guerreiro et al.,
2013; Jonsson et al., 2013). TREM2 is highly expressed on
microglial cells and its expression is thought to suppress
pro-inflammatory cytokine production (Neumann and
Takahashi, 2007) suggesting that these variants confer a
heightened risk of AD by increasing the pro-inflammatory
response.
Thus, while early genetic studies found variation in
genes affecting amyloid metabolism as being the key genetic
component of early-onset AD, more recent studies have now
identified inflammatory pathways as a major component of
late-onset AD.
49.3.2 BLOOD AND CEREBROSPINAL
FLUID (CSF) MARKERS
A number of studies have tried to establish differences
in serum or plasma markers of inflammation between
AD populations and aged matched control groups in
cross-sectional studies. A meta-analysis of these studies
(Swardfager et al., 2010) suggests that overall there are
increases in pro-inflammatory cytokines in AD compared
with control groups, although clearly cross-sectional
studies cannot establish whether this is cause or effect.
More convincing data come from longitudinal studies.
Thus, C-reactive protein (CRP) and IL-6 have been found
to be elevated 5 years before the clinical onset of dementia
(Engelhart et al., 2004; Tilvis et al., 2004; Kuo et al., 2005).
Indeed, a raised CRP in midlife has been associated with
a threefold increased risk of developing AD up to 25 years
later (Laurin et al., 2009) and has been shown to be raised
in prodromal AD (Hu et al., 2012). Another study has found
that higher levels of serum soluble TNF receptors (TNFR1
and TNFR2) in mild cognitive impairment (MCI) subjects
are also associated with an increase in the development of
dementia over a 4- to 6-year follow-up period (Buchhave
et al., 2010). Furthermore, a proteomics study that had
not a priori identified inflammatory protein candidates
as potential markers of disease development reported the
­presence of a number of plasma inflammatory proteins,
including complement factors and clusterin to be associated
with hippocampal atrophy and clinical progression in MCI
and AD (Thambisetty and Lovestone, 2010). In another AD
cohort, evidence of acute and chronic systemic inflamma-
tory diseases was associated with raised serum TNF-α levels
and an exacerbation of sickness behaviour-like symptoms
and increased cognitive decline (Holmes et al., 2009, 2011).
Several studies have also examined concentrations of
cytokines in the CSF of patients with MCI and AD. Here
increased concentrations of the pro-inflammatory cytokine
TNF-α and decreased levels of the anti-inflammatory cyto-
kine TGF-β have been shown to be risk factors for increased
rates of cognitive decline as well as conversion of MCI to
AD (Tarkowski et al., 2003; Galimberti et al., 2008).
49.3.3 IMAGING STUDIES
Most imaging studies of inflammation have focused on the
direct examination of microglial activation using transloca-
tor protein (TSPO) ligands. Cross-sectional positron emis-
sion tomography (PET) studies support evidence of an up
to 50% increased binding of 11C-PK11195 in the frontal and
temporal cortex of AD (Diorio et al., 1991; Cagnin et al., 2001;
Edison et al., 2008; Okello et al., 2009; Venneti et al., 2009;
Wiley et al., 2009) and an increase uptake of up to 33% of
11C-DAA1106 in patients with AD (Yasuno et al., 2012). AD

studies that have examined both microglial and Aβ markers
have found significant correlations between cognitive scores
and both TSPO ligands 11C-PK11195 and 11C-PBR28 (Kreisl
et al., 2013) but not with the amyloid ligand Pittsburgh com-
pound B (11C-PIB) binding (Edison et al., 2008; Yokokura
et al., 2011) supporting the view that microglial activation
rather than Aβ alone may be a key change leading to neuro-
degeneration. The lack of correlation of 11C-PIB binding and
cognitive scores together with the failure to find a strong
relationship between the 11C-PK11195 microglial activation
marker and 11C-PIB binding (Edison et al., 2008; Okello
et al., 2009; Wiley et al., 2009; Yokokura et al., 2011) is sup-
portive of the hypothesis that microglial activation follow-
ing the initial priming of microglial is independent of the
continued presence of Aβ and may explain why removal of
Aβ in established AD does not influence cognitive decline
(Holmes et al., 2008).
In MCI, the detection of inflammation is mixed. Thus,
one study using 11C-PK11195 detected inflammation in 40%
of amnestic cases (Okello et al., 2009). An MCI study using
11C-DAA1106 showed a 30% increase in uptake in the lat-
eral temporal cortex compared with controls (Yasuno et al.,
2012). In this study, around 70% patients with MCI with
high 11C-DAA1106 uptake progressed to dementia during a
2-year follow-up period.
Few studies have examined the effects of inflammation
on other brain imaging markers in AD. However, interest-
ingly one study has shown increased fibrillar Aβ deposi-
tion as shown by 11C-PIB in the brains of subjects carrying
the rs3865444 allele in the CD33 AD susceptibility locus
(Bradshaw et al., 2013).
49.4 THERAPEUTIC STRATEGIES
Given the increasing evidence for a role for inflammation in
the development and progression of AD it is disappointing
to see mixed findings from a wide range of treatment stud-
ies aimed at modulating inflammatory pathways.
In AD, small early trials with indomethacin suggested
some evidence of reduced cognitive decline (Rogers et al.,
1993). However, this study was not replicated in a later
follow-up study (de Jong et al., 2008). Large-scale studies
of other nonsteroidal anti-inflammatory drugs (NSAIDs)
including naproxen (Aisen et al., 2003) and rofecoxib
(Reines et al., 2004) in AD have also been unsuccessful.
Randomized trials with a range of other anti-inflammatory
drugs, including prednisolone (Aisen et al., 2000), hydroxy-
chloroquine (Van Gool et al., 2001), simvastatin (Simons
et al., 2002), atorvastatin (Sparks et al., 2005; Feldman
et al., 2010), aspirin (Bentham et al., 2008) and rosiglitazone
(Harrington et al., 2011) have also shown no clinically sig-
nificant changes in primary cognitive outcomes in patients
with AD. More recently, a small study of AD subjects using
the TNF-α inhibiting agent etanercept in AD does show
some evidence of a reduction of decline on a number of
Inflammation in Alzheimer’s disease 513
clinical outcomes, but it has yet to be replicated (Butchart
et al., 2015).
Epidemiological studies of the protective effects of
NSAIDs are more positive. Thus, the incidence of AD in
cohorts of older people taking NSAIDs has been examined
in several large prospective studies (McGeer and McGeer,
2007). The largest of these prospective studies, the Baltimore
Longitudinal Study of Aging, found a relative risk of AD
of 0.35 for 10 years of NSAID use (Stewart et al., 1997). A
meta-analysis of case–control studies found that regular
NSAID use was associated with a twofold reduction in the
odds of developing AD (odds ratio [OR] = 0.5; p = 0.0002)
(McGeer et al., 1996) and, not included in this analysis,
the largest case–control study to date (49,349 cases and
196,850 matched controls) (Vlad et al., 2008) also showed
a significant reduction in odds of developing AD after
5 years of regular use, with a combined OR of 0.76. However,
randomized placebo control trials examining the possible
protective effects seen in these epidemiological studies
are more mixed. Thus a large trial of rofecoxib examin-
ing conversion of MCI subjects to AD found an increased
risk of conversion in the MCI-treated group (Thal et al.,
2005). Likewise a large randomized study of the NSAIDs
naproxen and celecoxib in asymptomatic individuals with a
family history of AD initially reported an increased risk of
increased cognitive decline or development of AD for both
drugs (ADAPT Research Group et al., 2007). However, a
longer-term follow-up of these patients suggests that care-
ful selection of asymptomatic patients and the choice of
the specific NSAID are important (Breitner et al., 2011).
Thus, the early detrimental effects were mostly in a small
group of patients with early cognitive impairment and
naproxen seemed thereafter to be protective in patients
for up to 4 years in those who had been asymptomatic at
baseline (Breitner et al., 2011; Alzheimer’s Disease Anti-
inflammatory Prevention Trial Research Group, 2013).
Although speculative, the reasons for these mixed find-
ings are likely to be found in the variability in the inflam-
matory state as the disease progresses and in the ability of
agents to target the key pathways. Thus, early interventions
prior to development of Aβ may benefit from approaches
aimed at dampening down the largely peripherally driven
M1 activation state seen in inflammaging and thus reduc-
ing the drive towards Aβ deposition. However, once Aβ is
deposited and microglial cells are primed the high sensitiv-
ity of these cells to central and systemic pro-inflammatory
signals and the damaging nature of the activated primed
microglial cell response is likely to require a peripheral
and/or centrally targeted robust suppression of the pro-
inflammatory pathway to reduce neuronal damage at the
potential expense of reducing Aβ phagocytosis. Finally, in
the later stages of AD, when the inflammatory state more
closely resembles an acquired deactivation state interven-
tions aimed at reducing the pro-inflammatory drive or
promoting an anti-inflammatory drive are less likely to be
beneficial and other approaches, e.g. anti-apoptotic drugs,
may be needed.
514 Dementia
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Genetics of Alzheimer’s disease
MARGIE SMITH
50.1 INTRODUCTION
The genetic architecture of Alzheimer’s disease (AD) remains
elusive despite the success in identifying patients with rare
autosomal dominant early-onset AD (EOAD). Mutations
in three genes, the amyloid protein precursor (APP or AD1)
and the presenilin genes (PSEN1 or AD3 and PSEN2 or
AD4), located on chromosomes 21, 14 and 1, respectively,
exert their effect in a fully penetrant manner.
The gene that encodes apolipoprotein E (ApoE or AD2)
is the only genetic variant, which consistently influences
disease risk and it is reported in association with late-onset
AD (LOAD). Contrastingly, susceptibility for LOAD shows
a less obvious familial aggregation and is, therefore, likely to
be governed by a number of risk alleles located on a number
of different genes. Continued research in this complex area
of the genes and proteins involved in AD will help establish
a logical basis for therapeutics and management.
50.2 HERITABLE CAUSES OF AD
50.2.1 CHROMOSOMAL
All individuals with Down’s syndrome (trisomy 21) will
develop AD after the age of 40 due to the lifelong overex-
pression of APP located on chromosome 21, which encodes
the amyloid precursor protein. The neuropathologic hall-
marks of AD presumably are due to the APP gene.
It was the observation that all individuals with Down’s
syndrome develop AD that implied a relationship between
chromosome 21 and AD pathology (Mann et al., 1984, 1989).
50.2.2 LATE-ONSET FAMILIAL AD (AD2)
Molecular genetic investigations have revealed that 25%
of LOAD is familial, which is defined as two or more
50
family members having AD. However, both familial
and non-­familial cases of AD have the same clinical and
pathological presentations. Familial and non-familial AD
­differ in relation to family history and molecular analysis.
The molecular and genetic basis of AD has been ­studied
Rosenberg et al. (2000), Sleegers and Van Duijn (2001),
Nussbaum and Ellis (2003), Goedert and Spillantini (2006)
and Roses and Saunders (2006).
A diagnosis of late-onset familial AD (FAD) is estab-
lished with multiple cases of AD with an age of onset after
the age of 60–65 years. Molecular genetic investigations
support the concept that AD2 is a complex disorder that
may involve a large number of susceptibility genes. Bertram
et al. (2008) reported the findings of meta-analysis of this
data.
50.2.3 ApoE GENETICS AND LOAD
The associations of the ApoE genotypes ε2/ε4, ε3/ε4 and ε4/
ε4 with LOAD have been verified in a number of studies
(Jarvik et al., 1996; Khachaturian et al., 2004; Martins et
al., 2005).
●● The ApoE ε4 allele shows the strongest association in
AD compared with normal population. The ε4 allele
occurs in 19% of FAD cases versus 1% found in the
normal control population.
●● The presence of the ApoE ε4/ε4 genotype in a patient
with a clinical diagnosis of AD elevates the diagnostic
certainty to 97%.
●● The ApoE genotype is not specific for AD since 42% of
persons with AD do not harbour an ApoE ε4 allele. In
summary, the absence of an ApoE ε4 allele does not rule
out the diagnosis of AD (Mayeux et al., 1998).
●● The ApoE ε4 allele is associated with late-onset FAD
with those individuals harbouring an ε4 allele being
at a greater risk of developing AD at an earlier age
(Khachaturian et al., 2004).
519
520 Dementia
●● The estimated lifetime risks for developing AD based
on ApoE genotype and gender have been determined
(Breitner et al., 2009).
●● The clinical utility of ApoE genotyping remains
unclear with the presence of either one or two copies
of the ε4 allele being sufficient to establish a diagnosis
of AD.
●● The clinical utility of ApoE genotyping may be as an
adjunct to confirm a diagnosis of AD in those present-
ing with the clinical symptoms of AD.
50.2.4 OTHER GENETIC CONTRIBUTIONS
UNDER INVESTIGATION
●● Researchers have simultaneously implicated the
p.Arg47His genetic variant in TREM2. The frequency of
this genetic variant in the general population is 0.5%–1%.
●● A2M is located on chromosome 12 (Dodel et al., 2000;
Gibson et al., 2000; Depboylu et al., 2006).
●● CALHM1 is located on chromosome 10q24 and has
a role in calcium homeostasis and a single nucleotide
polymorphism (SNP) has been reported to be associated
with LOAD (Dreses-Werringloer et al., 2008).
●● A SNP has been identified in CD33 (Bertram et al.,
2008). CD33 that inhibits microglia uptake of amyloid
beta has been implicated in AD (Griciuc et al., 2013).
●● Clusterin has been reported to collate with AD sever-
ity, pathology and clinical progression. Confirmatory
genetic association studies supported the finding as
well as CR1 and a phosphatidylinositol-binding clath-
rin assembly protein (PICALM) (Harold et al., 2009;
Lambert et al., 2009).
●● GAB2 is located on chromosome 11q14 and ApoE ε4
(Reiman et al., 2007).
●● GST01 and GST02 are located on chromosome 10 (Li et
al., 2003).
●● PLD3 is on chromosome 19q13.2 (Cruchaga et al., 2014).
●● TOMM40 is located in close proximity to the ApoE
locus on chromosome 19 and has been implicated in
relation to LOAD first by linkage analysis (Potkin et
al., 2009) and second by the presence of poly-t variable
length repeat region (Roses et al., 2010).
50.2.5 OTHER CANDIDATE GENES
GWAS meta-analysis has implicated the following can-
didate genes, some of which have been previously indi-
cated, as risk factors for AD (Lambert et al., 2013). Eleven
new susceptibility loci were identified in addition to the
already known apolipoprotein E (ApoE), ATP-binding cas-
sette sub-family A member (ABCA7), bridging integrator
1 (BIN1), clusterin (CLU), complement component (3b/4b)
receptor (CRI), CD2-associated protein (CD2AP), EPHA1,
membrane-spanning 4-domains, subfamily A, member 6A
(MS4A6A-MS4A4E) and PICALM genes. The importance
of the 11 newly identified loci was significant since it rein-
forced the importance of possible pathways thought to be
involved in the pathogenesis of AD.
The candidate genes are involved in pathways that have
been reported to be enriched in AD, specifically inflamma-
tion and immune response (HLA-DRB5-DRB1, INPP5D
and MEF2C), cell migration (PTK2B), lipid transport and
endocytosis (SORL1). It has been postulated that newly
identified pathways include hippocampal synaptic func-
tion (MEF2C and PTK2B), regulation of gene expression
(INPP5D) and cytoskeletal function and axonal transport
(CELF1, NME8 and CASS4).
50.3 MOLECULAR GENETICS OF EOAD
The three known genetic subtypes of familial EOAD APP,
PSEN1 and PSEN2 can only be distinguished by molecular
genetic testing (Tsuang et al., 1999). A diagnosis of famil-
ial EOAD is made in families with multiple cases of AD in
which the mean age of onset is 60–65 years.
Mutations in three genes, APP, PSEN1 and PSEN2 genes,
alter the production of the amyloid-β (Aβ) peptide, the
principal component of senile plaques (Tanzi and Bertram,
2005). In the 20 years since the discovery of the APP gene,
it has only been relatively recently that the interaction with
the PSEN1 and PSEN2 genes has been elucidated. Aβ is gen-
erated from APP by sequential cleavage of two enzymes:
β-secretase and β-secretase. All of the pathogenic mutations
that are currently known to cause autosomal dominant
EOAD are located either in the APP gene itself or in genes
that encode the proteins that are located in the catalytic cen-
tre of the β-secretase complex.
Unique pathologies not seen in the ‘sporadic’ or LOAD
have been reported when these genes are mutated. The
historical review of each gene gives a perspective into the
understanding of EOAD, the phenotypes and the early
understanding of the biochemical pathways involved. To
molgen website has a catalogue of all of the reported muta-
tions in the APP, PSEN1 and PSEN2 genes (http://www.
molgen.ua.ac.be/AD).
50.3.1 MUTATIONS IN THE APP GENE
The APP gene was implicated as a potential locus for AD
mutations based on four main intersecting lines of evidence.
First, it is well known that individuals with Down’s syn-
drome (Trisomy 21) develop the pathological lesions of AD
by the fourth decade. This evidence implied a relationship
between chromosome 21 and AD pathology (Mann et al.,
1984, 1989). Second, a 40- to 42-amino acid proteolytic pep-
tide (Aβ) of the full-length APP is a major constituent of
senile plaques (Masters et al., 1985; Goldgaber et al., 1987
Kang et al., 1987). Genetic linkage studies have shown an
additional line of evidence for linkage to a locus associated
with EOAD in the region of chromosome 21 containing the

APP gene (St George-Hyslop et al., 1987; Goate et al., 1989).
Finally, a missense mutation (APP E693Q) was identified in
the Aβ region of the APP gene characterized by hereditary
cerebral haemorrhage with amyloidosis of the Dutch type
(HCHWA-D) (Levy et al., 1990; Kamino et al., 1992). This is
a rare disorder caused by severe βA4 amyloid deposition in
meningeal and cerebral microvessels (Levy et al., 1990; Van
Broeckhoven et al., 1990). It was then shown that E693G
mutation causes AD by increasing amyloid β-protofibril
formation and decreasing amyloid β levels in plasma and
conditioned media (Nilsberth et al., 2000). Three different
mutations were reported at codon 693: the ‘Dutch’ muta-
tion (Glu22Gln), the Arctic Glu22Gly mutation and ‘Italian’
mutation (Glu22Lys). Peptides of the wild-type ‘Dutch’
and ‘Italian’ variants were made and their cytotoxic effects
were evaluated in human cerebral endothelial cells in cul-
ture. The effect of each mutation was different under these
conditions, the E22Q peptide exhibiting the highest con-
tent of beta-sheet formation and aggregation properties.
In contrast, the ‘Dutch’ variant peptide induced apoptosis
of cerebral endothelial cells. These results indicated that a
change in amino acid at position 22 confers distinct struc-
tural properties on the peptides that affect the onset of the
inexorable disease process (Miravalle et al., 2000). After the
initial finding of the E693Q mutation, a sequence variation
affecting the valine at codon 717 (position 46 relative to the
βA4 sequence) was found to be associated with the EOAD
phenotype. At least 13 families worldwide were identi-
fied with a V717I mutation, conferring an age of onset for
AD in the mid-fifties (Goate et al., 1991; Hardy et al., 1991;
Naruse et al., 1991; Fidani et al., 1992; Sorbi et al., 1993, 1995;
Brooks et al., 1995; Campion et al., 1996; Matsumura et al.,
1996; Campion et al., 1999; Finckh et al., 2000). A ‘mixed’
phenotype of AD and/or severe cerebral amyloid angiopa-
thy is caused by a mutation (A692G) at the βA4 residue 21
adjacent to the E693Q HCHWA-D (Hendriks et al., 1992).
This finding provided supporting evidence for the hypoth-
esis that HCHWA-D and AD are pathological variants of
the same disease, being associated with a phenotype of AD
or other βA4 amyloidosis-related disorders. A double muta-
tion (K670N and M671L) in a large Swedish EOAD kindred
with a mean age of onset of 55 years was identified (Mullan
et al., 1992). More recently, four other APP mutations
have been identified, the Austrian (Thr714Ile) (De Jonghe et
al., 2000), Florida (Ile716Val) (Eckman et al., 1997), French
(Val715Met) (Ancolio et al., 1999) and the Australian
(Leu723Pro) (Kwok et al., 2000a).
The Swedish double mutation was the first APP muta-
tion for which a direct effect on βA4 processing could be
demonstrated (Mullan et al., 1992). This double point muta-
tion (the ‘Swedish’ mutation) Lys670Met and Asp671Leu
is upstream of the β-secretase cleavage site and results in
a fivefold to eightfold increase in the formation of both
Aβ40 and Aβ42 (Citron et al., 1992). Two single-point muta-
tions at amino acid 717 (the ‘London’ mutation Val717Ile;
and the ‘Indiana’ mutation Val717Phe) are adjacent to the
β-secretase site and specifically increase the production of
Genetics of Alzheimer’s disease 521
Aβ42 (Suzuki et al., 1994), which is known to form insoluble
amyloid fibrils (Selkoe, 1994). Synthetic peptides contain-
ing the HCHWA mutation show accelerated fibril formation
(Wisniewski et al., 1991). The majority of APP mutation’s
molecular effect is to increase Aβ42 production (Hardy,
1997); however, overexpression of the Val715Met mutation
in human HEK293 cells and murine neurones reduces the
total Aβ production and increases the recovery of the physi-
ologically secreted product, APPβ. It was initially thought
that some cases of FAD were associated with a reduction of
in the overall production of Aβ; however, it was shown to be
caused by an increased production of truncated forms of Aβ
ending at the 42 position (Ancolio et al., 1999).
To date, there have been 32 APP mutations identified in
86 kindreds. These mutations exert their effect by increas-
ing Aβ production or Aβ42/Aβ40 ration. The mutations
are located in the Aβ coding region or close to the β- and
β-secretase sites of APP (Hardy, 1997). Recently, three
groups have reported a chromosome 21 genomic dupli-
cation of unknown size. The phenotype is variable with
congophillic amyloid angiopathy and Lewy body demen-
tia being described (Rovelet-Lecrux et al., 2006, 2007;
Sleegers et al., 2006). The duplications are of unknown
size and include not only the APP gene but also NCAM2,
NMRPL39, JAM2, ATPJ, GABPA, CYYR1, ADAMTS1 and
ADAMTS5 genes or APP, MRPL39, JAM2, ATP5J, GABPA,
CYYR1, ADAMTS1, ADAMTS5, ZNF294, USP16, CCT8
and BACH1 genes (Rovelet-Lecrux et al., 2006). The age of
onset and duration of the early-onset disease are variable
across the eight kindreds reported.
50.3.2 MUTATIONS IN THE PSEN1 GENE
After the initial finding of an EOAD locus on chromosome
21 it became apparent that the majority of EOAD kindreds
did not show linkage to chromosome 21 (Tanzi et al., 1987;
Van Broeckhoven et al., 1987; Schellenberg et al., 1988;
St George-Hyslop et al., 1990). The PSEN1 gene was iden-
tified in 1995 through positional cloning strategies. Five
mutations were identified in 8 of 14 pedigrees analysed
(Sherrington et al., 1995). All the mutations occurred within
highly conserved domains of the PS1 protein as shown by
comparison to the murine homologue that provides sup-
porting evidence that these mutations are indeed patho-
genic. Not all mutations occur at residues that are conserved
between PSEN1 and PSEN2. The PSEN1 gene was previ-
ously denoted as the S182 or AD3 locus; to date 177 muta-
tions have been detected in 392 kindreds in the PSEN1 gene.
The age of onset of AD due to PS1 mutations is accel-
erated; however, variability in age onset is observed.
The M139V and M146V mutations have an age of onset
around 40 years (Clark et al., 1995; Van Broeckhoven, 1995),
whereas for kindreds identified with the E280 and C410Y
mutations the age of onset is between 45 and 50 (Clark et
al., 1995; Sherrington et al., 1995); the Ala409Thr muta-
tion has an onset of 85 years (Aldudo et al., 1999). EOAD
linked to chromosome 14 is estimated to account for 70%
522 Dementia
of all EOAD pedigrees (St George-Hyslop et al., 1992; Van
Broeckhoven et al., 1992).
The phenotype of PSEN1 mutations is heterogeneous.
It was initially thought that the only difference between
AD and EOAD was the earlier age of onset (Sherrington et
al., 1995); however, there are five reports of AD associated
with spastic paraparesis (SP) of the lower limbs. The brain
pathology in one kindred was described as unique with
large plaques lacking the classical core of amyloid fibrils.
The term ‘cotton wool’ was coined by virtue of their size
and appearance (Crook et al., 1998). PSEN1 mutations asso-
ciated with SP include a small deletion in exon 4 (DeltaI83/
M84) (Steiner et al., 2001), an insertion of six nucleotides in
the coding region of exon 5 (from TAC to TTTATATAC)
between amino acids K155 and Y156, point mutations in the
coding region of exon 8 (Val261Phe) (Farlow et al., 2000)
and (Arg278Thr) (Kwok et al., 1997), a point mutation in the
splice acceptor consensus of intron 8 resulting in in-frame
skipping of exon 9 and an amino acid change at the splice
junction of exon 8 and exon 10 (g.58304G. A, c.869–955del)
(Sato et al., 1998; Kwok et al., 2000b), (g.58304G. T, c.869–
955del) (Perez-Tur et al., 1995; Hutton et al., 1996; Kwok
et al., 1997, 2000b) and large genomic deletions (g.56305–
62162del) (Kwok et al., 1997; Smith et al., 2001) identified in
an Australian kindred and (g.56681–61235) the Delta9Finn
kindred (Crook et al., 1998). Interestingly, a point muta-
tion in the splice donor consensus site of intron 4 resulting
in three different transcripts with a single-codon inser-
tion, partial and complete deletion of exon 4, respectively,
the latter two resulting in a frameshift and premature stop
codon (g.23024delG, c.338–339insTAC, c.170–338del, c.88–
338del) (Tysoe et al., 1998) is not associated with SP. It was
hypothesized that this mutation leads to AD through haplo-
insufficiency of full-length PSEN1. This is in direct contrast
to other PSEN1 mutations, which are thought to confer a
‘toxic’ gain of function in which Aβ42 secretion is selectively
increased (Tysoe et al., 1998). Other phenotypes associated
with EOAD are frontotemporal features (Raux et al., 2000),
myoclonic seizures (Ezquerra et al., 1999) and a psychiatric
disorder (Tedde et al., 2000).
Mutations are located throughout the PSEN1 protein;
however, their distribution may not be random. Mutations
tend to occur at residues conserved between PSEN1 and
PSEN2 and as such the majority are in transmembrane
domains. Specifically, the cluster of mutations in trans-
membrane 1, 2, 3, 4 and 6 line up on one side of the β-helix.
This helical face may be important for the interaction with
other transmembrane proteins (Clark et al., 1995). It was
suggested that disruption of the helical faces impaired
presenilin function so that more Aβ42 is produced (Hardy
and Crook, 2001). The majority of PS1 mutations cluster in
exon 8, which is close to the cleavage site. If this is a func-
tional domain then disruption of its function may be critical
to pathogenicity. The clustering of APP mutations around
the β-secretase, β-secretase and β-secretase sites lead to dif-
ferent molecular mechanisms; however, the outcome is the
same.
The normal biological and pathological functions of
PSEN1 were at that time poorly understood; however, there
was ample evidence for a role of PSEN1 in the proteolytic
processing of APP and in Notch processing (Wolfe et al.,
1999). PSEN1 is endoproteolytically cleaved between amino
acids 291 and 299 resulting in an N-terminal fragment of 30
kDa and a C-terminal fragment of 18 kDa (Thinakaran et
al., 1996). The proteolytic cleavage site is located in that part
of PSEN1 encoded by exon 9; therefore, the delta 9 mutant
does not undergo cleavage and accumulates as full-length
PS1 (Thinakaran et al., 1996). Conversely, the efficiency
of processing was shown not to be affected by missense
mutations in AD brains (Hendriks et al., 1997), in brains
of transgenic mice (Duff et al., 1996) and in transfected
cells (Borchelt et al., 1996). Cells transfected with PSEN1
mutants (M146V, A246G, A260V, G384A, C410T) have
impaired proteolysis (Mercken et al., 1996) and in lympho-
cytes of mutation carriers (Takahashi et al., 1999). There is
no correlation between different PS1 mutations, age onset
and Aβ42 (43) production in transfected embryonic kidney
cells (Mehta et al., 1998).
Overall, PSEN1 mutations increase the Aβ42/Aβ40 ratio.
The mutations are located throughout the protein and it has
been shown to have an enzymatic role in the β-secretase
complex. To date, 177 PSEN1 mutations have been identi-
fied in 392 kindreds, (http://www.molgen.ua.ac.be/AD).
50.3.3 MUTATIONS IN THE PS2 GENE
Directly after the identification of the PSEN1 cDNA
sequence, ‘expressed sequence tags’ (ESTs) were described
with a considerable homology to two different segments
within the PSEN1 open reading frame (T03796). Cloning
of the full-length complementary DNA (cDNA) of this cor-
responding gene, mapped to chromosome 1 enabled the
identification of missense mutations in cDNAs in affected
Volga-German subjects (Levy-Lahad et al., 1995). Evidence
of the physical genome mapping of PSEN2 on chromosome
1q42.1 was performed using fluorescence in situ hybridiza-
tion (Tokano et al., 1997). The majority of kindreds analysed
exhibited the N141I missense mutation, thereby identifying
a founder effect. EOAD onset in these kindred’s generally
occurs later than in EOAD kindreds linked to chromosome
14 but with a broader range of age at onset from 54.8 ± 8.4
years. The mean duration of disease is 11.3 ± 4.6 years and
the mean age at death approximately 66 years. Clinically
kindreds with PSEN1 mutations have a more aggressive
disease than those with PSEN2 mutations (Lampe et al.,
1994). The wide variation in age of onset indicates that other
genetic and or environmental factors influence the age of
onset. Non-penetrance over the age of 80 years has also been
observed (Sherrington et al., 1996). The penetrance is over
95% for PSEN2 kindreds; however, pre-symptomatic indi-
viduals harbouring the mutation over the age of 80 may
escape disease.
The exon 5 T122P mutation was found to be highly pen-
etrant unlike the previously reported PS2 mutations N141I

and M239V (Levy-Lahad et al., 1995). Consistent with the
variable penetrance of the N141I and M239V mutations, the
M239I mutation has associated phenotypic variability with
some affected individuals having an earlier onset and more
severe course than the index case (Finckh et al., 2000).
Fourteen mutations have been identified in 23 kindreds
(http://www.molgen.ua.ac.be/AD). The majority of these
mutations are localized to exons 3, 5, 6, 7, 10 and 12 of the
PSEN2 gene.
50.4 DIAGNOSTIC GENETIC TESTING
FOR AD
The identification of three genes causative for EOAD,
APP and recently PS1 and PS2 raises the question of the
role for genetic testing in AD. A consensus statement dis-
cussing the ethical aspects of the clinical introduction of
genetic testing for AD concluded, ‘except for autosomal
dominant early-onset families, genetic testing in asymp-
tomatic individuals is unwarranted’. Predictive testing
for EOAD was offered in research settings following the
identification of APP mutations on chromosome 21 using
established Huntington’s disease guidelines (Lennox et al.,
1994). The experience of three individuals belonging to a
Swedish kindred with early-onset autosomal dominant
AD was documented. Only three members of this large
kindred proceeded with predictive testing, indicating a
low demand for testing. One individual who was found
to harbour the mutation reacted with depressive and sui-
cidal feelings, while the other two subjects expressed relief
(Lannfelt et al., 1995).
The ApoE gene, which confers some susceptibility to
LOAD, has high commercial potential but the sensitivity
and specificity of the test are low. A asymptomatic individual
with an ε4 allele will not necessarily develop AD. However,
testing for ApoE ε4 may be useful as an aid for the diagno-
sis of individuals presenting with AD. Use of ApoE genetic
testing as a diagnostic adjunct in patients already present-
ing with dementia may prove useful, but it remains under
investigation. The premature introduction of genetic testing
and possible adverse consequences ‘are to be avoided’ (Post
et al., 1997). Athena Neurosciences in 1996 introduced the
Admark ApoE Genetic Test ‘for greater certainty in differ-
ential diagnosis of AD’. The requesting physician must sign
a consent stating that the individual has dementia prior to
ApoE genotyping being performed.
Predictive testing is performed when a known family
mutation has been identified in at least one other affected
family member. Pretest assessment and counselling involves
obtaining an accurate pedigree, neurological examination
(not compulsory) and psychological appraisal. This is criti-
cal to understanding the individual’s ability to cope with
the results of the test. EOAD contributes less than 5% of all
AD cases; therefore, there is no logical reason to perform
genetic testing beyond this small cohort.
Genetics of Alzheimer’s disease 523
50.5 CONCLUSIONS
Genetic studies of EOAD have had a significant impact on
our understanding of the pathogenesis of AD that in turn
has led to research into diagnostic and therapeutic strate-
gies and the availability of predictive testing of EOAD fami-
lies. However, as people with EOAD represent only 5% of all
those with AD, some of the focus of genetic research has now
shifted towards LOAD. Currently in LOAD, there appears to
be a complex interplay of many risk factors, much as is seen
in other pathogenic processes such as atherosclerosis. The
current complexity of this area undermines the role for risk
factor testing in LOAD. Understanding this genetic inter-
play is pivotal and likely to be the focus of genetic research
in the next decade.
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Blood and cerebrospinal fluid biomarkers for
Alzheimer’s disease
SIMONE LISTA, HENRIK ZETTERBERG, SID E. O’BRYANT, KAJ BLENNOW AND HARALD
HAMPEL
51.1 ROLE OF BIOMARKERS IN THE
DIAGNOSIS AND TREATMENT OF
ALZHEIMER’S DISEASE
In general, a biomarker defines a biological process or dis-
ease characteristic that is objectively measured (Biomarkers
Definitions Working Group, 2001). Such measurements
may be used for diagnostic purposes, but also to study phys-
iological or pathophysiological mechanisms and to evaluate
desired pharmacodynamic effects or side effects of pharma-
cological treatments. According to Biomarkers Definitions
Working Group: ‘Molecular and Biochemical Markers of
Alzheimer’s Disease’, the ideal biomarker for Alzheimer’s
disease (AD) should detect a fundamental feature of neu-
ropathology and be validated in neuropathologically con-
firmed cases as well as have a diagnostic accuracy of at least
80% (The Ronald and Nancy Reagan Research Institute
of the Alzheimer’s Association and National Institute on
Aging Working Group, 1998). With respect to clinically
relevant questions, such as detection, diagnosis, prediction
and treatment of a given disease, biomarkers may serve cer-
tain distinct functions (Hampel et al., 2010b; Hampel and
Lista, 2013), which are detailed in Table 51.1.
51.2 BIOMARKER DEVELOPMENT
Ideally, a biomarker should be reliable, reproducible, non-
invasive, simple to perform and inexpensive. Recommended
steps to establish a biomarker include confirmation by at
least two independent studies conducted by qualified inves-
tigators with the results published in peer-reviewed journals
528
51
(The Ronald and Nancy Reagan Research Institute of the
Alzheimer’s Association and National Institute on Aging
Working Group, 1998). Although, several AD biomarker
studies have been published, the clinical relevance and fea-
sibility of the investigated biomarkers are not completely
elucidated (Buerger and Hampel, 2009; O’Bryant, 2012;
Blennow et al., 2015a). A number of systematic development,
validation and standardization steps are required before a
biomarker becomes a reliable and precise asset to clinicians.
This process is as risky and may take as long as the devel-
opment period of a pharmacological compound in the neu-
roscience sector moving from preclinical stages to Phases 1–3
and finally regulatory approval. For a long time, this develop-
ment has been primarily done in academic institutions and
consortia, mostly independent from industry-led drug devel-
opments. In the advent of many failed trial programmes, the
significance of a parallel development of both compounds
and biomarkers through all development stages is begin-
ning to be appreciated. More than a decade of fragmented
work has substantially slowed and weakened drug develop-
ment within the neuroscience sector, particularly, in the AD
indication with the lowest number of successful regulatory
approvals. Since the field is moving into earlier disease stages,
prodromal forms and asymptomatic at risk stages, with no
clinical signs or symptoms, biomarker development is gain-
ing all the more importance in evolving trial designs.
First, the technical feasibility of the new marker has to
be established, including the availability of a validated assay
with high precision and reliability of measurement and well-
described reagents and standards. A relatively large number
of potential markers have successfully passed this first step.
Second, the possible marker has to be evaluated in a rela-
tively pure sample of diseased and comparison groups. This
is similar to the Phase 2 trial in therapeutics, but the goal
here is to make an initial assessment of its sensitivity and
 Blood and cerebrospinal fluid biomarkers for Alzheimer’s disease 529

Table 51.1 The same marker may subserve different listed functions, or it might be diagnostic and also be a useful
screening tool, or it may be both predictive and prognostic, or it can be used for monitoring purposes. It is also possible
that different biomarkers will be needed for different purposes

Function of biomarkers Description with Alzheimer’s disease (AD) as the example

Diagnostic function
Screening function
Prognostic function
Predictive (stratification)
function
Monitoring function
Abbreviation: MCI, mild cognitive impairment.
Biomarkers may assist in the clinical diagnosis. They may also facilitate the differentiation of
neurodegenerative from functional cognitive disorders (e.g. depression) in the elderly or
enable the differentiation of AD from non-AD dementias. A diagnostic biomarker should have
a sensitivity for detecting AD of at least 85% and its specificity in differentiating AD patients
from age-matched control subjects and from patients with other forms of dementia should
reach a sensitivity detection of at least 75% (The Ronald and Nancy Reagan Research Institute
of the Alzheimer’s Association and National Institute on Aging Working Group, 1998).
Biomarkers discriminate the ‘healthy’ state from early disease state, preferably in the
asymptomatic phase (pre-dementia stage of AD). They might assist early (preclinical)
diagnosis of AD and enable early intervention. Targets for the screening approach can be
entire population or subpopulations at risk (e.g. MCI).
Biomarkers can predict the likely course of the disease. They are associated with outcome
regardless of the treatment used on patients.
Biomarkers may be associated with outcome from a particular therapy directed against a
specific pathogenic mechanism identified by the biomarker. They predict the likely response
to a drug (e.g. an anti-amyloid substance) before starting treatment; thus, they classify
individuals as ‘responders’ as compared to likely ‘non-responders’.
Biomarkers can be used to monitor efficacy of a drug treatment once the responder status is
established. Within the setting of a clinical drug trial, a monitoring marker serves as a
‘surrogate marker’ if it is closely linked to a clinically meaningful treatment outcome (e.g.
cognition, functional abilities, quality of life); thus, it can be used as an outcome parameter
under a particular treatment.

specificity. Only very few AD biomarker candidates have
passed this step. In the next step, the new marker has to be
studied in a more representative population-based sample,
providing an assessment of its true diagnostic properties and
thus demonstrating its clinical usefulness within the clini-
cal setting and purpose for which the biomarker is intended.
Large-scale controlled multicentre biomarker trials are cur-
rently being conducted in American, Asian, Australian and
European Alzheimer networks in an attempt to systemati-
cally develop and validate core feasible candidate biomarkers
in research areas such as, neurobiochemistry and structural,
functional and metabolic neuroimaging (Blennow et al.,
2014; Hampel et al., 2012, 2014; Lista et al., 2014).
Two different approaches exist for the identification of
cerebrospinal fluid (CSF) biomarkers: the hypothesis-driven
candidate biomarker approach and the hypothesis-indepen-
dent exploratory -omics approach. The candidate biomarker
approach tries to identify a protein or molecule reflecting
known or hypothesized neurochemical changes underlying
mechanistic molecular and pathogenic processes, i.e. leading to
neurodegeneration. In AD biomarker research, the candidate
approach should reflect neuronal and synaptic degeneration,
‘mis-metabolism’ of the amyloid precursor protein (APP) and/
or aggregation of Aβ with subsequent deposition in plaques
and/or hyperphosphorylation of tau with subsequent formation
of paired helical filaments and tangles. The -omics based (i.e.
proteome) exploratory approach uses unbiased hypothesis-free
high throughput-omics (i.e. proteomic/molecular) methods
that try to identify biomarkers that can differentiate affected
cases from healthy controls and other comparisons, such as
various brain disorders, regardless of whether the biomarkers
may be directly known as linked to molecular or pathogenetic
processes. Exploratory proteome-based methods include two-
dimensional gel electrophoresis (2-DE), protein chips, or liquid
chromatography combined with liquid chromatography–mass
spectrometry (LC-MS) (Brinkmalm et al., 2015). Recent
approaches also involve the use of tandem mass tags for quan-
titative proteomics and peptidomics, which allow for the detec-
tion and quantification of hundreds of endogenous and tryptic
peptides in much larger sample numbers than what has been
possible before (Brinkmalm et al., 2015). Till date, the -omics
(i.e. proteomics) approach has not provided any validated and
standardized AD biomarkers.
51.3 DIAGNOSTIC BIOMARKERS
FOR AD
51.3.1 ESTABLISHED CSF BIOMARKERS
FOR AD
A large number of studies have shown that three core fea-
sible CSF biomarkers reflecting neuropathological changes
530 Dementia
associated with AD, namely the 42-amino acid form of
amyloid β (Aβ1-42), which correlates inversely with brain Aβ
plaque pathology and total and phosphorylated forms of tau
(T-tau and P-tau, respectively), which correlate with neu-
rodegeneration and tau pathology in AD, distinguish AD
patients from control individuals, as well as from patients
with other neurodegenerative diseases, such as Parkinson’s
disease and frontotemporal dementia (Blennow et al., 2010).
Further, these three biomarkers identify patients with mild
cognitive impairment (MCI) due to AD from patients with
MCI due to non-AD causes with positive and negative pre-
dictive values above 90% (Hansson et al., 2006; Shaw et al.,
2009; Visser et al., 2009) and are more than often dynami-
cally altered already during preclinical disease stages (Skoog
et al., 2003; Fagan et al., 2014). The CSF Aβ and tau mark-
ers were developed using a targeted approach; the molecu-
lar composition of the plaque and tangle changes originally
described by Alois Alzheimer in 1906 was revealed during
the 1980s and quantitative enzyme-linked immunosorbent
assays (ELISA) for the proteins were developed and refined
during the 1990s (Blennow et al., 1995).
The clear diagnostic utility of CSF Aβ1-42, T-tau and P-tau
have made it important to standardize the biomarker mea-
surements into clinical routine tests, where different meth-
ods can be calibrated to each other to give similar results
(low bias) with high analytical precision (low random
variation). Standardization efforts are ongoing within the
Global Biomarkers Standardization Consortium (GBSC),
Materials and Methods Working Groups (available at http://
www.alz.org/research/funding/global_biomarker_CSF_­
materials.asp) within the Alzheimer’s Association (AA)
and the International Federation of Clinical Chemistry
and Laboratory Medicine Working Group for CSF Proteins
(IFCC-WG-CSF) (available at http://www.ifcc.org/ifcc
-scientific-division/sd-­working-groups/csf-proteins-wg
-csf/), with the aim to standardize both pre-analytical and
laboratory procedures and to harmonize levels between assay
formats (Carrillo et al., 2013). Protocols for standardization
of procedures for CSF collection and sample handling as well
as shipment have been proposed, together with laboratory
procedures for run acceptance and batch bridging to main-
tain long-term stability of ELISA-based CSF biomarkers
(Palmqvist et al., 2014). Within the IFCC-WG-CSF, selected
reaction monitoring (SRM) mass spectrometry-based refer-
ence measurement procedures (RMP), i.e. ‘gold standard’
methods for CSF Aβ1-42, have been published (Leinenbach et
al., 2014; Korecka et al., 2014) and projects to develop RMPs
for CSF tau are ongoing. These methods for absolute quan-
tification of CSF Aβ1-42 will be used to set the exact levels
on a certified reference material (CRM), i.e. aliquoted CSF
pools with clinically relevant levels (high, medium and low)
of Aβ1-42, that will be used to normalize levels between assay
formats (Mattsson et al., 2012; Carrillo et al., 2013). Between-
laboratory and longitudinal (batch-related) variations are
monitored in the Alzheimer’s Association Quality Control
(QC) Programme for CSF biomarkers (Mattsson et al.,
2011a). These standardization efforts have also stimulated
biotech companies to develop upgraded and validated ver-
sions of assays and to set up CSF biomarker assays on fully
automated laboratory analyzers. These developments will
pave the way for uniform cut-off levels for the CSF biomark-
ers and a more general use of these diagnostic tools.
51.3.2 PLASMA BIOMARKERS
Several efforts to discover and develop diagnostic biomark-
ers for AD in peripheral blood have been done, as summa-
rized above (Lista et al., 2013). Plasma or serum biomarkers
are still experimental at Phases 1 and 2 of diagnostic vali-
dation; there are few candidates in pilot- and single-centre
studies, first of their kind that seem to perform close to
the diagnostic accuracy range achieved by established core
feasible CSF biomarkers (see below). The best studied can-
didate biomarker in plasma so far is Aβ, but the findings
are contradictory. In plasma, current assays allow the reli-
able measurement of Aβ1-40 and Aβ1-42 (although, additional
species most likely exist) and several studies have exam-
ined their association with dementia, AD and/or cerebral
β-amyloidosis. However, the results are less clear than those
derived from measuring CSF Aβ1-42 or from positron emis-
sion tomography (PET) studies and the significant associa-
tions, if any, are weak and go in either direction (Zetterberg
and Blennow, 2006; Ritchie et al., 2014). As no correlation
exists between CSF and plasma Aβ levels (Mehta et al., 2001;
Hansson et al., 2010), it is possible that most of the Aβ pep-
tides measured in plasma are derived from extra-cerebral
sources such as platelets in which APP expression and pro-
cessing are high in the α granules (Van Nostrand et al.,
1990). In the Alzheimer’s Disease Neuroimaging Initiative
(ADNI), plasma Aβ levels fail to differentiate AD patients
from control individuals and amyloid-positive from amy-
loid-negative individuals, although a weak positive rela-
tionship between plasma Aβ1-40:Aβ1-42 ratio and Aβ ligand
retention on PET was observed in APOE ε4-negative subjects
only (Swaminathan et al., 2014). Data from the Australian
Imaging, Biomarker and Lifestyle Flagship Study of Ageing
(AIBL) have highlighted that plasma Aβ levels are influ-
enced by inflammatory and renal function covariates and
that absolute levels of either Aβ1-40 or Aβ1-42 do not associate
with AD or neocortical Aβ burden (Rembach et al., 2014).
However, the Aβ1-42:Aβ1-40 ratio (note inverse ratio as com-
pared to the ADNI results above) was slightly reduced in
patients with AD and correlated inversely with neocortical
amyloid burden as determined by amyloid PET. In essence,
the ADNI and AIBL results corroborate each other and sug-
gest that plasma Aβ levels per se are not diagnostically use-
ful, but that the Aβ1-42:Aβ1-40 ratio may reflect mechanisms
loosely associated with cerebral β-amyloidosis.
Interestingly, recent ‘spectacular’ data based on a
highly sensitive immunoprecipitation mass spectrometry
approach have revealed a novel plasma Aβ fragment start-
ing at 3 amino acids N-terminally of Asp1 in the Aβ domain
and ending at Val40 (Kaneko et al., 2014). The ratio of this
fragment to Aβ1-42 discriminated 40 amyloid-positive (as
 Blood and cerebrospinal fluid biomarkers for Alzheimer’s disease 531
determined by amyloid PET) from 22 amyloid-negative
individuals with sensitivity and specificity of 92.5% and
95.5%, respectively (Kaneko et al., 2014). These promising
pilot data await independent replication.
With regard to other blood biomarker candidates,
researchers from AIBL, ADNI and AddNeuroMed have
identified multi-protein plasma biomarker panels that
together seem to identify individuals with pathological
brain Aβ accumulation with reasonable accuracy (Kiddle et
al., 2012; Burnham et al., 2014). As a consequence, a con-
siderable recent attention has been devoted towards multi-
marker blood-based biomarker panels that have utility in
detecting AD with recent work also examining the capacity
of the multi-marker approach in distinguishing AD from
non-AD dementias (O’Bryant et al., 2010; Doecke et al.,
2012; Hu et al., 2012; Burnham et al., 2014; Sattlecker et al.,
2014).
In a seminal study, Ray et al. (2007) identified a panel of 18
markers that were highly accurate in detecting AD as well as
predicting conversion from MCI to AD. Unfortunately, this
work was not replicated on an independent assay platform
(Soares et al., 2009). On the other hand, recent analyses have
been validated across cohorts (O’Bryant et al., 2011; Doecke
et al., 2012; Hu et al., 2012), assay platforms (Kiddle et al.,
2014; O’Bryant et al., 2014a) and even species (O’Bryant et
al., 2014b). Recent investigation also demonstrates the pos-
sibility that the blood-based biomarker profile approach can
be accurate in discriminating AD from Parkinson’s disease
(O’Bryant et al., 2014b). Altogether, these data suggest that
blood-based biomarker profiles are expected to be of great
utility in detecting AD and need to be validated in larger
population-based and/or primary care clinical settings.
However, it should also be taken into account that the
different biomarker panels are non-overlapping, some pro-
tein identities are surprising, with no clear link to known
disease mechanisms and therefore, additional validation
work is needed. Especially, multi-marker blood-based
biomarker studies are based on analysing a large set of
unselected proteins followed by generation of a multivari-
ate models showing diagnostic separation, while individ-
ual proteins show huge overlaps. Such statistical models
introduce a large risk of statistical overfitting of data (with
many more proteins than patients and controls introduced
into the model). Thus, models based on specific cohort
often fail to replicate in independent clinical cohorts. One
can conclude that additional efforts are required in order
to determine the potential of these approaches in discrim-
inating AD from non-AD dementia diseases.
51.3.3 NOVEL CANDIDATE BIOMARKERS
The search for new AD biomarker candidates may be
facilitated by the enrichment of core CSF AD biomarkers.
By including patients with characteristic biological signs
of an AD pathological process and ensuring that control
subjects lack this profile, future biomarker studies may be
more successful. Results from earlier studies may have been
clouded by the presence of non-symptomatic AD patients
in the control groups. A recent study on the effect size of
the major susceptibility gene for AD, APOE ε4, supports
this reasoning; when disregarding clinical information on
patients with cognitive impairment and simply grouping
them on the basis of CSF tau and Aβ markers, the associa-
tion of APOE ε4 with AD was twice as strong as compared to
classifying patients according to clinical status (Andreasson
et al., 2014).
The potential functions of AD biomarkers are many.
Besides diagnostics, CSF biomarkers may be utilized for
prognosis, assessing disease progression, developing treat-
ments, monitoring treatment effects and studying disease
mechanisms. Several studies have investigated the AD bio-
marker potential of various analytes related to Aβ.
51.3.4 BACE1
For Aβ to be produced, the APP is cut by two different
enzymes, β-secretase and γ-secretase. The major β-secretase
in the brain is called β-site APP cleaving enzyme-1 (BACE1).
Several studies have investigated the levels of CSF BACE1
activity in patients with MCI and AD but the results are not
univocal. Three small studies found that patients with AD
had increased BACE1 activity compared with non-demented
controls (Holsinger et al., 2004; Verheijen et al., 2006) or
patients with other dementia disorders (Holsinger et al.,
2006). One study found higher activity in patients with MCI
and dementia due to AD compared with controls (Zetterberg
et al., 2008). Another study found significantly elevated
BACE1 activity in subjects with MCI but not in patients
with AD when compared with controls (Zhong et al., 2007).
One study failed to show any differences in BACE1 activ-
ity between MCI and AD patients compared with controls
(Mulder et al., 2010). However, when patients with a patho-
logic profile of the core AD biomarkers were compared with
controls with a normal biomarker pattern, a significant eleva-
tion of BACE1 activity was found in the patient group. The
MCI subjects contributed the most to this elevation. Finally, a
large study conducted did not find any differences in activity
between AD patients and controls (Rosén et al., 2012). When
the AD patients were stratified into mild and moderate-to-
severe AD, an increased BACE1 activity could be seen in
the group with mild AD compared to the more affected AD
patients and controls. These studies indicate that the activity
of BACE1 may be mildly elevated in the early stages of AD
but the diagnostic usability of the biomarker seems limited.
BACE1 may, however, prove to be valuable for target engage-
ment or outcome in clinical trials of BACE1 inhibitors.
51.3.5 SAPPα/SAPPβ
The levels of sAPPα and sAPPβ correlate very well in
AD patients as well as controls (Zetterberg et al., 2008).
Several studies have failed to show any differences in the
532 Dementia
levels of these biomarkers between AD patients and con-
trols (Olsson et al., 2003; Zetterberg et al., 2008; Hertze
et al., 2010; Johansson et al., 2011; Rosén et al., 2012).
One study found higher levels of sAPPβ in MCI subjects
compared with controls (Olsson et al., 2003) and another
showed MCI subjects that upon follow-up developed AD
and had higher levels of sAPPβ than patients who did
not (Perneczky et al., 2011). However, Hertze et al. (2010)
found no differences in sAPP levels in MCI subjects with
incipient AD compared to stable MCI or patients that
developed other dementias. Studies that compared sub-
jects with MCI or dementia that had a pathologic core
CSF AD biomarker profile with controls with a normal
profile found that the former group had increased lev-
els of sAPPα and sAPPβ, but there were large overlaps
between these groups (Gabelle et al., 2010; Lewczuk et al.,
2010, 2012;). The diagnostic value of sAPPα and sAPPβ
thus appears limited. Yet, the proteins may be used for
studying effects on the APP metabolism in clinical trials
(Blennow et al., 2010).
51.3.6 Aβ OLIGOMERS
Soluble oligomers of Aβ may be more toxic than fibrillar
Aβ aggregates (Sakono and Zako, 2010). They can inhibit
hippocampal long-term potentiation in vivo (Walsh et al.,
2002) and cause abnormal tau phosphorylation and neu-
ritic dystrophy (Jin et al., 2011). A relatively large number
of assay formats to measure Aβ oligomers in CSF have been
published. These papers differ in size and molecular weight
of investigated oligomers and have shown that the CSF level
of Aβ oligomers is generally very low, probably, less than 1%
of total Aβ levels, and thereby very difficult to quantify in a
reliable manner.
In AD patients, elevated Aβ oligomer levels have been
found in brains (Shankar et al., 2008; Bruggink et al., 2013)
and CSF (Pitschke et al., 1998; Gao et al., 2010; Fukumoto
et al., 2010; Hölttä et al., 2013). However, not all studies
have found altered levels in AD patients versus controls
(Santos et al., 2012; Bruggink et al., 2013), but the latter of
these found a negative correlation between oligomer levels
and cognitive status, indicating a potential use for assess-
ing disease stage even as late as the AD dementia stage
(not correlation for the core CSF markers). This suggests a
potential value for Abeta oligomers as surrogate outcomes.
One study found elevated levels of oligomers in human and
mouse brains but not in CSF (Yang et al., 2013). Handoko
et al. (2013) found that CSF oligomer levels increased
with age and correlated with levels of T-tau in cognitively
normal older adults. Also, increased levels were found in
cognitively normal subjects with a biomarker profile indi-
cating impending AD (Handoko et al., 2013). Except for
technical difficulties to measure minute amounts of Aβ
oligomers in CSF samples, it is also possible that different
assays measure different variants of Aβ oligomers, which
might explain the divergent results. The studies provide
little characterization of what the various assays are even
measuring. Two recent studies have employed the ultra-
sensitive Erenna® platform (Singulex, Alameda, CA) to
measure CSF Aβ oligomers using oligomer-selective anti-
bodies, one of which reported elevated (Savage et al., 2014)
and the other unaltered (Yang et al., 2015) CSF levels of Aβ
oligomers.
51.3.7 OTHER CANDIDATE MARKERS
In addition to Αβ, tau and related markers, many other
biomarkers have been investigated to detect pathophysi-
ological processes that may be involved in or reflect AD
pathogenesis, e.g. microglial activation and synaptic
degeneration, or may aggravate the effects of AD neuro-
pathology more or less independently of the primary dis-
ease process, e.g. cerebrovascular disease or concomitant
Lewy body disease (LBD) or TAR-DNA-binding protein 43
(TDP-43) pathology.
The best established CSF biomarkers for microglial
activation so far are chitotriosidase, YKL-40 and che-
mokine CC motif ligand 2 (CCL2) (Craig-Schapiro et al.,
2010; Mattsson et al., 2011b). These markers are elevated
in CSF AD, but till date we do not know if they also reflect
disease intensity and clinical disease progression. To
that end, longitudinal studies are needed. With regard to
synaptic degeneration, several research groups have suc-
cessfully detected synaptic proteins in CSF (Davidsson
and Blennow, 1998; Davidsson et al., 1999; Thompson
et al., 2003; Zougman et al., 2008; Thorsell et al., 2010).
However, these studies have been performed on relatively
large quantities of pooled CSF. Moreover, it has also been
necessary to selectively purify and concentrate the tar-
get proteins in several steps and the quantitative aspects
of the techniques have been suboptimal. Recent break-
throughs in ultra-sensitive measurement techniques may
help resolving these issues (Rissin et al., 2010). There are
a number of other tau-independent markers of neurode-
generation also, e.g. heart-type fatty acid-binding protein
and visinin-like protein 1 (VILIP-1) (Steinacker et al.,
2004; Lee et al., 2008), which may be useful in clinical
trials to detect effects of tau-targeting therapies on neu-
rodegeneration in which the tau markers per se may be
affected by the treatment.
Cerebrovascular disease is at present best diagnosed
using neuroimaging, but there are CSF biomarker pat-
terns that may indicate changes typical of cerebral small
vessel disease, including elevated levels of neurofilament
light and matrix metalloproteinase proteins (Bjerke et al.,
2011). Alpha-synuclein (α-syn) is a potential biomarker
for LBD, but this association is less well established
than the relationship between CSF Aβ1-42 and cerebral
β-amyloidosis (Zetterberg et al., 2014). Assays of CSF
TDP-43 have been published (Geser et al., 2011), but the
association of this marker with TDP-43 pathology is so
far unknown.
 Blood and cerebrospinal fluid biomarkers for Alzheimer’s disease 533
51.4 THE ROLE OF BLOOD AND
CSF BIOMARKERS IN DRUG
DEVELOPMENT
51.4.1 BIOMARKERS AS END POINTS IN
AD CLINICAL DRUG TRIALS
51.4.1.1 Biomarkers for inclusion
The diagnostic accuracy of clinical MCI criteria for pre-
dementia or prodromal AD is low to moderate (Visser et
al., 2005). Their use may lead to inclusion of many patients
who do not have pre-dementia AD or exclusion of many
who suffer from it. This might partly explain the failure of
many of the previous drug trials in MCI target populations
(Jelic et al., 2006). In future trials, CSF-derived biomarkers
(e.g. different species of Aβ and tau protein) can serve as
early diagnostic indicators in order to enrich the number
of high-risk ‘true’ cases among subjects selected primar-
ily on clinical criteria (Hampel and Broich, 2009; Hampel
et al., 2015). There are currently two biomarkers for cere-
bral β-amyloidosis: (1) CSF levels of Aβ1-42 and (2) amyloid
PET. Both have been validated against neuropathology and
they show high diagnostic performance to identify AD as
well as are highly concordant with approximately 90% of
cases being either positive or negative for both biomarkers
(Blennow et al., 2015b). CSF Aβ1-42 and amyloid PET have a
central position in the newly revised criteria for prodromal
AD outlined by the International Working Group (IWG) for
the diagnosis of AD (Dubois et al., 2014) and in the National
Institute on Aging and Alzheimer’s Association (NIA-AA)
criteria for AD dementia (McKhann et al., 2011) and MCI
due to AD (Albert et al., 2011). Although, these two Aβ bio-
marker modalities provide independent information about
some aspects of the disease process related to AD (Mattsson
et al., 2014), the high concordance between CSF and PET
Aβ for classification of AD suggests that they may be used
interchangeably for diagnosis (Blennow et al., 2015b). This
approach could considerably increase the statistical power
and, in turn, decrease sample size and trial costs. Core
feasible CSF biomarker candidates, in addition to APOE
genotyping are currently recommended to be introduced
for meaningful enrichment in MCI populations to decrease
heterogeneity of study in target population, data variance
and enhance rate of cognitive decline and progression as
well as time taken to conversion to AD, particularly, in
proof of concept studies (Siemers et al., 2007, 2009; Hampel
and Broich, 2009). As an example, the Phase 3 solanezumab
and gantenerumab trials employ CSF Aβ1-42 or amyloid PET
(depending on availability) of enrichment of prodromal AD
cases in the screening of MCI cases.
It has also been proposed that the cardiovascular dis-
ease approach of subgrouping patients based on molecular
biomarkers has potential for improving therapeutic inter-
ventions in AD. That is to say, should specific subgroups
of AD patients be identified and targeted for precision-
based medicine approaches rather than the ‘one-size-fits-
all’ approach? Proof of concept data was recently presented
demonstrating that a blood-based profile of baseline
inflammatory status was highly accurate in identifying
treatment responders as well as adverse responders in a
previously conducted nonsteroidal anti-inflammatory
drug (NSAID) trial in AD (O’Bryant et al., 2014a). It seems
possible that CSF and blood-based biomarkers have poten-
tial for advancing a precision-medicine approach to treat-
ing and preventing AD.
51.4.1.2 Pharmacodynamic biomarkers
Depending on the mechanism of action of the drug, dif-
ferent biomarkers may be needed to detect target engage-
ment. Most disease-modifying drug candidates so far are
directed against Aβ pathology and different CSF Aβ mark-
ers (reviewed above) or amyloid PET may be useful to
detect pharmacodynamic effects of such drug candidates.
A ­disease-modifying drug against AD is not expected to
enhance cognition but should stop or at least slow down the
neurodegenerative process, which eventually should trans-
late into reduced cognitive decline over time (Citron, 2010).
In order to help detecting positive drug effects on neu-
rodegeneration, a number of CSF biomarkers are available.
These include biomarkers for (1) neuroaxonal degeneration,
(2) tangle pathology and (3) synaptic loss.
CSF biomarkers for neuroaxonal degeneration include
T-tau (measured using assays that detect all tau isoforms
irrespective of phosphorylation state), neurofilament light
and VILIP-1. Although tau is highly expressed in thin
unmyelinated axons of the cerebral cortex (Trojanowski et
al., 1989), neurofilament light is predominantly a marker
of large calibre myelinated axons that extend subcortically
connecting brain regions (Blennow et al., 2010). VILIP-1 is
highly expressed in neurones (Laterza et al., 2006) and CSF
levels of VILIP-1 correlate tightly with T-tau levels (Lee et
al., 2008). Both CSF T-tau and VILIP-1 levels are robustly
elevated in AD but not specific to the disease process as
such (Lee et al., 2008; Hampel et al., 2010a). CSF neurofila-
ment light levels are elevated in frontotemporal dementia,
amyotrophic lateral sclerosis and other disorders with pre-
dominant long white matter fibre tract involvement such
as vascular dementia, but is also significantly increased
in AD, especially, in late onset of the disease (Sjögren et
al., 2000; Zetterberg et al., 2007; Skillbäck et al., 2014a).
All three markers correlate positively with measures of
disease intensity and predict both clinical disease progres-
sion and survival, not only in AD but also in other dis-
eases (Wallin et al., 2010; Fagan et al., 2014; Skillbäck et
al., 2014a, 2014b).
Elevated CSF P-tau levels have been regarded as a rather
AD-characteristic phenomenon, which indicates tau phos-
phorylation in a manner that may be downstream of Aβ
pathology (Hampel et al., 2010a; Buchhave et al., 2012). CSF
534 Dementia
P-tau levels correlate with presence of cortical tangle pathol-
ogy (Buerger et al., 2006; Seppälä et al., 2012) and elevated
CSF P-tau levels support a diagnosis of AD (Hampel et al.,
2004). There are, in fact, differences in the classification
performance of different P-tau epitopes developed as ELISA
assays, favouring P-tau phosphorylated at threonine 231
as an earlier marker and significantly better differentiator
between AD and frontotemporal dementia (FTD) (Hampel
et al., 2004). Research into developing and comparing dif-
ferent assays looking at a variety of tau epitopes, which may
reflect different molecular signatures of distinct neurode-
generative diseases is promising and part of currently ongo-
ing studies.
Finally, synaptic loss and degeneration in AD and most
likely in other neurodegenerative diseases also may be
detected and monitored using CSF levels of the dendritic
protein neurogranin (Thorsell et al., 2010; Kvartsberg et al.,
2015) and the presynaptic SNARE complex component syn-
aptosomal-associated protein 25 (SNAP-25) (Brinkmalm
et al., 2014).
These three CSF biomarker categories all reflect inter-
related aspects of molecular mechanisms and subsequent
neuropathology, such as neurodegeneration in AD. Drug
candidates with a disease-modifying effect should nor-
malize or lower CSF levels of these proteins over a 6- to
12-month period of treatment. This time window is at pres-
ent hypothetical and extrapolated from studies on acute
conditions such as stroke and traumatic brain injury (Hesse
et al., 2001; Neselius et al., 2014) and the time window may
also depend on the mode of action of the drug and how
strong the disease-modifying effect is. Absence of such
changes speaks against the drug, irrespective of its precise
mode of action, being effective against the generic patho-
genic process in AD.
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Established treatments for Alzheimer’s disease
ALEXANDER KURZ AND NICOLA T. LAUTENSCHLAGER
52.1 INTRODUCTION
Approved treatments for Alzheimer’s disease (AD) target
biochemical abnormalities, which are a consequence of
nerve cell loss in forebrain nuclei and in the cerebral cor-
tex. Their mode of action thus addresses the final stretch of
a complex pathological cascade (Hardy, 2009) but does not
interfere with the mechanisms that induce neuronal degen-
eration. Cholinesterase inhibitors (ChEIs) partially restore
the deficit in acetylcholine, which arises from a significant
deficit of neurones in the nucleus basalis of Meynert and
in the central septal area, both of which project to corti-
cal regions (Bartus et al., 1982). Memantine attenuates the
toxic effects of glutamate, which is released in excess from
degenerating cortical neurones, but preserves physiological
glutamate-mediated signalling (Greenamyre et al., 1988).
Whether these therapies confer additional neuroprotective
potential in addition to purely symptomatic effects, has been
widely debated, but has not been demonstrated in human
studies (Lleó et al., 2006). ChEIs and memantine may only
be used for the treatment of patients with AD diagnosed
with dementia. In subjects with pre-dementia AD, ChEIs
did not achieve a clinically meaningful slowing of progres-
sion in the disease (Raschetti et al., 2007). The potential of
memantine for the secondary prevention of dementia has
not been explored.
52.2 CLINICAL EFFICACY
The clinical efficacy of anti-dementia treatments has been
evaluated in double-blind, randomized controlled clini-
cal trials (RCTs). These studies are usually designed to meet
the requirements for approval by regulatory authorities.
Current criteria for efficacy require demonstration of statisti-
cally significant differences between patients receiving active
52
treatment and patients receiving placebo on two or more rele-
vant domains. The U.S. Food and Drug Administration (FDA)
applies a dual outcome, which includes cognition to document
the specificity of the effect and a global assessment of overall
functioning to ensure that the effect is clinically meaningful
(Ad-hoc-FDA-Dementia-Assessment-Task-Force, 1991). The
European regulatory authority (The European Medicines
Agency [EMEA]) favours a triple outcome including global
impression, cognition and functional ability (Broich, 2007;
Katona et al., 2007). Treatment differences on these domains
are assessed using standardized and validated psychometric
instruments. Some frequently used clinical scales are listed in
Table 52.1. Since AD is a progressive disorder, deterioration
will occur in the placebo group over time. Hence, a difference
between active treatment and placebo does not necessarily
imply improvement from baseline, but often indicates less
worsening in actively treated patients. Participants in clinical
drug trials, particularly, in studies commissioned by manufac-
turers, are usually selected in terms of high treatment expecta-
tions, low co-morbidity, restricted concomitant medications
and few neuropsychiatric symptoms. Therefore, these popula-
tions are often not representative of patients seen in primary
or secondary care settings. Industry-sponsored trials typically
apply strict inclusion and exclusion criteria, which exclude the
majority of outpatients with AD (Gill et al., 2004). Treatment
duration is usually short, not exceeding 12–24 weeks. Only
few studies of anti-dementia drugs provide ­placebo-controlled
data beyond 6 months. For these reasons, clinical trials pur-
vey an incomplete and biased perspective on the efficacy and
tolerability of anti-dementia treatments. Many important
questions regarding generalizability of effects on less selected
patient populations, optimal duration of treatment, impact
on neuropsychiatric symptoms of dementia and relevance to
patient or caregiver quality of life remain largely unanswered.
This chapter draws primarily on meta-analysis. Individual
studies are referred to, with regard to patient subgroups who
are not covered by these analyses and in consideration of
less frequently used outcomes, treatment combinations and
539
540 Dementia

Table 52.1 Frequently used assessment instruments in clinical antidementia trials

Domain Instrument Score range Polarity References

Global assessment CIBIC, CIBIC-Plus 1–7 ≤3 better (Schneider, 1997)
4 no change
≥5 worse
GBS 0–162 Lower better (Gottfries et al., 1982)
CDR-SB 0–18 Lower better (Morris, 1993)
Cognitive ability MMSE 0–30 Higher better (Folstein et al., 1975)
ADAS-cog 0–70 Lower better (Rosen et al., 1984)
SIB 0–100 Higher better (Schmitt et al., 1997)
Activities of daily ADCS-ADL 0–110 Higher better (Galasko et al., 1997)
living
ADCS-ADL sev 0–54 Higher better (Galasko et al., 2005)
PDS 0–100 Higher better (DeJong et al., 1989)
DAD 0–40 Higher better (Gelinas, 1999)
Neuropsychiatric NPI 0–14 Lower better (Cummings et al.,
symptoms 1994)
Abbreviations: CIBIC, Clinician’s Interview-Based Impression of Change; CIBIC-Plus, Clinician-Based Impression of Change-Plus Caregiver
Input); GBS, The Gottfries–Brane–Steen Scale; CDR-SB, Clinical Dementia Rating Sum of Boxes; MMSE, The Mini-Mental
State Examination; ADAS-cog, Alzheimer’s Disease Assessment Scale-cognitive subscale; SIB, Severe Impairment Battery;
ADCS-ADL, Alzheimer’s Disease Cooperative Study-Activities of Daily Living scale; ADCS-ADL sev, Alzheimer’s Disease
Cooperative Study-Activities of Daily Living Scale for severe impairment; PDS, Progressive Deterioration Scale; DAD,
The Disability Assessment for Dementia; NPI, The Neuropsychiatric Inventory.

comparisons between drugs prescribed. Data are presented
on intent-to-treat ­populations if available.
52.2.1 TACRINE
Tacrine (tetrahydroaminoacridine, THA) is a non-­
competitive, reversible ChEI with a higher affinity for
­ was 2 points on the Alzheimer’s Disease Assessment Scale-
butyryl cholinesterase (BChE) than acetylcholinesterase
(AChE). In addition to its effects on cholinesterases, tacrine
inhibits monoamine oxidase activity, affects noradrena-
line, dopamine and serotonin uptake and release, increases
histamine levels, stimulates insulin secretion and increases
glucose metabolism (Wagstaff and McTavish, 1994). Tacrine
is metabolized in the liver. The plasma elimination half-life
is 3–4 hours with repeated oral doses. Tacrine was the first
ChEI approved for use in mild-to-moderate AD in the year
1993. Dosage is titrated according to tolerability, starting
with 10 mg four times daily to a patient, increasing up to
40 mg four times daily and a further increase at 4-to 6-week
intervals. Weekly monitoring of serum transaminase levels
is recommended for the first 18 weeks of therapy and for
the 6 weeks following each increase in dosage. Monitoring
should be carried out every 3 months after this course is
over. The clinical efficacy of tacrine was evaluated initially
in crossover studies taking into consideration small patient
samples with mixed results. These studies were followed by
larger trials, which shaped the current methodology of anti-
dementia drug evaluation (Wagstaff and McTavish, 1994).
In a meta-analysis, data were summarized from 12 studies
on a total of 1984 patients. Six studies had a crossover design
of which four involved exposure to tacrine prior to ran-
domization (enrichment), another six had a parallel-group
design of which three employed an enrichment strategy
(Qizilbash et al., 1998). Outcome measures varied greatly
across these studies. In these studies, which had durations
of 12–30 weeks, significant a­ dvantages were found favour-
ing tacrine on global assessment and cognition, but not on
activities of daily living (ADL). The difference from placebo
cognitive subscale (ADAS-cog) at 12 weeks and 1.4 units on
the Mini-Mental State Examination (MMSE) after 24 weeks
(Table 52.2). The major side effect of tacrine is liver toxicity,
which manifests as serum transaminase elevation (Watkins
et al., 1994). An increase above the upper limit of the norm
occurs in 36%–66% of patients, an increase more than three
times the upper limit of the norm is observed in 13%–50%
of treated individuals (Wagstaff and McTavish, 1994). Most
instances of liver toxicity are asymptomatic and reverse
within 4 weeks. Changes in liver function are rare. Tacrine
treatment is also associated with dose-dependent cholinergic
adverse events including nausea, vomiting, diarrhoea, dys-
pepsia and anorexia. Reported incidence rates are 14%–35%
for nausea and 4%–18% for diarrhoea (Raina et al., 2008).
In non-enriched studies, the likelihood of withdrawal was
significantly greater for tacrine as compared with ­placebo.
The most frequent reason for premature termination was
transaminase elevation.
52.2.2 DONEPEZIL
Donepezil is a piperidine-based, non-competitive revers-
ible ChEI, which shows much greater selectivity for AChE
than for BChE. It has a half-life of approximately 70 hours,
 Established treatments for Alzheimer’s disease 541

allowing once daily administration. Absorption of donepezil
is complete and uninfluenced by food or time of adminis-
tration. The drug is available in 5 and 10 mg preparations,
the lower dose often being prescribed in the initial 4 weeks
of treatment. Donepezil is metabolized via the liver and
eliminated primarily through the kidneys (Wilkinson,
1999). It received FDA approval for the treatment of mild-
to-­moderate dementia in AD in the year 1996, which was
expanded to the treatment of severe dementia in AD in
the year 2006. The evidence that accrued from 15 clinical
trials including 4406 participants was summarized in a
meta-analysis (Birks and Harvey, 2006) (Table 52.3). Global
assessment scales revealed significant advantages favour-
ing donepezil at both the 5 and 10 mg daily doses after 24
and 52 weeks of treatment, respectively. The proportion of
patients rated as improved on the Clinician’s Interview-
Based Impression of Change Plus Caregiver Input (CIBIC-
Plus) was 10%–15% larger in actively treated patients than
in patients receiving placebo. On cognitive scales, there
were significant treatment differences on the ADAS-cog of
2.0 and 2.8 points for the 5 and 10 mg doses, respectively,
on the MMSE of 1.4 points at 24 weeks independently of the
dose and 1.8 points for the high dose at 52 weeks and on the
Severe Impairment Battery (SIB) of 5.5 points for the high
dose at 24 weeks. Donepezil significantly improved ADL
and neuropsychiatric symptoms relative to placebo levels.
Withdrawals due to adverse events and patients suffering at
least one adverse event were significantly more frequent in
the donepezil than in the placebo groups. Adverse events
seen more frequently in the donepezil groups than in the

Table 52.2 Summary of clinical trials with tacrine

Statistical
Domain Instrument Duration (weeks) Treatment difference significance
Global assessment CIBIC 12–30 OR 1.58 0.002
Cognitive ability ADAS-cog 12 2.07 <0.001
MMSE 24 1.41 0.001
Activities of daily PDS 6 0.75 n.s.
living
Tolerability Withdrawals 12–30 OR 3.68 <0.001
Source: Qizilbash, N. et al., JAMA, 281, 2287–2288, 1998.
Abbreviations: OR, odds ratio; n.s., not significant.

Table 52.3 Summary of clinical trials with donepezil

Dosage (mg/ Duration Treatment Statistical

Domain Instrument day) (weeks) difference significance
Global assessment CIBIC-Plus 5 24 15 <0.0001
% improved 10 11 <0.0001
GBS 10 52 6.01 0.05
CDR-SB 5 24 0.51 <0.0001
Cognitive ability ADAS-cog 5 24 2.02 <0.0001
10 2.81 <0.0001
MMSE 5 24 1.44 0.0004
10 52 1.34 <0.0001
10 1.84 0.006
SIB 10 24 5.55 <0.0001
Activities of daily DAD 10 24 8.00 0.0004
living ADCS-ADL 10 52 1.60 0.02
PDS 10 3.80 0.0004
Neuropsychiatric NPI 10 24 2.62 0.02
symptoms
Tolerability Withdrawals due 10 24 5 0.003
to adverse
events %
Patients with at 5 24 7 0.03
least one 10 5 0.008
adverse
event %
Source: Birks, J., Cochrane Database Systematic Reviews, (1), CD005593, 2006.
542 Dementia
placebo groups were cholinergic in nature and included
nausea, vomiting and diarrhoea. No significant group dif-
ference was found in this trial regarding global assessment.
In patients with moderate-to-severe dementia (MMSE base-
line score 5–17) statistically significant advantages of done-
pezil in relation to placebo were observed at 24 weeks on
global assessment, cognitive ability, ADL and behavioural
disturbances of similar magnitude as seen in the mild-to-
moderate subgroup (Feldman et al., 2001). In one study con-
ducted on patients with severe dementia (baseline MMSE
score ≤ 10), a statistically significant improvement of cog-
nitive ability over baseline was observed in conjunction
with less decline on ADL (Winblad et al., 2006). In a second
independent study on patients with severe dementia (base-
line MMSE score ≤ 12), subjects receiving donepezil showed
a significant advantage of cognitive ability in relation to
placebo-treated patients at 24 weeks, which was mainly
due to deterioration in the placebo group. There was also
a significant advantage on global assessment but no treat-
ment difference on ADL in this study (Black et al., 2007).
No effect of donepezil on neuropsychiatric symptoms was
seen in studies involving patients with severe dementia.
At the other end of the severity spectrum, in subjects with
amnestic mild cognitive impairment (aMCI), donepezil had
a small effect on cognitive ability but not on global func-
tion after 48 weeks of treatment (Doody et al., 2009). There
was no significant effect of donepezil on the progression to
dementia within 3 years in a patient (Petersen et al., 2005).
Donepezil is the only anti-dementia medication for
which placebo-controlled data are available beyond treat-
ment durations of 6 months. Information on 12 months was
obtained from a trial on 286 patients with mild-to-­moderate
dementia (MMSE scores 10–26). On a global assessment
scale (Gottfries–Bråne–Steen [GBS] scale) patients receiving
donepezil had declined by week 52, as had placebo-treated
subjects, but there was a statistically significant advantage
for active treatment. Regarding cognitive ability, patients
treated with donepezil showed little deterioration on the
MMSE at study end point relative to baseline, whereas
worsening by 2.2 points had occurred in patients receiv-
ing placebo. This indicates that donepezil offset cognitive
decline in this patient group by almost 1 year. No statisti-
cally significant effects on neuropsychiatric symptoms were
observed (Winblad et al., 2001). Another 12-month study on
531 patients with moderate dementia (MMSE score 10–20)
used predefined clinically evident decline in function as the
primary outcome. Significantly, more patients in the pla-
cebo group than in the donepezil group reached this end
point. Survival analysis revealed that the mean time to clini-
cally evident functional decline was 5 months longer in the
actively treated patients (Mohs et al., 2001). The only study
which provided randomized and placebo-controlled evi-
dence on the efficacy of donepezil beyond 1 year was carried
out in a primary care setting, independent of the manufac-
turer. Small but statistically significant treatment differences
on cognitive ability and ADL were maintained for 2 years.
However, no significant effect of donepezil was detected
on nursing home admissions and progression of disability,
which had been defined as the primary outcomes in this
study (Courtney et al., 2004). Due to methodological prob-
lems including lack of statistical power, high dropout rate
and unusual treatment schemes, this trial probably underes-
timated the true drug effects (Black and Szalai, 2004).
The symptomatic benefits of ChEI treatment may be
lost with disease progression despite continued treatment.
It was, therefore, hypothesized that higher than standard
doses might sustain treatment-related benefits for longer. In
a study on 1371 patients with moderate-to-severe demen-
tia in AD who had received donepezil at 10 mg/day for ≥12
weeks were randomized to receive 23 mg/day or conven-
tional 10 mg/day for 24 weeks. Small but statistically signifi-
cant benefits favouring the higher-than-standard dose were
observed for cognitive ability but not for global assessment.
The rate of treatment-associated adverse events was higher
in the higher-dosage group (Farlow et al., 2010).
52.2.3 RIVASTIGMINE
Rivastigmine is a slowly reversible, non-competitive
inhibitor of AChE and BChE and has a phenylcarbamate
structure. Since the activity of AChE declines, the activ-
ity of BChE remains unchanged or even increases as AD
progresses (Perry et al., 1978), the dual-enzyme inhibition
holds particular promise for patients with moderate and
severe dementia. The metabolism of rivastigmine is largely
independent of the cytochrome P450 (CYP) liver enzyme
system and the risk of interactions with other drugs is low.
After binding to its target enzyme, the carbamate por-
tion of rivastigmine is slowly hydrolyzed and eliminated.
Rivastigmine has a half-life of 2 hours and requires at least
twice daily oral dosage, starting with 3 mg/day, increased
to between 6 and 12 mg/day, according to individual tol-
erability (Polinsky, 1998). Rivastigmine was approved for
the treatment of mild-to-moderate dementia in AD in the
year 2000. A meta-analysis summarized the results of 13
RCTs, which included 5121 participants with mild-to-
severe dementia in AD (baseline MMSE 10–26) who were
treated for up to 12 months (Birks et al., 2009) (Table 52.4).
After 24 to 26 weeks of treatment, rivastigmine at a dose
of 6–12 mg/day was associated with significant advantages
relative to placebo on global assessment, cognitive abil-
ity and ADL. The treatment differences were 2 ADAS-cog
points, 0.8 MMSE points and 4.5 points on the SIB. No sig-
nificant effect on neuropsychiatric symptoms was found.
The lower dosage of 1–4 mg/day was associated with sig-
nificant treatment differences on global assessment and
cognition, but not on ADL. The incidence of withdrawals
due to adverse events and the proportion of patients suf-
fering at least one adverse event were significantly higher
in patients treated with 6–12 mg/day rivastigmine than in
patients receiving placebo. The most frequent adverse event
seen in these patients were vomiting, diarrhoea, anorexia,
 Established treatments for Alzheimer’s disease 543

Table 52.4 Summary of clinical trials with rivastigmine

Dosage (mg/ Duration Treatment Statistical

Domain Instrument day) (weeks) difference significance
Global assessment CIBIC-Plus 1–4 26 6 0.01
% improved 6–12 7 <0.0001
Cognitive ability ADAS-cog 1–4 26 0.84 0.01
6–12 1.99 <0.0001
ADAS-cog 1–4 26 2 n.s.
% ≥ 4 units 6–12 6 <0.01
MMSE 1–4 26 0.43 0.02
6–12 0.83 <0.0001
SIB 6–12 26 4.53 0.03
Activities of daily PDS 1–4 26 0.4 n.s.
living ADCS-ADL 6–12 2.15 <0.0001
6–12 1.8 0.03
Neuropsychiatric NPI 3–12 24 2.2 n.s.
symptoms
Tolerability Withdrawals due 1–4 26 0 n.s.
to adverse 6–12 15 <0.01
events %
Patients with at 1–4 26 1 n.s.
least one 6–12 12 <0.01
adverse event
%
Source: Birks, J. et al., Cochrane Database Systematic Reviews, (1), CD001191, 2009.

headache, syncope, abdominal pain and dizziness. In one
study on patients with severe dementia in AD (MMSE
score 5–12), there were statistically significant advantages
of rivastigmine relative to placebo on global assessment
and cognitive ability but not on ADL or behavioural dis-
turbance at 26 weeks (López-Pousa et al., 2004). The treat-
ment difference was 4 points on the SIB. There is only one
small placebo-controlled RCT on rivastigmine over 12
months (Karaman et al., 2005). Patients were included
with ‘advanced moderate’ dementia in AD (MMSE score
≤ 14). At study end point, statistically significant treat-
ment differences favouring rivastigmine were observed
in 0.4 units on the Alzheimer’s Disease Cooperative Study
(ADCS) – Clinical Global Impression of Change (CGIC),
of 5.3 points on the ADAS-cog and of 4.3 units on the
Progressive Deterioration Scale (PDS). Patients treated
with 6–12 mg/day showed greater benefit than patients
treated with a lower dose. In subjects with aMCI, no dif-
ferences between rivastigmine and placebo were observed
on cognitive ability or on progression to dementia after 48
months of treatment (Feldman et al., 2007).
In 2007, a transdermal formulation of rivastigmine
became available, which delivers 9.5 mg/24 hours. The effi-
cacy of the rivastigmine patch is equivalent to the capsule
at a dose of 12 mg/day, but tolerability is better (Winblad
et al., 2007). The number of patients experiencing at least
one adverse event was 51% in patients using the patch
as compared to 63% in patients treated with capsules
(p = 0.02). The incidence of gastrointestinal side effects
including nausea, vomiting and weight loss was particu-
larly reduced. Mild skin irritation appears to be common
with 7%–8% of patients experiencing moderate-to-severe
erythema or pruritus (Cummings et al., 2010). As the effi-
cacy of rivastigmine has been shown to be dose dependent
a 13.3 mg/24 hours patch was developed and approved for
mild-to-severe dementia in the United States. A study on
567 patients with mild-to-moderate dementia in AD who
showed a prespecified amount of cognitive and functional
decline following 24 to 48 weeks of open-label treatment
with 9.5 mg/24 hours rivastigmine were randomized to
receive either 9.5 or 813.3 mg/24 hours patch. At all time
points, cognitive scores and ratings of ADLs favoured
the higher dosage formulation. On the other hand, gas-
trointestinal side effects were more frequent in the higher
dosage group (Cummings et al., 2012). Specifically, nau-
sea, vomiting, lack of appetite and weight loss were about
twice as common with the 13.3 mg/24 hours patch as
compared with the 9.5 mg/24 hours patch. However, this
is still a lower rate than that associated with the capsule
formulation.
52.2.4 GALANTAMINE
Galantamine is a tertiary alkaloid, first isolated from
the bulbs of snowdrop and narcissus, now produced
­synthetically. It is a competitive, reversible inhibitor of
AChE with very little BChE activity (Harvey, 1995). In
addition, galantamine is an allosteric potentiatior of the
544 Dementia

action of AChE on nicotinic receptors (Maelicke, 2000). It
has a half-life of approximately 6 hours. The recommended
maintenance dose is 16–24 mg/day taken in two daily
doses. Galantamine was approved by the FDA for the
treatment of mild-to-moderate dementia in AD in the year
2001. A meta-analysis summarized the data from 10 clini-
cal trials on a total of 6805 patients with mild-to-moder-
ate dementia (Loy and Schneider, 2004) (Table 52.5). In
6-month studies, galantamine treatment was associated
with significant advantages relative to placebo on global
assessment, cognitive ability, ADL and neuropsychiatric
symptoms at the 16 mg/day dose. For the 8 mg/day dose,
the only significant treatment difference was observed on
measures of cognition. The 24 mg/day dose was not supe-
rior to the 16 mg/day dose. The treatment difference on
the ADAS-cog was 3 points at 6 months. At a dose of 24
mg/day, but not at a dose of 16 mg/day, the incidence of
withdrawals due to adverse events was higher in patients
treated with galantamine than in patients receiving pla-
cebo. Adverse events that were frequently observed in
patients on an active treatment with 16 mg/day galan-
tamine included nausea, vomiting and diarrhoea. The
higher dose galantamine treatment was associated with
an increased incidence of nausea, vomiting, dizziness,
weight loss, anorexia, tremor and headache. In nursing
home residents with severe dementia (n = 407), galan-
tamine titrated up to a maximum dose of 24 mg/day over
6 months was associated with a significant advantage over
placebo on cognitive ability but not on ADL (Burns et al.,
2009). Two studies on individuals with aMCI galantamine
did not show an effect on progression to dementia within
24 months (Winblad et al., 2008). Since 2005, galantamine
has been available as a prolonged release once daily dos-
age formulation (8, 16 and 24 mg), which shows similar
efficacy and tolerability to immediate release galantamine
at comparable doses (Brodaty et al., 2005).
52.2.5 MEMANTINE
Memantine is a non-competitive modulator of the N-methyl
d-aspartate (NMDA) receptor and works by normalizing
glutamatergic neurotransmission. It prevents excitatory
amino acid neurotoxicity, but does not interfere with the
physiological function of glutamate for learning and mem-
ory (Butterfield and Pocernich, 2003). Memantine reaches
maximal plasma concentrations 3–8 hours after oral
administration, is eliminated renally and has no inhibi-
tory effect on the cytochrome P450 (CYP) system, as well
as does not inhibit ChEIs (Jarvis and Figgitt, 2003). It is
administered twice daily up to a maximum dose of 20 mg/
day. Memantine was approved by the FDA in 2003 for use in
moderate-to-severe dementia in AD. A meta-analysis sum-
marized data from three clinical trials on 1291 patients with
moderate-to-severe dementia (baseline MMSE 3–14) and
from three unpublished studies in 997 patients with mild-
to-moderate dementia in AD, all of which were conducted
over 6-month periods (McShane et al., 2009) (Table 52.6).
In the moderate-to-severe groups data pooled indicated a
beneficial effect after 6 months on cognition, activities of
daily living, neuropsychiatric symptoms and global assess-
ment. In the mild-to-moderate groups, there was a marginal
beneficial on cognition that was barely detectable clinically
and was not accompanied by effects on behaviour or every-
day functioning. The tolerability of memantine does not
differ from placebo (Farlow et al., 2008). There are no con-
trolled data on the efficacy of memantine beyond 6 months.
In individuals with age-associated memory impairment,
memantine improves attention and information processing

Table 52.5 Summary of clinical trials with galantamine

Dosage (mg/ Duration Treatment Statistical

Domain Instrument day) (months) difference significance
Global assessment CIBIC-Plus 8 6 6 n.s.
% no change or 16 17 <0.0001
improved 24 16 <0.0001
Cognitive ability ADAS-cog 8 6 1.30 <0.05
16 3.10 <0.0001
24 3.13 <0.0001
Activities of daily ADCS-ADL 8 6 0.60 n.s.
living 16 3.10 <0.0001
24 2.30 <0.01
DAD 24 6 3.66 <0.01
Neuropsychiatric NPI 8 6 0.30 n.s.
symptoms 16 2.10 0.034
24 1.49 n.s.
Tolerability Withdrawals due 8 6 1 n.s.
to adverse 16 0 n.s.
events % 24 7 <0.001
Source: Loy, C. and Schneider, L., Cochrane Database Systematic Reviews, (1), CD001747, 2004.
 Established treatments for Alzheimer’s disease 545

Table 52.6 Summary of clinical trials with memantine

Duration Treatment Statistical

Domain Instrument Severity (months) difference significance
Global assessment CIBIC-Plus Mild to 6 0.13 0.03
moderate 0.28 <0.0001
Moderate to
severe
Cognitive ability ADAS-cog Mild to 6 0.99 0.001
moderate
SIB Moderate to 6 2.97 <0.0001
severe
Activities of daily ADCS-ADL Mild to 6 0.20 n.s.
living moderate
ADCS-ADL sev Moderate to 6 1.27 0.003
severe
Neuropsychiatric NPI Mild to 6 0.25 n.s.
symptoms moderate 2.76 0.004
Moderate to
severe
Tolerability Withdrawals Mild to 6 1.4 n.s.
before end % moderate 7.6a 0.005
Moderate to
severe
Patients with at Mild to 6 3 n.s.
least one moderate 2 n.s.
adverse event Moderate to
% severe
Source: McShane, R. et al., Cochrane Database Systematic Reviews., (1), CD003154, 2009.
a In favour of memantine.

speed (Ferris et al., 2007). No studies have been conducted
to determine whether memantine has a potential of delay-
ing the progression from aMCI to dementia. In 2010 an
extended-release formulation of memantine was approved
for the treatment of moderate-to-severe dementia in AD in
the United States and other countries, but not in Europe.
The advantages of this once-daily capsule are more conve-
nient dose regimen and lower pill burden (Plosker, 2015).
Efficacy and tolerability of the extended-release formulation
was examined in a RCT on an already ongoing ChEI treat-
ment (see Section 52.2.7).
52.2.6 COMPARISON BETWEEN
TREATMENTS
Donepezil was directly compared with rivastigmine in a
12-week trial and a 2-year study. The short-term trial was
sponsored by the makers of donepezil and included 111 sub-
jects with mild-to-moderate dementia. The study was not
blinded since dosage scheme and number of study visits
was different. Mean changes from baseline were similar in
both groups, with treatment differences of 0.16 points on
the ADAS-cog and 0.49 points on the MMSE. ADL and
behavioural disturbance were not assessed in this study. The
proportion of study completers was significantly greater in
the donepezil group (89%) than in the rivastigmine group
(60%), whereas the frequency of adverse events resulting in
premature discontinuation was higher in the rivastigmine
group (22%) than in the donepezil group (11%) (Wilkinson
et al., 2002). The 2-year study was sponsored by the manu-
facturer of rivastigmine. It included 998 individuals with
moderate dementia and preserved blinding by employing
a double-dummy design and identical visit schedules in
both groups. There was an almost identical decline of cog-
nitive ability from baseline in both groups at end point.
On ADL, however, patients treated with donepezil showed
significantly greater deterioration than patients receiving
rivastigmine. The treatment difference was 2 units on the
Alzheimer’s Disease Cooperative Study-Activities of Daily
Living (ADCS-ADL) scale. No statistically significant dif-
ference was detected between the two groups on neuro-
psychiatric symptoms. During the 16-week dose, titration
period of the study, more gastrointestinal adverse events
and more premature discontinuations were recorded in the
rivastigmine group than in the donepezil group. During
the maintenance period, however, the incidence of gastro-
intestinal adverse events and the number of withdrawals
before the end of study was similar in both groups (Bullock
et al., 2005). There are also two studies comparing done-
pezil with galantamine. A 12-week study sponsored by
546 Dementia
the makers of donepezil which included 120 subjects with
mild-to-­moderate dementia showed significantly greater
improvements from baseline on cognitive ability and ADL
in the donepezil group as compared with the galantamine
group. Treatment differences were 2.5 points on the ADAS-
cog, 1 point on the MMSE and 2.1 units on the Disability
Assessment for Dementia (DAD) (Jones et al., 2004). In con-
trast, a 52-week head-to-head trial including 182 patients
with moderate dementia sponsored by the manufacturer
of galantamine did not demonstrate statistically signifi-
cant differences between the two treatments on cognition
(ADAS-cog, MMSE), Bristol Activities of Daily Living Scale
and neuropsychiatric symptoms (the Neuropsychiatric
Inventory [NPI]). Rates of gastrointestinal adverse events
were similar in both groups (Wilcock et al., 2003). The only
study that directly compared donepezil with memantine
was conducted in China, where 100 patients with mild-
to-moderate dementia were randomized to receive either
donepezil at 5mg/day or memantine titrated up to 20 mg/
day throughout the trial. At the 16-month end point there
were no statistically significant differences between the two
groups regarding cognitive ability (MMSE) or ADL (Blessed
scale) (Hu et al., 2006). Results are questionable because
donepezil was administered at a low dose and the instru-
ment used for assessing everyday activities probably lacked
sensitivity to change.
52.2.7 TREATMENT COMBINATIONS
Pooled data from four trials including 1549 patients with
moderate-to-severe dementia in AD demonstrated small
but significant beneficial effects of the combination of ChEI
and memantine over ChEI alone for global assessment, cog-
nitive ability and neuropsychiatric symptoms. There were
no major differences between the combination therapy and
ChEI monotherapy regarding the rate of adverse events
(Schmidt et al., 2015). This systematic review and meta-
analysis includes a large RCT on 677 patients, which showed
that the extended release formulation of memantine (28 mg/
day) added to ongoing ChEI treatment also provided sig-
nificant gains on these three outcomes and was generally
well tolerated (Grossberg et al., 2013).
52.3 CLINICAL IMPORTANCE
The advantages provided by the active treatments relative to
P0125 placebo are small in comparison to the range of the
assessment instruments used for measurement. The average
treatment differences of ChEIs are 3%–4% on the ADAS-
cog (range 0–70), 3%–7% on the MMSE (range 0–30),
1%–2% on the ADCS-ADL (range 0–110) and 1%–2% on the
NPI (range 0–144). For memantine, the average treatment
differences are less than 2% on the ADAS-cog, less than 1%
on the ADCS-ADL and 1%–2% on the NPI. Even if treat-
ment gains of this magnitude attain statistical significance
in sufficiently large patient samples, whether they are
clinically meaningful or not is questionable (Molnar et al.,
2009). In the absence of a general consensus, several criteria
have been proposed for the evaluation of treatment effects
in the real-world context. These include improvement on
global assessment, slowing of cognitive deterioration, delay
in reaching significant clinical end points, reduction of
behavioural disturbance, attainment of individual patient
and caregiver goals and lowering the incidence of nursing
home admissions (Chin, 2008; Qaseem et al., 2008; Molnar
et al., 2009).
52.3.1 IMPROVEMENT ON GLOBAL
RATING
A 1-unit change on a seven-stage global assessment instru-
ment such as the CIBIC, would probably qualify as clini-
cally meaningful. However, the average advantage of
anti-dementia treatments relative to placebo is less than 0.5
units. In a pooled analysis of clinical trials with ChEIs, the
proportion of patients on active treatment who were rated as
improved on a global scale varied between 18% and 35% as
compared with 11%–28% in patients receiving placebo. This
means that less than 10% of patients improve with treatment
than without the same (Lanctôt et al., 2003).
52.3.2 SLOWING OF COGNITIVE
DETERIORATION
According to the FDA, compensating the natural history
of cognitive decline by at least 6 months is clinically rel-
evant. This equates to a 4 points or greater difference on
the ADAS-cog (Kramer-Ginsberg et al., 1988). None of the
approved AD treatments has achieved an average effect of
this magnitude. However, it should be noted that in a 1-year
study on patients with mild-to-moderate dementia in AD,
donepezil delayed the decline of cognitive ability by almost
1 year (Winblad et al., 2001) and memantine treatment
reduced the proportion of patients with moderate-to-severe
dementia showing marked clinical worsening (including a
deterioration on the ADAS-cog by ≥4 points) from about
21% to 11% (Wilkinson and Andersen, 2007).
52.3.3 DELAY IN REACHING SIGNIFICANT
CLINICAL END POINTS
Progression to disability is a robust criterion for the clini-
cal relevance of treatment effects. This outcome was
addressed in two double-blind, placebo-controlled studies
with donepezil. A 1-year study showed that donepezil treat-
ment extended the time to loss of critical ADL by 5 months
(Mohs et al., 2001). On the other hand, a long-term study
conducted independently of the pharmaceutical industry
in a primary care setting failed to demonstrate a delay in
the progression of disability and in reaching the threshold
of severe cognitive impairment. However, methodological

problems (idiosyncratic patient selection procedures and
criteria, lower than expected recruitment, high attrition
and repeated washout periods) may have affected the results
detrimentally (Courtney et al., 2004).
52.3.4 REDUCTION OF
NEUROPSYCHIATRIC SYMPTOMS
Clinical trials of anti-dementia drugs usually were not
designed to evaluate their effects on neuropsychiatric
symptoms associated with dementia, but measures of
behavioural problems were often secondary outcomes. Two
independent meta-analysis studies evaluating the behav-
ioural effects of ChEIs concluded that active treatment was
associated with an advantage relative to placebo of less than
2 units on the NPI. Even smaller effects were seen in patients
with moderate-to-severe dementia where neuropsychiatric
symptoms are particularly prevalent and effective treatment
is most needed (Trinh et al., 2003; Campbell et al., 2008). A
systematic review concluded that ChEIs have a weak impact
on behavioural disturbance of doubtful clinical impor-
tance (Grimmer and Kurz, 2006). The only RCT examining
the effects of a ChEI on acute neuropsychiatric symptoms
in patients with severe dementia was negative (Holmes et
al., 2007). According to a review of three double-blind,
placebo-controlled trials with memantine in patients with
moderate-to-severe dementia in AD, two studies found no
statistically significant difference between memantine and
placebo. One study detected a significant advantage favour-
ing memantine of 3.84 units on the NPI which was due to
worsening in the placebo group (Grossberg et al., 2009).
52.3.5 ATTAINMENT OF INDIVIDUAL
PATIENT AND CAREGIVER GOALS
In a 24-week study with galantamine, 12 weeks of which
were double-blind and placebo-controlled, patients on
active treatment showed statistically significant advantages
relative to placebo of 2 points on the ADAS-cog and 0.4 units
on the CIBIC-Plus. These treatment gains were entirely con-
sistent with the results of the meta-analyses reviewed above.
The attainment of individual goals, however, as defined by
patients and caregivers, was not different between the two
groups (Rockwood et al., 2006). Few trials included care-
giver burden or time spent on caregiving as an outcome and
showed small overall effects (Lingler et al., 2005).
52.3.6 LOWERING THE INCIDENCE OF
NURSING HOME ADMISSIONS
As a criterion for the clinical relevance of anti-dementia
drug effects, the incidence of nursing home admissions is
problematic. Institutionalization is not exclusively deter-
mined by factors that are modifiable through medications
such as cognitive impairment, limitation of everyday activi-
ties or neuropsychiatric symptoms. It is also triggered by
Established treatments for Alzheimer’s disease 547
factors which are intangible in anti-dementia drugs includ-
ing patient and caregiver physical health and availability
of community resources (Gaugel et al., 2009). Moreover,
depending on individual circumstances, nursing home
care may be a better alternative for patients with dementia
than remaining in the community. For ChEIs, uncontrolled
studies have demonstrated that higher dosage and longer
duration of the treatment were associated with reduced
incidence (Knopman et al., 1996; Beusterien et al., 2004) or
delay (Lopez et al., 2002; Geldmacher et al., 2003; Feldman
et al., 2009) of nursing home admissions. The risk of insti-
tutionalization was further reduced by combining ChEI
treatment with memantine (Lopez et al., 2009). These inves-
tigations are flawed, however, because patients were not ran-
domly allocated to dosage and duration of drug exposure
(Karlawish, 2004; Schneider and Quizilbash, 2004). The
only long-term placebo-controlled RCT which incorpo-
rated nursing home admission as a primary outcome cri-
terion failed to show an impact of donepezil on the rate of
institutionalization (Courtney et al., 2004).
52.4 PRACTICAL CONSIDERATIONS
The pharmacological effects of current AD treatments are
not large. Among the various outcomes examined, the delay
of cognitive and functional decline can be considered as
clinically meaningful, whereas the impact on neuropsychi-
atric symptoms and caregiver burden is of questionable sig-
nificance. Even modest clinical benefits, however, are highly
desirable in a disease which deprives affected individuals of
their intellectual capacity, undermines personal autonomy
and heavily burdens family carers (Burns and O’Brien,
2006). Against this background, opportunities for better
quality of life, more activity and increased participation
must not be missed, while avoiding treatment which lacks
practical utility. Achievement of these goals require timely
initiation of treatment, careful monitoring of individual
response, attention to safety issues, skilful use of switching
and combination strategies and long-term continuation.
52.4.1 TREATMENT INITIATION
To take full advantage of the symptom-delaying effect of
current medications, treatment should be initiated early, as
soon as the clinical diagnosis can be established with confi-
dence. Due to ceiling effects of the most common assessment
instruments (MMSE, ADAS-cog) this rational strategy col-
lides with treatment guidelines requiring improvement
rather than maintenance of cognition as a criterion of effi-
cacy. The role of early treatment is to preserve a maximum
of cognitive ability and functional independence for as long
as possible. In patients with mild dementia, a ChEI should
be used; in patients with moderate dementia either a ChEI
or memantine may be prescribed. Treatment expectations
of patients and carers should be focused on delaying decline
548 Dementia
and extending patient independence, rather than on overall
and durable improvement of symptoms (Farlow et al., 2008).
52.4.2 SAFETY ISSUES
The only contraindication to the use of anti-dementia med-
ication is known hypersensitivity to a specific drug or its
derivatives. ChEIs should be used with caution in patients
with a previous history of severe liver disease, pre-­existing
bradycardia, peptic ulcer disease, current alcoholism,
asthma or chronic obstructive pulmonary disease (Bonner
and Peskind, 2002). Memantine should be used at a lower
dose than usual in patients with severe renal impairment.
Possible interactions with drugs which inhibit the CYP
pathways can be observed in the case of tacrine, donepezil
and galantamine, but are uncommon in the case of rivastig-
mine (Standridge, 2004). No metabolic interactions with
other drugs have been observed with memantine (Farlow
et al., 2008).
52.4.3 MONITORING TREATMENT
RESPONSE
Evaluating whether and to what extent an individual
patient has responded to the treatment provided, is a dif-
ficult task in a gradually progressive disease such as AD.
The rate of clinical worsening varies widely across patients,
is unforeseeable and previous deterioration is not help-
ful for predicting further decline (Swanwick et al., 1998).
Response to treatment is also highly variable with only a
minority of patients showing true drug-related improve-
ment. On the other hand, placebo effects are large. For
these reasons, the paradigm of treatment decisions guided
by the patient’s feeling or doing better is inappropriate with
regard to AD (Swanwick and Lawlor, 1999). In particular,
lack of improvement does not provide an indication for sus-
pending treatment. No change in the patient’s condition is
the most likely outcome after 3 to 6 months’ treatment with
an anti-dementia agent. Moreover, a true pharmacological
gain may be masked by a dip in the natural progression.
Therefore, the only rational grounds for discontinuation
are poor tolerance, low compliance, dramatic decline fol-
lowing the initiation of treatment and absence of deterio-
ration after a drug-free period of 6 weeks (Swanwick and
Lawlor, 1999).
52.4.4 SWITCHING DRUGS
The ChEIs share one basic mode of action but differ with
regard to other pharmacological properties. In case of poor
tolerance or rapid deterioration despite treatment, switch-
ing to another drug within the same class is a viable thera-
peutic option (Gauthier et al., 2003). Several open-label
studies have demonstrated that up to 50% of patients who
experienced lack of efficacy or poor tolerability with the
initial drug responded favourably to subsequent treatment
with another ChEI. In the case of intolerance, switching to
a second agent should only be performed after full resolu-
tion of side effects associated with the initial agent. In the
case of lack of efficacy, switching can be done overnight,
with a quicker titration scheme thereafter (Massoud et al.,
2011). In patients with moderate-to-severe dementia switch-
ing to memantine is another possibility. Open-label studies
have demonstrated that many patients experience improve-
ment or stabilization after previously unsatisfactory treat-
ment response and that tolerability is good (Waldemar
et al., 2008). Conversely, improvement has been reported
in patients with moderate-to-severe dementia who were
switched to donepezil and who experienced lack of efficacy
from previous treatment with memantine (Sakka et al.,
2007).
52.4.5 TREATMENT COMBINATIONS
Patients with moderate-to-severe AD who have received
donepezil for several months may derive significant ben-
efits from the addition of memantine in terms of cognition,
activities of daily living, global outome and behavioural
symptoms. Combination treatment may also be beneficial
for patients who experience tolerability problems or unusual
deterioration upon treatment with a ChEI (Cummings et al.,
2015). Another important way to optimize the management
of dementia is to combine pharmacological treatment with
non-pharmacological interventions, since the effects of the
two strategies are partly synergistic (Rodakowski et al.,
2015). An enhancement of clinical efficacy over standard
pharmacological treatment has been particularly demon-
strated for cognitive stimulation (Ballard et al., 2011).
52.4.6 DISCONTINUATION
There is no evidence from RCTs on the efficacy of cur-
rent treatments beyond 12 months. After this duration of
treatment, patients receiving donepezil do significantly
better in terms of cognitive performance and functional
ability than patients on placebo. Several open-label exten-
sion studies have suggested that treatment gains are main-
tained for significantly longer periods, although, both the
actively treated group and the placebo group will continue
to decline. These results must be interpreted with caution
because patients remaining in treatment were positively
selected in terms of treatment response and drug tolerabil-
ity and because placebo data were generated by statistical
extrapolation (Rodda and Walker, 2009). It is likely that
the trajectories of treated and placebo groups will meet
but it is not clear when this will occur. In a well-conducted
12-month double-blind drug discontinuation study of
295 patients with ­moderate-to-severe dementia due to AD,
Howard et al. (2012) found that patients who discontinued
donepezil, scored 1.9 points worse on the MMSE than those
who continued it for 12 months. Discontinued patients also
did worse on an ADL measure. Donepezil-treated patients
who switched to memantine did nearly as well as those who
stayed on donepezil.

Gradual deterioration despite treatment is not a criterion
for withdrawing treatment because the natural course of
symptoms in an individual patient is unknown. A drug-free
interval of several weeks is one way to determine whether
a patient still benefits from treatment. On the other hand,
drug withdrawal carries a risk of rapid deterioration, which
may not be fully compensated by reinitiating treatment.
At present, it appears to be a rational strategy to continue
treatment as long as neither tolerability problems nor rapid
worsening occurs and as long as the patient’s condition can
be maintained at a stage where the pharmacological prop-
erties of the present treatment still have a chance of being
beneficial.
52.5 CONCLUSIONS
We concur with other comparative reviews in concluding
that the clinical effects of the currently approved AD treat-
ments are modest (Harry and Zakzanis, 2005; Birks, 2006;
Hansen et al., 2007; Shah et al., 2008; Rodda and Walker,
2009). The most salient outcome is a temporary delay of
decline in cognitive performance and everyday activi-
ties by up to 12 months. In some patients, improvement
of cognition and functional ability occurs, which is clini-
cally detectable. The effect size is dose related for donepezil
and rivastigmine (Ritchie et al., 2004). Impacts on neu-
ropsychiatric symptoms have been demonstrated but are
probably not clinically important (Campbell et al., 2008;
Cummings et al., 2008). None of the current pharmaco-
logical treatments for AD has a potential of delaying the
progression from the pre-dementia stage to the dementia
stage (Tricco et al., 2013). The ChEIs do not show clinically
relevant differences regarding efficacy and are therefore
interchangeable. Advantages for the dual-enzyme inhibi-
tion of rivastigmine or for the nicotinic receptor enhance-
ment of galantamine are not clinically apparent. Most
likely, ChEIs achieve similar clinical benefits in patients
with mild dementia and in individuals with severe demen-
tia as in the mild-to-moderate dementia subgroup (Birks,
2006). Memantine is probably less efficacious than ChEI
in patients with mild dementia and has not been approved
for this population. In patients with moderate-to-severe
dementia, data on clinical efficacy are less consistent for
memantine than for ChEIs. Premature withdrawals are
more frequent in patients treated with ChEIs compared
to patients receiving placebo. The most common adverse
events are nausea, vomiting, diarrhoea, dizziness and
weight loss. Differences between drugs regarding the fre-
quency of these adverse events (Lanctôt et al., 2003) have
become negligible with the introduction of a rivastigmine
patch. A high incidence of liver enzyme elevations in con-
junction with a four times daily dosage scheme significantly
limits the usefulness of tacrine. Memantine has an excellent
tolerability with adverse event rates being no different from
placebo. Reliable placebo-controlled data are only available
Established treatments for Alzheimer’s disease 549
for treatment with cholinesterase inhibitors up to 1 year. At
that point, patients on active treatment do better in terms of
global assessment, cognitive ability and ADL than patients
receiving placebo. It is likely that treatment differences are
maintained beyond 12 months, although gradual decline
will invariably occur. How long ChEI treatment can main-
tain patients above placebo levels is unclear. To provide
meaningful benefits to patients with AD and their carers,
the modest effects of current treatments must be applied
within a skilful management strategy. It includes early
treatment initiation, observation of safety issues and moni-
toring of individual treatment response using appropriate
criteria. Physicians must be aware of existing alternatives
in case of tolerability problems or marked deterioration
and they should not give up treatment too early. Wherever
possible, pharmacological treatments should be combined
with non-pharmacological interventions such as cognitive
stimulation, reminiscence therapy, occupational therapy or
physical exercise (Hogan et al., 2008). The current approved
symptomatic AD treatments will remain the standard of
care until novel disease-modifying therapies are deter-
mined to be safe and efficacious. They will continue to be
an important component of dementia managment even
after new pharmacological strategies become available.
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Drug treatments in development for
Alzheimer’s disease
PAUL YATES AND MICHAEL WOODWARD
53.1 INTRODUCTION
Approaching 30 years after initial descriptions of the ther-
apeutic benefits of tacrine (Summers et al., 1986), we still
only have symptomatic therapies for Alzheimer’s disease
(AD) and no therapies for the other dementias. Only four
drugs are regularly used for AD (donepezil, galantamine,
rivastigmine and memantine) and no new drug has been
marketed for almost 20 years. Disease-modifying therapies
for dementia are desperately needed.
In many respects the course of developing therapies for
AD has resembled that of developing cancer drugs. There
were initially only symptomatic therapies, then, as the
molecular basis of cancer was better understood, an enthu-
siasm emerged that a single magic bullet would be devel-
oped that would cure and indeed prevent all cancer. It is
likely that the future course of AD drug development will
also track that of cancer drugs, with therapies that have
modest effects on the disease process often used sequen-
tially or in combination, along with symptomatic therapies,
without a sudden major development that cures all. As with
some cancer therapies, there are likely to be some drugs
that dramatically alter the course of some types of demen-
tia (e.g. ­progranulin-mutation-related frontotemporal lobar
degeneration [FTLD]) rather than being effective for all
dementias. Over decades, we may achieve a situation, where
most people with dementia treated with the new therapies
can look forward to another 15–20 years of productive life,
rather than the current average of 5–10 years. Unlike cancer,
most people with dementia are already of advanced age and
even without dementia their life expectancy is limited.
The holy grail of dementia therapies is primary
­prevention – identifying those at increased risk of develop-
ing a form of dementia, then treating them with a therapy
that prevents dementia from developing. Such a therapy
554
53
would need to be very safe, as it will be given to many peo-
ple who would never develop dementia. These therapeutic
agents may also be effective in treating established demen-
tia too. Conversely, a drug that fails in dementia therapeu-
tic trials may be effective as a preventative agent.
The non-steroidal anti-inflammatory drugs (NSAIDs)
could fall into this class – all therapeutic trials for AD were
negative but they still may have a preventative role. Indeed,
this hypothesis was to be tested in the ADAPT trial of the
AD Cooperative Studies group (ADAPT Research Group,
2008), but the trial was terminated early due to concerns
about toxicity of the agent (celecoxib) in a large healthy pop-
ulation. The ASPREE trial of aspirin in primary prevention
may yet shed more light on this area (ASPREE Investigator
Group, 2013).
There is some recent evidence from several epidemiolog-
ical cohort studies suggesting that public health interven-
tions such as cardiovascular risk modification may already
be playing a role in reducing dementia incidence – although
with a growing aged population, the prevalence is still rising
(Qiu et al., 2013). Chapter 55 addresses prevention of AD.
Over recent years, observational cohort studies in early-
onset/genetic (Dominantly Inherited Alzheimer Network
[DIAN]) and late-onset/sporadic AD (e.g. Alzheimer’s
Disease Neuroimaging Initiative [ADNI] and the Australian
Imaging, Biomarkers and Lifestyle [AIBL] studies) have led
to an appreciation of an evolution of preclinical changes in
brain, cerebrospinal fluid (CSF) and blood-based biomark-
ers occurring more than 20 years prior to the emergence of
cognitive sequelae and dementia diagnosis (Bateman et al.,
2012; Villemagne et al., 2013). This suggests that there may
be a substantial window period during which therapeutics
could be implemented to slow or even ward off the progres-
sion of dementia due to AD.
The ability to identify and monitor prodromal and
preclinical AD using disease-specific biomarkers (e.g.

β-amyloid positron emission tomography [PET] and CSF
β-amyloid and tau assays) has revolutionized clinical trial
design and given fresh hope to research in AD therapeutics
(Sperling et al., 2011).
However, the recent run of disappointing results from
trials of high-profile agents targeting β-amyloid (e.g. bap-
ineuzumab, semagacestat, solanezumab and gantenerumab)
has led to many questioning the very basis for the ‘amyloid
hypothesis’ of AD pathogenesis – although several of these
trials had an unacceptably high proportion of ‘biomarker-
negative’ participants, who undermined their potential to
demonstrate efficacy (Broadstock et al., 2014).
At the time of writing there are close to 200 therapeutic
agents that have been tested for AD treatment in humans.
Only five have been approved for clinical use: the cholines-
terase inhibitors (ChEIs), such as donepezil, galantamine,
rivastigmine and tacrine, and the N-methyl-d-aspartate
(NMDA) antagonist memantine. Of the remainder, 73 agents
are no longer in active trials, and at least 87 are active in cur-
rent trials. Nineteen therapeutics are in Phase III (including
Phase II/III) trials, 45 are in Phase II trials (including Phase
I/II) and 17 are in Phase I trials. There are also six Phase IV
trials of agents already approved for use in other conditions
(including prazocin, carvedilol and simvastatin).
Among the trials in Phase II/III stages are a number cur-
rently in recruitment that involves participants with pre-
clinical or prodromal AD.
In addition to approaches directed at β-amyloid produc-
tion and clearance, there are agents targeting alternative
disease pathways such as tau-related neurodegeneration
(with trials for both AD and FTLD participants) and novel
cholinergic and other neurotransmitter targets, with results
to become available over coming years.
53.2 TARGETS OF DEMENTIA
THERAPIES
An increase in understanding of the genetic, cellular and
molecular basis of dementia has led to a wide range of
potential therapeutic targets. Only those targets with cur-
rent therapeutic trials are described in this chapter, but it
is highly likely that many more molecules and disease pro-
cesses will be targeted in future.
The majority of dementia therapeutics currently in clini-
cal trials target AD; however, a growing number of thera-
pies in other dementias are also in development.
53.2.1 AMYLOID
The ‘amyloid cascade’ hypothesis of AD proposes that
either overproduction or reduced clearance of the protein
amyloid-β (Aβ) from the brain (or both) lead to both direct
neuronal toxicity and downstream damage via hyperphos-
phorylation of intracellular tau (see Section 53.2.2) (Hardy
and Selkoe, 2002; Chiang and Koo, 2014).
Drug treatments in development for Alzheimer’s disease 555
Aβ is produced by sequential cleavage of the transmem-
brane amyloid precursor protein (APP) by enzymes called
secretases. APP processing may either follow a protec-
tive/neutral or an injurious/harmful pathway. In the for-
mer, initial cleavage of APP by α-secretase promotes the
‘non-amyloidogenic’ pathway, resulting in the harmless
fragments sAPP-α and C83. In the latter, APP is cleaved
by β-secretase (BACE1) in the extracellular region and
γ-secretase within the transmembrane domain to release
the soluble Aβ monomer, which may be 38–42 amino
acid residues long. The Aβ42 fragments then aggregate as
oligomers and insoluble extracellular β-amyloid plaques.
Aβ42, in particular its oligomeric species, is has neuro-
toxic properties and is usually considered to be implicated
in neurodegeneration in AD. By contrast, Aβ40 tends to
accumulate within cerebral vessel walls as cerebral amy-
loid angiopathy (CAA) and is associated with intracere-
bral haemorrhage (Chiang and Koo, 2014).
Aβ within the circulation can also be taken up into the
brain via the receptor for advanced glycation end products
(RAGE), a multiligand cell-surface receptor. When circu-
lating lipids and proteins are exposed to sugars (as occurs
in diabetes and with ageing), they become glycated to form
advanced glycosylation end products (AGEs), which bind
to RAGE resulting in oxidative damage and inflamma-
tion. RAGE, which is upregulated in AD, also transports
circulating Aβ across the blood–brain barrier (BBB) into
the brain and interacts with Aβ to mediate inflammatory
responses, oxidative stress and reduced blood flow (Deane,
2012). Aβ–apolipoprotein J (Aβ–ApoJ) complexes are also
taken up by the low-density lipoprotein receptor-related
protein 2 (LRP2/gp330/megalin) (Ghiso et al., 2004).
Aβ is cleared from the brain by several mechanisms.
These include enzymatic degradation (e.g. insulin-degrad-
ing enzyme [IDE] or neprilysin) or transport from brain
interstitial space to the circulation via low-density lipopro-
tein receptor-related protein (LRP, also influenced by apo-
lipoprotein E [ApoE]). In addition, some solutes and waste
products, including Aβ, can exit the brain interstitium via
convective bulk flow through aquaporin-4 water channels
on astrocyte end-feet (termed the ‘glymphatic’ system) (Iliff
and Nedergaard, 2013).
Once in the peripheral circulation, the majority of Aβ is
taken up and cleared by the liver, with a smaller proportion
excreted by the kidneys or taken up into circulating mono-
cytes and erythrocytes (Liu et al. 2014).
Thus, potential anti-amyloid approaches include those
that reduce production (including inhibitors of γ- and
β-secretase and enhancers of α-secretase), that increase
clearance from the brain or from the peripheral circulation
and that mitigate its deleterious effects.
53.2.2 TAU
Tau is a protein that stabilizes microtubules, allowing
transport of vesicles and other products of neuronal cell
bodies down the axon to the synapse. In AD, tau is noted
556 Dementia
to become hyperphosphorylated, with associated disrup-
tion to the microtubules and eventual aggregation into
neurofibrillary tangles. Several mechanisms can be tar-
geted therapeutically, including hyperphosphorylation
and tau aggregation. Such approaches may also work in
some of the non-AD dementias, including types of FTLD
(Warren et al., 2013).
53.2.3 NEURONES AND SYNAPSES
Neural regeneration and replacement is being attempted
with stem cell transplants/infusions and the delivery of
nerve growth factors (NGFs) and other neurotrophic
agents. It is reassuring that in regions of most intense neu-
ral response to dementia pathology (e.g. around amyloid
plaques), there are often neurones that can be revived and
any cell death is more from apoptosis than necrosis, mean-
ing damage to other cells is limited. However, the brain is
the most complex organ with respect to cellular structure,
so neural regeneration or replacement may never be fully
possible.
53.2.4 INFLAMMATION
There is an inflammatory response around amyloid plaques
in AD, proximal to ischaemic or hypoxic tissue with cere-
brovascular disorders, and inflammation may also occur
with other dementias. This presents potential targets, using
anti-inflammatory agents to limit cell damage and modify
the clinical course of dementia.
53.2.5 MITOCHONDRIA
These organelles generate the energy required for cellular
processes and damage to mitochondria has been implicated
as one of the primary causes of cell damage in dementia.
Mitochondria have their own genes and are the site of
numerous metabolic pathways, many of which present
potential targets for dementia therapies.
53.2.6 OXIDATIVE PROCESSES
Closely linked with mitochondrial function, all cells gen-
erate damaging oxidative species and have regulatory
antioxidant mechanisms. AD therapies that enhance this
antioxidant response may protect cells from damage and
alter dementia’s course.
53.2.7 NEUROTRANSMITTERS AND
RECEPTORS
Symptomatic AD therapies to date have targeted a small
number of neurotransmitters and their receptors, and other
neurotransmitter symptoms are potential targets for new
symptomatic therapies. These include the various histamin-
ergic, 5-hydroxytryptamine (5-HT) and glutamatergic neu-
rotransmitters and receptors.
53.2.8 INSULIN-SENSITIZING
TREATMENTS AND PEROXISOME
PROLIFERATOR–ACTIVATED
RECEPTOR-γ (PPAR-γ)AGONISTS
Diabetes increases risk for AD, and impaired glucose toler-
ance and insulin resistance have been associated with hippo-
campal volume loss and cognitive decline. Patients with AD
have reduced expression of insulin and insulin-like growth
factor (IGF) within the brain and reduced insulin- and IGF-
receptor sensitivity. In the brain, insulin and β amyloid also
share a common enzymatic degradation pathway (IDE),
meaning that peripheral and central nervous system (CNS)
insulin resistance could contribute to the neuropathology
and clinical features of AD (Craft, 2005).
53.2.9 OTHER MECHANISMS
There are innumerable other approaches to remediate
pathology and symptoms in dementia, as well as therapies
to target non-AD forms of dementia (see Section 53.3.9).
53.3 THERAPEUTIC TRIALS
The numerous potential targets described above have led to
a plethora of well-constructed trials of new dementia thera-
pies. This chapter concentrates on therapeutic areas where
trials have been conducted and results presented. However,
it is likely that many new targets and agents are being
developed and may soon have sufficient data to review. As
the field is constantly changing, some data are still as yet
unpublished and available only from conference proceed-
ings or media statements. We have preferentially included
references to large pivotal publications; however, other
information contained within this chapter has been sourced
from the public domain including alzforum.org and clini-
caltrials.org.
53.3.1 AMYLOID
Anti-amyloid approaches include those that reduce produc-
tion of Aβ, that increase clearance and that mitigate its del-
eterious effects. Some may also exert their effects through
multiple mechanisms (e.g. CHF5074, a γ-secretase modu-
lator, also has effects on neurogenesis, reduces tau and has
anti-inflammatory properties).
β -Secretase
53.3.1.1 
The BACE1 enzyme releases the major portion of APP and
subsequently the γ-secretase complex liberates Aβ – either
Aβ40 or the more toxic and aggregation-prone Aβ42.
Interestingly, ‘proof of mechanism’ for BACE1-inhibition
has been demonstrated in individuals expressing A673T

mutations in the APP gene. This mutation, proximal to the
BACE1 cleavage site, prevents the action of BACE1, reduc-
ing Aβ production in vitro by 40% and protect against the
development of cognitive decline (Jonsson et al., 2012).
BACE1 is very large, which presents difficulties in pro-
ducing an inhibitor capable of crossing the BBB. In addi-
tion, many early BACE1 inhibitors were also substrates for
p-glycoprotein-mediated efflux from the CNS, impeding
attempts to achieve therapeutic concentrations at its site of
action (Vassar et al., 2009).
The enzyme has been crystallized and knowledge of its
structure has assisted rational drug development, with sev-
eral small molecule inhibitors that bind to the active enzy-
matic site now in trials.
Recent Phase I data presented from Eisai/Biogen (E2609),
Merck (Verubecestat/MK-8931), Astra Zeneca (AZD3293)
and Boeringer Ingelheim/Vitae (BI1181181) are very promis-
ing, with each demonstrating significant reductions in plasma
and CSF Aβ. However, as BACE1 also has other substrates,
there are potential for side effects. BACE knockout mice
exhibit behavioural change, seizures, myelination abnor-
malities and retinal vascular pathologies. In mice treated
with high doses of BACE1-inhibitors, dendritic spine loss and
altered synaptic function have also been observed (although
these findings did not occur at lower doses). Careful safety
monitoring of in-human studies is essential (Hu et al., 2010)!
In 2013, Eli Lilly and Company terminated trials of
LY2886721 due to hepatotoxicity, which emerged in almost
10% of patients. In the same year, Roche terminated devel-
opment of its RG7129 in Phase I, without explanation.
53.3.1.1.1 VERUBECESTAT/MK-8931
In Phase I trials in healthy volunteers, the Merck BACE1
inhibitor MK-8931 reduced CSF Aβ by over 90% without
dose-limiting side effects.
MK-8931 is currently in Phase II/III trials in both mild-
to-moderate AD (EPOCH) and prodromal AD (APECS).
In December 2013, Merck announced that the EPOCH
study had met its initial safety requirements, following a
3-month safety substudy of the first 200 patients. The EPOCH
study is now continuing recruitment towards the proposed
1960 patients. The primary outcomes are change in cognitive
(Alzheimer’s Disease Assessment Scale-Cognition [ADAS-
Cog]) and functional (Alzheimer’s Disease Cooperative Study
– activities of daily living [ADCS-ADL]) measures from
baseline. Secondary measures include change in the sum of
boxes of the Clinical Dementia Rating (CDR-SB), total hip-
pocampal volume (volumetric magnetic resonance imaging
[MRI]), Neuropsychiatric Inventory (NPI) and Mini-Mental
State Examination (MMSE) score. The study also includes two
optional substudies examining change in CSF biomarkers and
total tau, brain amyloid burden on 18F-flutemetamol PET.
The APECS study began in November 2013. It aims to
recruit 1500 people diagnosed with amnestic mild cognitive
impairment (aMCI) with positive 18F-flutemetamol PET
amyloid scans (prodromal AD), to receive either 12 or 40 mg
MK-8931 daily for 2 years. The primary outcome measure
Drug treatments in development for Alzheimer’s disease 557
is change CDR-SB relative to placebo. Secondary outcome
measures include time to clinical diagnosis of probable AD
dementia, as well as change in cognitive (three-domain
composite cognition score), functional (ADCS-ADL score)
and biomarker (hippocampal volume) measures, with
optional PET and CSF substudies as per EPOCH. The esti-
mated completion date is March 2018.
53.3.1.1.2 E2609
Several Phase I trials have been completed for the Eisai
BACE1-inhibitor E2609, comprising 336 healthy controls
and people with early AD. In the first, single ascending-dose
study of 73 healthy adult participants, E2609 reduced plasma
Aβ by between 52% (5 mg dose) and 92% (800 mg dose) rela-
tive to baseline levels. In a second, multiple ascending dose
study of 50 healthy adults administered 25–400 mg/day for
14 days; there were both reductions in plasma Aβ and a dose-
dependent reduction in CSF Aβ of up to 80% compared with
placebo. No clinically significant adverse effects were noted;
however, headache and dizziness were the most common
adverse events (AEs) reported. A third Phase I study tested
a single dose of E2609 in 65 participants with MCI with bio-
marker evidence of AD, with the primary outcome measure
change in CSF Aβ levels 36 hours post-dose. Although this
trial was completed in October 2013, no data have been dis-
closed to date. Despite this, a Phase II trial has commenced,
enrolling participants with MCI due to AD or mild AD
dementia. Screening includes amyloid-PET, and the primary
outcome is AD Composite Score (ADCOMS), a cognitive
composite score. Secondary outcomes include change in hip-
pocampal volume (volumetric MRI) and CSF Aβ from base-
line. This trial is estimated to be completed in 2019.
53.3.1.1.3 AZD3293
Following the withdrawal of its BACE1 inhibitor (LY2886721),
Eli Lilly teamed up with Astra Zeneca in a Phase II/III trial of
their compound, AZD3293. In Phase I studies of AZD3293,
CSF Aβ levels were reduced by 75% and took 2–3 weeks to
return to baseline after treatment. Named AMARANTH,
this large Phase II/III trial will compare AZD3293 (20 mg or
50 mg orally daily) to placebo in 1551 participants with MCI
due to AD or mild AD, over 2 years. The screening phase will
include biomarker evidence of AD (CSF or PET). Primary
outcome is CDR-SB, and secondary measures include ADAS-
Cog, ADCS-ADL, Functional Activities Questionnaire
(FAQ), NPI, as well as change in CSF biomarkers, functional
and amyloid PET and MRI. The study is estimated to be com-
pleted by May 2019.
53.3.1.1.4 BI1181181
Boehringer Ingelheim recently reported results of two
Phase I trials of its BACE inhibitor, BI1181181. This com-
pound also shows promise; it was well-tolerated, with a
greater than 80% reduction in CSF Aβ in healthy controls.
In 2015, BI1181181 was placed on a temporary clinical hold
to investigate skin reactions seen in some participants in in
a subsequent ascending dose study.
558 Dementia
53.3.1.1.5 LY3202626
LY3202626 (Lilly) is another small-molecule BACE1-
inhibitor. In 2016 it entered Phase II in participants with
mild AD (with an amyloid biomarker). The study’s primary
outcome measure is change in uptake seen on Tau PET as a
marker of disease progression.
53.3.1.1.6 THALIDOMIDE
Thalidomide has diverse properties including immunomod-
ulation and anti-angiogenesis. It was marketed as an over-
the-counter anti-emetic in the 1950s and was responsible for
approximately 10,000 cases of phocomelia (congenital limb
malformation) worldwide, prompting its withdrawal. It has
since shown efficacy in several autoimmune conditions, as
well as multiple myeloma and other cancers.
It has effects on numerous inflammatory mediators
including tumour necrosis factor-α (TNF-α), which is impli-
cated in AD. It also appears to reduce the activity of BACE1.
In transgenic mice, chronic administration of thalido-
mide led to decreased activation of microglia and astro-
cytes, as well as reductions in both quantity and activity
of BACE1, with subsequent reduction in total and fibrillar
Aβ (He et al., 2013). A Phase II/III study of thalidomide in
patients with mild-to-moderate AD (MMSE 12–26) with
CSF and plasma biomarker outcome measures was com-
menced in 2010; however, recruitment has proved challeng-
ing and no data are available to date.
53.3.1.1.7 MINOCYCLINE
The tetracycline antibiotic, minocycline, also inhibits BACE1
and has anti-inflammatory properties demonstrated in mouse
models (Ferretti et al., 2012). It is currently in Phase II (mino-
cycline 200 mg/400 mg/placebo, n = 480) in participants with
very mild AD, with cognitive and functional end points.
γ-Secretase inhibition/modulation
53.3.1.2 
γ-Secretase is a complex of four proteins – presenilin, nica-
strin, Aph-1 and Pen-2 – that cleaves the transmembrane
region of APP to produce Aβ (Panza et al., 2009). It also has
numerous substrates apart from APP, including some (e.g.
Notch) that are vital to embryogenesis, cell differentiation
and communication. If the components of γ-secretase can
be differentially inhibited, this may enable lowering of Aβ
production, with sparing of its other functions, and avoid-
ance of unwanted toxicities.
New molecules targeting γ-secretase may not fully inhibit
the enzyme, but act more as a modulator of the enzyme’s
function. As γ-secretase is capable of cleaving APP at sev-
eral sites, its Aβ product may vary in length, from Aβ38
to Aβ42. γ-Secretase modulators promote production of
shorter Aβ fragments over the aggregation-prone Aβ42. By
sparing Notch, unwanted adverse effects are avoided, while
maintaining therapeutic efficacy. Intriguingly, a substrate-
labelling technique has suggested that some γ-secretase
modulators may also reduce Aβ aggregation as well as Aβ
production (Kukar et al., 2008).
To date, at least six agents influencing the γ-secretase
enzyme have entered human studies. Two of these,
semagacestat and avagacestat, advanced to Phase III trials,
but ultimately were unsuccessful.
53.3.1.2.1 SEMAGACESTAT
Semagacestat (previously known as LY450139) was noted
to lower CSF Aβ in a Phase I trial in healthy individuals
(Bateman, 2009). However, in Phase II trials in mild-to-
moderate AD, there was an effect seen with plasma but not
with CSF Aβ (Fleisher et al., 2008).
Two large Phase III trials of semagacesat involving over
3000 AD patients, IDENTITY-1 and IDENTITY-2 were
terminated prematurely due to lack of efficacy and adverse
effects. The active treatment was associated with a signifi-
cantly greater risk of skin cancer and infections, as well as
gastrointestinal symptoms. In addition, ADAS-Cog and
ADCS-ADL outcomes were worse in the treatment groups
than placebo (Doody et al., 2013).
53.3.1.2.2 AVAGACESTAT
Avagacestat (BMS-708163) is an arylsulfonamide γ-secretase
inhibitor, reported to selectively target the enzyme’s APP
substrate, sparing Notch. In animal models and Phase I tri-
als, it was found to reduce CSF Aβ levels without Notch-
related toxicity.
Two Phase II trials were conducted in 2009 – one in
mild-to-moderate AD and another in prodromal AD (using
CSF biomarkers for enrichment). The first, involving 209
participants from across 41 sites, showed a higher rate of
adverse effects (skin cancer – including non-melanoma skin
cancers – and gastrointestinal symptoms) and poorer cog-
nitive outcomes in those receiving highest doses, similar to
semagacestat.
Out of 100 AD participants receiving avagacestat, three
(compared with 0/29 placebo) developed vasogenic edema
(VE). This suggests that some target engagement (i.e. mobi-
lization of Aβ) may have occurred as a response to the
treatment (see Section 53.3.1.7), although the CSF results
reported were not statistically significant (Coric et al., 2012).
The second trial was halted following an interim analysis of
263 participants, which also demonstrated higher rates of
skin and gastrointestinal effects, with no change in rate of
progression to dementia (Coric et al., 2013).
53.3.1.2.3 TARENFLURBIL
Tarenflurbil (Flurizan) was originally developed as an
anti-inflammatory with anti-amyloid effects. In fact, it
is primarily a selective amyloid-lowering agent through
modulating γ-secretase, with no anti-inflammatory
effects (Weggen et al., 2003). Tarenflurbil decreased brain
levels of Aβ42 and improved spatial learning and mem-
ory performance in mouse models of AD (Weggen et al.,
2003; Kukar et al., 2007). A 3-week Phase I study in 48
healthy volunteers using doses up to 800 mg twice daily
were as well-tolerated as placebo and higher plasma drug

levels were related to lower plasma Aβ42 levels (Galasko
et al., 2007). A 12-month Phase II study in 210 subjects
on stable doses of ChEIs again using doses up to 800 mg
twice daily, showed a significantly lower rate of decline in
activities of daily living (ADCS-ADL) and global function
(CDR-SB) compared to placebo, along with an insignifi-
cantly slower rate of cognitive decline (ADAS-Cog), in the
milder AD patients (Wilcock et al., 2008). In a 12-month
extension all patients were treated with tarenflurbil and
when those treated for the full 24 months with the agent
were compared with the delayed start group, there was
a significantly (p < 0.001) slower rate of decline on each
of the primary outcome measures, suggesting a disease-
modifying effect.
Unfortunately, the 18-month Phase III trial results
using 800 mg tarenfurbil twice daily were negative. In one
of the two large studies, in 1684 randomized participants,
tarenfurbil had no beneficial effect on either of the two
primary outcomes: difference in change from baseline to
month 18 versus placebo for the ADAS-Cog and for the
ADCS-ADL. There was also no significant benefit seen
in any of the secondary outcomes (Green et al., 2009).
The second large Phase III trial was also negative. It is
highly unlikely that this drug will be further developed
for AD.
53.3.1.2.4 EVP-0962
EVP-0962 (FORUM Pharmaceuticals) is another NSAID-
derivative γ-secretase modulator. In vitro, it increases lev-
els of CSF Aβ-38 while reducing Aβ42, without altering
the total Aβ level or affecting Notch. Treatment with EVP-
0962 in Tg2576 transgenic mice resulted in reductions in
Aβ aggregates and plaques, reduced neuroinflammation
(astrocyte and microglial activation) and reversed memory
deficits (Rogers et al., 2012). Phase I and II trials have been
undertaken in healthy adults and in those meeting National
Institute on Aging – Alzheimer’s Association (NIA-AA) cri-
teria for MCI due to AD. Primary outcomes are tolerability
and safety as well as concentration and rate of synthesis of
Aβ in CSF.
53.3.1.2.5 NIC5-15/PINITOL
NIC5-15/Pinitol (James J. Peters Veterans Affairs Medical
Center/National Center for Complementary and Alternative
Medicine/Humanetics Corporation) is a cyclic sugar alco-
hol (in the same class as sweeteners sorbitol and xylitol)
that is found naturally in legumes, soy and pine trees. It
has insulin-sensitising and anti-inflammatory proper-
ties and may also influence γ-secretase activity (Do et al.,
2008).
Although no clinical trials data have been published,
Phase IIa results were presented in 2009, reporting good
tolerability and cognitive benefits in a very small trial of 15
mild-to-moderate AD patients. A second Phase IIa trial is in
progress (n = 40, mild-to-moderate AD), to assess pharma-
cokinetics/pharmacodynamics, cognitive and biomarker
(plasma Aβ) outcomes.
Drug treatments in development for Alzheimer’s disease 559
α-Secretase enhancement
53.3.1.3 
The α-secretase enzyme processes APP in a non-­
amyloidogenic pathway by cleaving APP near the middle of
the Aβ portion, generating the peptide sAPP-α, and prevent-
ing Aβ formation. Thus, a potential AD therapy is α-secretase
enhancement (Chiang and Koo, 2014). Unfortunately there
is only a limited amount of natural α-secretase so augmen-
tation may not lead to a large reduction of Aβ. However, the-
oretically it is possible to introduce extra α-secretase, akin to
enzyme replacement therapy in deficiency disorders. Such
replacement therapy could be genetically based.
53.3.1.3.1 ETAZOLATE
Etazolate (EHT-0202, Exonhit) is a pyrazolopyridine-
derivative α-secretase activator EHT-0202, which also has
affinity for multiple other receptor-binding sites including
GABA A, adenosine A1 and A2 and phosphodiesterase (PDE)
E4. It has neuroprotective properties in vitro and increases
levels of sAPP-α (the ‘non-amyloidogenic pathway’). In
Phase IIa (n = 159, mild-to-moderate AD, adjunct to ChEI),
EHT0202 (40 mg or 80 mg twice daily) etazolate was gen-
erally well-tolerated, although at higher doses there were
increased CNS AEs and withdrawals. No significant cogni-
tive effects were seen, although the study was not powered
for efficacy (Vellas et al., 2011).
53.3.1.3.2 ACITRETIN
Acitretin (Stiefel laboratories) is a vitamin A derivative
(retinoid) currently indicated for treatment of psoriasis. It
also increases expression of the α-secretase, a disintegrin
and metalloproteinase 10 (ADAM10). In a small Phase II
study, 21 participants with mild-to-moderate AD (MMSE
14–27) were randomized to acitretin 30 mg/day or placebo
for 4 weeks. Those on drug had significant increases in CSF
sAPP-α levels compared with the placebo group (difference
0.38, 95% confidence interval [CI] 0.03–0.72, p = 0.035) and
it was well-tolerated (Endres et al., 2014).
53.3.1.4 RAGE antagonists
RAGE is a multi-ligand receptor on cell surfaces. Ligands
recognized by RAGE include Aβ, which is first released
from APP extracellularly, so uptake into cells may be inhib-
ited by RAGE antagonism, reducing intracellular amyloid
load and the inflammatory effects of Aβ (Deane, 2012).
53.3.1.4.1 
A ZELIRAGON/TTP488/PF-04494700
Azeliragon/TTP488 is a small-molecule RAGE antagonist,
originally developed by TransTech Pharma for diabetic
neuropathy, and subsequently licensed to Pfizer. In APP
transgenic mice, TTP488 treatment was associated with a
significant reduction in inflammatory markers (TNF-α,
TGF-β and IL-1) and CNS Aβ deposition (Sabbagh et al.,
2011). In humans, it progressed to a large 18-month Phase
IIb trial, which recruited 399 patients randomised to one of
two oral TTP488 dosing regimes (60 mg for 6 days followed
560 Dementia
by 20 mg/day; 15 mg for 6 days followed by 5 mg/day) or
placebo. The trial was terminated early after interim analy-
ses suggested increased adverse outcomes (falls, confusion,
cognitive decline) in the higher-dose group and lack of effi-
cacy (but no safety concerns) in the lower-dose group. Later
analyses revealed slight decreased decline on the ADAS-
Cog in the lower-dose group at 18 months, but difference
in CR-SB, MMSE or ADCS-ADL and no change in CSF
biomarkers or hippocampal volume (Galasko et al., 2014).
A Phase III study of TTP488 in mild AD began recruit-
ment in 2016, with ADAS-Cog and CDR-SB as co-primary
endpoints.
53.3.1.5 Active immunization (vaccination)
Antibodies against Aβ can be induced by injecting Aβ or its
fragments, to stimulate an immune response. The antibod-
ies generated may modify the amyloid cascade, preventing
AD progression (Schenk et al., 1999). The first trial of the
active immunization against Aβ began after transgenic ani-
mal studies showed that such an approach prevented depo-
sition of amyloid (if used early) and reduced amyloid load (if
used later), leading to clinical benefits including prevention
of memory loss (Morgan et al., 2000).
53.3.1.5.1 AN-1792
A Phase I clinical trial of immunotherapy of patients with
AD, using full-length synthetic Aβ42 as the antigen (AN-
1792), showed a highly variable development of antibodies
(Bayer et al., 2005) but no significant clinical benefits (though
the trial was not powered for clinical end-points). A subse-
quent Phase IIa study was halted when 6% of the patients
developed a sterile meningoencephalitis (Orgogozo et al.,
2003), but showed no major differences in cognitive outcomes
when antibody responders were compared with the placebo
group after 1 year, despite evidence of high serum antibodies
to Aβ42 in a group who received active treatment (Hock et al.,
2003). Follow-up 4 years later demonstrated small differences
in functional decline in those with a positive antibody titre
response only (25/129 participants) but no significant differ-
ence in cognitive end points (Vellas et al., 2009).
Neuropathological examination of 10 Phase I participants
who had received active immunization revealed removal
of amyloid plaque proportional to the antibody response.
There was no reduction in neurofibrillary tangles seen within
neuronal cell bodies; however, reduction in p-tau was noted
within neuronal processes (Boche et al., 2010).
The finding that plaque removal is not enough to halt
progressive neurodegeneration in AD poses challenges
to the amyloid hypothesis. It is possible that a specific
amount of amyloid amyloid may be needed to initiate,
but not to maintain, progressive neurodegeneration. It is
also hypothesized that it is oligomeric Aβ, rather than the
fibrillar Aβ in plaques, that is responsible for most neuro-
degeneration in AD and that as immunization had failed
to reduce oligomeric Aβ (or indeed increases this as Aβ
in plaques is mobilized), this approach may be ineffective
(or deleterious). Additionally, full-length Aβ immuniza-
tion may be over-activating the immune system, caus-
ing the meningoencephalitis seen (Orgogozo et al., 2003)
and compromising potential clinical improvements from
plaque removal.
Thus, more recent active immunization approaches
have utilized Aβ fragments that are less likely to activate
unwanted (T-cell-mediated) immune responses.
ACC-001, also known as vanutide cridificar (Janssen/
Pfizer/Wyeth/Elan), used N-terminal fragments of Aβ
(residues 1–7), whereas the T-cell lymphocyte response seen
with AN1792 targeted Aβ towards the C-terminus (residues
15–42).
53.3.1.5.2 ACC-001
In preclinical trials, vaccination with ACC-001 led to the
production of anti-Aβ antibodies but did not generate
a T-cell-mediated response. It also reduced plaques and
improved cognition in transgenic mice (Panza et al., 2014).
Several Phase II trials have been conducted and results were
presented. One study included 125 participants with mild-
to-moderate AD, receiving six intramuscular injections
of either placebo, 3 mg or 10 mg ACC-001 with the adju-
vant QS-21, with 2-year follow-up. Ninety percent of those
receiving the active vaccine produced a measurable antibody
response, and levels of Aβ in plasma correlated with anti-
body titres, suggesting it was being cleared from the brain.
Correspondingly, there was a dose-dependent reduction in
accrual of brain β-amyloid (measured with florbetapir PET)
in treated subjects, although at trend-level significance only.
There was also some suggestion of influence on downstream
processes, with a (non-significant) reduction in levels of CSF
p-tau. As seen with other agents, the treatment group had
greater brain atrophy at higher doses, though the signifi-
cance of this is unclear. Six percent of the active group also
developed imaging evidence of VE (also known as Amyloid-
Related Imaging Abnormalities-oEdema, ARIA-E [see
Section 53.3.1.6.1]), and there were no improvements seen
in cognition (although not powered to detect cognitive out-
comes). Despite some biomarker evidence of efficacy, clini-
cal development has been discontinued (Ketter et al., 2014).
53.3.1.5.3 AD02
As with ACC-001, AD02 (Affiris/GSK) mimics the
N-terminal (residues 1–6) of Aβ, without the T-cell epit-
ope. In Phase I trials to 12 months it was generally safe and
well-tolerated, with no meningoencephalitis. A Phase II
trial of AD02 in 332 patients with early AD, however, was
negative on its primary and secondary outcome measures.
Intriguingly, although data are yet to be published, partici-
pants receiving one of the placebo formulations (adjuvant
without vaccine) demonstrated superior performance to
all of the other groups – including a second placebo group
and three receiving the active AD02 treatment (including
with the adjuvant). Participants administered this pla-
cebo formulation (now identified as alum and renamed as
‘AD04’) demonstrated less cognitive decline (composite of

ADAS-Cog and ADCS-ADL) and hippocampal atrophy over
18 months. Vaccines are commonly administered along with
an adjuvant, to stimulate an immune response and improve
generation of antibodies. Alum is an aluminium salt (typi-
cally potassium aluminium sulphate) used as an adjuvant in
many vaccines. While trials of AD02, including an exten-
sion study, have been terminated, Affiris announced plans
to attempt to replicate the AD004 findings in its own trial
(Schneeberger et al., 2014). This concept has been suggested
already in animal models – Frenkel et al. (2008) administered
an intranasal adjuvant (‘Protollin’, derived from lipopolysac-
charide and Neisseria meningitidis outer membrane proteins)
to transgenic mice, resulting in reduction in soluble and
fibrillar Aβ. Other techniques of immune stimulation may
also be effective (see Section 53.3.1.9.1).
53.3.1.5.4 CAD106
Perhaps the most advanced active vaccine still in active tri-
als is CAD106 (Panza et al., 2014). This vaccine contains
multiple copies of the N-terminus Aβ epitope (residues 1–6),
conjugated to a carrier protein (180 copies of the Q-β coat
protein) that confers additional immunogenicity.
In animal studies, CAD106 was demonstrated to induce
anti-Aβ antibodies, without provoking a T-cell-mediated
direct toxicity and reduced amyloid accumulation. It was
most effective when administered to the transgenic mice
prior to the appearance of Aβ plaques (Wiessner et al., 2011).
Several Phase I and II trials have been conducted to date.
In one Phase I trial, 58 participants with mild-to-­
moderate AD (MMSE 16–26) received three doses of
CAD106 (50 or 150 μg) over 100 days. They showed dose-
dependent generation of anti-Aβ immunoglobulin G (IgG)
titres, with 82% at 150 μg and 67% at 50 μg reaching a
pre-specified ‘response’ threshold. Total plasma Aβ con-
centration increased with treatment, whereas free plasma
Aβ decreased (implying mobilization of brain Aβ, with
increased proportion of antibody-bound Aβ in plasma)
(Winblad et al., 2012).
Further Phase II studies have been conducted, including
PET and pharmacogenomic substudies, and both subcu-
taneous and intramuscular administration. Similar to the
Phase I trials, about 90% of participants developed adequate
antibody responses and those with the highest antibody
titres demonstrated the highest increases in total plasma
Aβ. In vitro studies of antibodies taken from participants
during these studies demonstrate that there is improved
antibody maturation (increased affinity to target) seen with
time and repeated administrations. Intramuscular admin-
istration was better tolerated and generated a greater anti-
body response than subcutaneous administration.
There were no differences seen in CSF biomarkers with
treatment, although the authors contend that the timing of
sampling was chosen for safety reasons and was not optimal
to detect biomarker changes (Winblad et al., 2014).
Following up to seven administrations, and 2.5 years’
follow-up, safety is reported as favourable, although mild
adverse effects including injection site erythema and
Drug treatments in development for Alzheimer’s disease 561
nasopharyngitis were common. The vaccine does not stim-
ulate an Aβ-specific T-cell response, and there have been no
cases of meningoencephaitis or VE (although one case of
intracerebral haemorrhage has been reported, not related
to antibody titres). The study authors suggest that CAD106
may potentially be amenable to long-term administration in
AD (Winblad et al., 2014).
To further investigate this hypothesis, in collaboration
with the Banner Alzheimer’s Institute, Novartis is planning
to use CAD106 as a treatment arm in a Phase II/III trial
recruiting more than 1300 cognitively normal individual
aged 60–75, at genetic risk of AD (APOE ε4 homozygotes).
53.3.1.5.5 ACI024
ACI024 is a liposomal vaccine, with N-terminal Aβ frag-
ments (Aβ1–15), attached to palmitoylated lysine residues,
incorporated into a phospholipid bilayer. In preclinical
studies, it induced high titres of oligo-specific anti-Aβ anti-
bodies, without causing cellular inflammation, increases in
pro-inflammatory cytokines or microbleeds. In addition, it
decreased concentrations of Aβ40 and Aβ42 and improved
cognition (Hickman et al., 2011).
In humans, a Phase I/II trial of up to 198 AD participants
is currently recruiting. Individuals are to be screened using
β-amyloid PET (florbetaben [FBB]), on stable doses of acetyl-
cholinesterase medication. Primary outcome measures will
include safety outcomes, antibody response titres and change
in neuropsychological test battery (NTB) at 12 months, with
secondary end points including CSF Aβ and tau, volumetric
MRI and change in brain amyloid on FBB PET.
53.3.1.5.6 UB-311
United Biochemical’s UB-311 uses two synthetic T-helper (Th)
epitopes (UBITh®), bound to the N-terminal Aβ1–14 fragment.
It also uses a proprietary delivery system (CpG oligonucle-
otide) that promotes Th type 2 (regulatory T-cell) responses
in preference to the Th type 1 (pro-inflammatory) response.
In a very small Phase I study with an observational extension
phase, 19 Taiwanese patients with mild-to-moderate AD aged
50–80, were administered three 300 μg doses of UB-311 intra-
muscularly (weeks 0, 4 and 12). All participants demonstrated
Aβ1–14 specific antibody responses, which were still detect-
able at week 48, with no serious adverse effects. In addition, in
older subjects with mild AD (n = 6; age ≥60 years with baseline
MMSE ≥ 20) there were small improvements in ADAS-Cog,
ADCS–Clinical Global Impression of Change (ADCS-CGIC)
and MMSE, although the numbers reported were very small.
A Phase IIa study is planned.
53.3.1.5.7 LU AF20513
One drawback limiting the efficacy of active immunization
is that the immune response declines with ageing, producing
fewer antibodies and requiring repeated doses. To address
this challenge, Lundbeck has developed Lu AF20513, which
combines Aβ1–12 with Th epitopes from the tetanus toxin,
aiming to stimulate existing memory-Thcells to promote
B-cell production of antibody. Preclinical studies have
562 Dementia
had promising results, with robust antibody generation
and reduction in Aβ40 and Aβ42 (soluble and Aβ plaques)
(Winblad et al., 2014).
53.3.1.5.8 V950
Merck has also completed a Phase I trial with its multivalent
Aβ peptide vaccine, V950; however, no further trials have
been initiated.
53.3.1.6 Passive immunization
An approach that bypasses the need to respond to an antigen
and, variably, produce antibodies is to inject the antibod-
ies themselves. This can be done by using pooled immuno-
globulin, which contain anti-Aβ antibodies, or developing
monoclonal antibodies (mAbs) against Aβ. These mAbs,
usually produced from animal immunoglobulin, can be
humanized and modified in other ways (e.g. by altering the
Fc or ‘backbone’ component) that can impact on efficacy
and reduce unwanted immune/inflammatory effects.
Currently mAbs in clinical trials are directed against
different conformational epitopes (binding sites) com-
prised by different regions of the Aβ peptide (e.g. the C-or
N-terminus or the midportion). This provides different effi-
cacy against the various forms of Aβ, from monomers (­single
units) through soluble aggregated oligomers/­ protofibrils
(dimers, tetramers etc.) to insoluble fibrillar (plaque) Aβ.
Unfortunately, while there have been several prominent
negative clinical trials to date, some have provided glim-
mers of positivity from encouraging subgroup analyses.
Others are yet to release results or are still under way.
53.3.1.6.1 BAPINEUZUMAB
Bapineuzumab is a humanized form of a murine mAb
directed against the N-terminus (residues 1–5), binding to
both soluble and fibrillar Aβ. Preclinical studies demon-
strated that 3D6 (the murine mAb) could bind to and reduce
burden of amyloid plaques, mitigate of Aβ-induced synap-
totoxicity and improve behaviour.
In Phase II (124 participants; mild-to-moderate AD; 6
infusions; 78 weeks follow-up) trial, there were no differ-
ences seen with the two pre-specified primary end points
(ADAS-Cog and disability assessment for dementia [DAD]);
however, post hoc analyses suggested benefit in APOE ε4
non-carriers and in those completing all six infusions.
Biomarker substudies showed some reduction in brain Aβ
burden (11C-PiB PET), a trend to reduced CSF p-tau (p =
0.056), but no difference in CSF Aβ or total tau. MRI vol-
umetric analyses showed less brain volume loss in treated
APOE ε4 non-carriers compared with placebo (p = 0.004).
Bapineuzumab was generally well-tolerated; however, in
the higher-dose groups, MRI abnormalities consistent with
VE were noted in 15 participants (3 Phase I and 12 Phase II).
Three presented with symptoms including confusion, head-
ache and gait disturbance, prompting off-protocol MRIs.
One was treated with intravenous corticosteroids with reso-
lution of symptoms. The remaining 12 were identified in per
protocol MRI surveillance, with 7 asymptomatic and 5 hav-
ing reported transient AEs (including confusion, headache
or visual disturbance) in the preceding weeks.
53.3.1.6.2 AMYLOID-RELATED IMAGING
ABNORMALITIES (ARIA)
In response to these findings and in accordance with guid-
ance issued by the U.S. Food and Drug Administration
(FDA), the Alzheimer’s Association Research Roundtable
convened a workgroup in July 2010. The term ‘Amyloid-
Related Imaging Abnormalities’ (ARIA) was coined, incor-
porating microhaemorrhage and haemosiderosis (ARIA-H)
and VE and effusions (ARIA-E).
A subsequent review of all MRI images from all Phase II
participants identified these lesions in 17% of those treated,
of whom 78% were asymptomatic, with coincident micro-
bleeds or haemosiderosis noted in 47%. ARIA-E was more
common with higher doses of bapineuzumab and in APOE
ε4 homozygotes. There was no association between ARIA-E
and age, gender or baseline white matter disease on MRI,
and presence of ARIA-H at baseline did not increase risk
of incident ARIA-E (although participants with multiple
microbleeds were excluded from participation).
The cases identified during the bapineuzumab trial were
perhaps the most prominent, although ARIA-E have also
been reported with another Aβ immunotherapeutic agent
(solanezumab) (Chen et al., 2012) and a γ-secretase inhibi-
tor (Freiherr et al., 2013). Similar phenomena had also been
described with active immunotherapy in humans and ani-
mal models, and rare spontaneous case reports associated
with neurological symptoms and evidence of CAA (Gold
et al., 2010; Sato et al., 2011; Moon et al., 2012; McClean
et al., 2014; Shah et al., 2014).
Although ARIA-E commonly preceded or coincided
with ARIA-H, the two findings were not necessarily co-
located, suggesting a generalised disruption of vascular
integrity, rather than a focal insult. It is hypothesized that
removal of amyloid from vascular deposits may lead to
causing transient leakiness and subsequent VE. An alterna-
tive hypothesis is that there is failure of saturable paravas-
cular Aβ clearance mechanisms, by massive mobilization of
soluble from sequestered Aβ. Hence, waste that is otherwise
soluble (e.g. Aβ) accumulates, causing altered vascular per-
meability and leakage of plasma and blood products; see
Figure 55.6 (Li et al., 2010).
Two large Phase III trials were conducted, involving 2452
patients with mild-to-moderate AD (one in APOE ε4 carri-
ers, n = 1121 and one in non-carriers, n = 1331) to receive
intravenous bapineuzumab or placebo every 13 weeks for
78 weeks.
Unfortunately, there was no difference between treat-
ment and placebo groups in the primary outcomes of
ADAS-Cog or DAD at 78 weeks in either study. Biomarker
results did, however, show less accumulation of Aβ (11C-PiB
PET) and a reduced CSF p-tau in APOE ε4 carriers but not
non-carriers. No treatment difference in volumetric MRI
was seen in either group.

So why did bapineuzumab fail? Some hypothesize that
the safety concerns meant that lower-than-efficacious doses
were used. Others have suggested that like AN1792, the
treatment may have worked, but was initiated too late, past
the point at which neurodegeneration could be reversed
or substantially modified. It should also be noted that a
high proportion of those in the PiB substudy fell below the
threshold attributed for a ‘positive’ amyloid scan (6.5% of
carriers and 36.1% of non-carriers), suggesting possible
non-AD pathology in these individuals — despite meeting
clinical criteria for AD-type dementia. This may partially
explain the negative biomarker results in the APOE ε4-
negative group. If this was extrapolated to the wider trial
population, this may have significant impact on overall
efficacy.
Despite the negative outcomes, there are several lessons
learned from the bapineuzumab study that has shaped sub-
sequent clinical trial design in AD. The phenomenon of
ARIA is now better characterized, and central MRI moni-
toring to assess for incident events has been widely adopted.
Second, the use of CSF and PET biomarkers for enrichment
or screening of clinical trial populations, a criticism of the
bapineuzumab study, is now a common practice.
53.3.1.6.3 PF-05236812/AAB-003
To counter its adverse safety profile, Pfizer has modified
the Fc component of bapineuzumab to dampen its effect on
microglial activation and hence, reduce incidence of ARIA
(Crespi et al., 2014). The product, PF-05236812/AAB-003, is
being tested in a Phase I trial of 88 mild-to-moderate AD
patients with subsequent open-label extension. Outcomes
will include safety measures (including ARIA), as well as
cognitive and biomarker changes.
53.3.1.6.4 SOLANEZUMAB
Although bapineuzumab was targeted against the
N-terminus of Aβ, solanezumab, derived from the mouse
mAb m266a, is directed against the mid-portion (Aβ16–24).
It has affinity for small Aβ oligomers, but does not bind
to fibrillar Aβ plaques. As only a small proportion (0.1%)
crosses the BBB, its predominant mechanism of action
is by capturing Aβ40 and Aβ42 in the plasma, increasing
efflux of Aβ from the brain and (potentially) decreasing
deposited Aβ.
Phase I and II trials demonstrated favourable safety and
tolerability, with no episodes of ARIA. It proceeded to two
large Phase III studies, the EXPEDITION-1 and -2, involv-
ing 2052 people with mild-to-moderate AD, to receive 400
mg solanezumab intravenously each month for 80 weeks.
Although the infusions were generally well-tolerated,
ARIA-E occurred in 1%, the studies were negative in their
primary cognitive and functional end points (ADAS-Cog11
and ADCS-ADL). However in the EXPEDITION-1 study,
a pre-specified secondary analysis in mild AD (MMSE
20–26), demonstrated reduced cognitive decline com-
pared with placebo. A subsequent analysis of pooled data
of mild AD participants from both studies suggested a
Drug treatments in development for Alzheimer’s disease 563
reduction in cognitive decline in individuals with mild AD
(MMSE 20–26) and a trend to reduced decline in function
(ADCS-ADL).
Although these differences are small and of limited clini-
cal significance, they were seen by many as an encouraging
signal, targeting the amyloid hypothesis in AD may, in fact
still hold promise.
The biomarker response outcomes showed increases in
total CSF Aβ42 and Aβ40 and increased plasma Aβ (bound
to antibody), supportive of the ‘peripheral sink’ hypothesis.
Consistent with prior animal models, despite evidence of
increasing peripheral Aβ, there was no measurable change in
fibrillar Aβ (using Amyvid-PET). There were also no changes
in CSF p-tau or MRI brain or hippocampal volumes.
Of note, as with the bapineuzumab Phase III trial, about
one in four participants did not demonstrate measurable
florbetapir (Amyvid) retention on PET imaging, which
would limit the effectiveness of the intervention.
Following from these results, Expedition-3, a trial of
solanezumab in mild AD with biomarker screening (Amyvid
PET) is under way, with results expected in late 2016.
Solanezumab has also been selected for use in two sec-
ondary prevention trials in asymptomatic (or very mildly
symptomatic) individuals at risk of AD: the Dominantly
Inherited Alzheimer’s Network–Trials Unit (DIAN–TU)
and Anti-Amyloid in Asymptomatic Alzheimer’s Disease
(A4) trials, both currently recruiting. DIAN-TU is a 5-year
Phase II/III trial, which is a collaboration between Eli Lilly,
Roche and the Alzheimer’s Association. This is using solan-
ezumab or gantenerumab (see Section 53.3.1.6.5) in 210
asymptomatic or mildly symptomatic APP/PS1/PS2 muta-
tion carriers, each responsibly for autosomal-dominant
forms of AD with consistent age at onset across generations.
Outcome measures will include biomarkers (at 2 years) and
cognitive outcomes (selected to be particularly sensitive to
early cognitive changes in AD).
The A4 Study trial will apply solanezumab in a 3-year
trial of 1000 individuals, age 65 or older, with biomarker
evidence of brain amyloid deposition (amyloid PET), but
normal cognition (i.e. NIA-AA-defined Stage 2 or 3 preclin-
ical AD[Sperling et al., 2011]).
53.3.1.6.5 GANTENERUMAB
The Roche IgG1 mAb, gantenerumab, binds to both N-terminal
and adjacent central Aβ sequences. Although bapineuzumab
and solanezumab are humanized murine antibodies, gan-
tenerumab is an entirely human antibody, selected from a
synthetic human antibody library (huCAL®).
This compound acts by recruiting microglia and macro-
phages to degrade fibrillar Aβ, both in parenchyma and ves-
sels. It also neutralizes inhibitory effects of oligomeric Aβ42
in vitro. It has the advantage of convenience of administra-
tion by monthly subcutaneous injection (Ostrowitzki et al.,
2012).
Phase I trials of 308 participants (healthy control vol-
unteers or AD patients) have been completed, with admin-
istration either subcutaneous or intravenous infusion.
564 Dementia
In general, gantenerumab was well-tolerated and safe, how-
ever, two of six participants in the highest-dose group dem-
onstrated ARIA (Ostrowitzki et al., 2012). Over 6 months,
this group also showed −35.7% mean difference in brain
amyloid change compared to placebo.
Subsequently a Phase II/III trial commenced in 770 indi-
viduals with prodromal AD, as well as a Phase III study in
1000 patients with (clinically diagnosed) mild AD.
The former, termed ‘SCarlet RoAD’, enrolled people
aged over 50, with amnestic MCI (using the Free and Cued
Selective Reminding Test [FCSRT-IR]), MMSE above 24
and CDR of 0.5 (mild or questionable dementia), with a
positive disease biomarker (using amyloid PET). This was
the first Phase III trial to utilize the Dubois research criteria
for prodromal AD (presence of episodic memory impair-
ment with biomarker evidence of pathology) (Dubois
et al., 2007). Co-primary end points for the trial were the
CDR-SB and change in brain amyloid burden (using PET).
Unfortunately, in December 2014, Roche announced that
SCarlet RoAD had failed a pre-specified interim futility
analysis. This suggests that at the time of the analysis, the
intervention and placebo arms did not differ sufficiently to
warrant the trial continuing. However, there were no new
safety concerns.
Although previous trials have been set later in the
dementia trajectory and relied on clinical diagnosis alone,
SCarlet RoAD was applied in prodromal disease with a rig-
orous screening process with biomarker support. Although
the reasons for study failure remain to be announced, there
have been some suggestions. As with bapineuzumab, gan-
tenerumab primarily targets fibrillar Aβ and not soluble
species (e.g. oligomers) that may have greater impact clini-
cal presentation. Second, as with bapineuzumab, gan-
tenerumab may be associated with risk of ARIA at higher
doses. So it is possible that while the doses used in Scarlet
RoAD did not impact on safety, they may not have been
sufficient to demonstrate a therapeutic response. A third
explanation could be that even though gantenerumab may
work, the intervention’s timing (i.e. MCI due to AD) may be
still too late to impact on clinical outcome, and still-earlier
intervention is necessary (i.e. in at-risk individuals with
normal cognition).
Although SCarlet RoAD is being terminated, a trial in
mild AD continues (Marguerite Road), and gantenerumab
is also being applied opposite to solanezumab in one of the
arms of the DIAN–TU, which is due to run until 2017.
53.3.1.6.6 CRENEZUMAB
Crenezumab (MABT510A, AC Immune/Genentech/Roche)
is an IgG4 mAb, which recognizes both oligomeric and
fibrillar Aβ with high affinity, and it also has low affinity for
the single-unit Aβ monomers. It was designed to reduced
effector T-cell response, limiting complement activation
and inflammation, while still stimulating microglial clear-
ance of Aβ (Adolfsson et al., 2012). After Phase I, studies
showed the drug was well-tolerated, with no ARIA; higher
doses were used in the Phase II trials.
The first, named ‘ABBY’ recruited individuals with mild-
to-moderate AD to receive 300 mg of crenezumab subcu-
taneously every 2 weeks (n = 122/62 placebo) or 15 mg/kg
intravenously monthly (n = 163, 84 placebo). The second,
‘BLAZE’ was a 91-patient biomarker substudy, with similar
treatment groups, using florbetapir PET as the primary out-
come. Both were completed in 2014 and preliminary data
presented.
Similar to the EXPEDITION-1 and -2 trials of solan-
ezumab, ABBY, while negative in its primary end points
(ADAS-Cog12 and CDR-SB) demonstrated trends to
cognitive differences in subgroup analyses of mild AD
(MMSE 20–26), which reached statistical significance when
restricted to those with MMSE of 22–26.
Larger effects were seen with intravenous compared with
subcutaneous administration, which received about half the
effective dose.
The biomarker substudy, BLAZE did not show any differ-
ence in its primary end point (brain Aβ by florbetapir PET);
however, there were significant increases in CSF Aβ with
treatment over time compared with placebo. Considerable
intra-scan variability was noted, prompting post hoc analysis
using different PET uptake standardization techniques (using
white matter, rather than cerebellar grey matter, as reference
regions to normalize the images). With these techniques, a
trend to reduced Aβ accumulation was seen with the intra-
venous, but not with subcutaneous treatment group. In both
ABBY and BLAZE, crenezumab was well-tolerated overall,
and there was only one single case of ARIA-E. There is now
an open-label extension of 361 participants, to run until 2016.
Crenezumab is also being tested in preclinical Familial
AD in the Alzheimer’s Prevention Initiative (API).
Commenced in 2013, this is an adaptive trial in pre-symp-
tomatic individuals carrying an autosomal-dominant
presenilin mutation to receive bimonthly subcutaneous
Crenezumab (at higher dose than used in ABBY/BLAZE).
The study aims to recruit 300 participants, the major-
ity of whom will be from a large kindred from Medellin,
Colombia, with some also from the United States with simi-
lar mutations. The primary outcome is change in a cognitive
composite score, with secondary outcomes including safety
measures, time to MCI and CSF/imaging biomarkers. It is
set to run until 2020.
53.3.1.6.7 BAN2401
BAN2401 (Eisai/BioArctic) is a humanized IgG1 mAb that
binds to and neutralizes large, soluble toxic Aβ oligomers,
also known as protofibrils. It has 1000-fold higher selec-
tivity for protofibrils over Aβ monomers. In cell culture,
BAN2401 lowered the binding of Aβ protofibrils to hip-
pocampal neurones and neutralized neurotoxicity, and in
mouse models, the murine form mAb158 reduced proto-
fibril levels in CSF by 53%, without change in monomeric
Aβ142 (Tucker et al., 2015).
In Phase I trials, BAN2401 was well-tolerated at all doses
(up to 10 mg/kg fortnightly and no episodes of ARIA were
reported (Lannfelt et al., 2014).

The drug is currently in a Phase II trial, with an adap-
tive study design testing five different doses of intravenous
BAN2401 in biomarker-confirmed MCI due to AD and
early AD (using amyloid-PET). Following recruitment of the
first 200 participants, frequent interim analyses will dictate
group allocation of additional participants joining the study
up to a recruitment target of 800. The primary outcome mea-
sure will be cognitive composite, with secondary outcomes
including change in brain β amyloid burden (PET) and hip-
pocampal volume (volumetric MRI) over 18 months.
53.3.1.6.8 PONEZUMAB
Ponezumab (PF-04360365, Pfizer/Rinnat) is a human-
ized IgG2A mAb against the free C-terminal amino acids
33–40 of Aβ 140 that progressed to Phase II trials in mild-
to-moderate AD (La Porte et al., 2012). Safety outcomes
were acceptable, with no ARIA reported; however, the drug
failed to demonstrate a significant effect on brain or CSF
Aβ, and its development for AD has been discontinued.
There was evidence of a dose-dependent increase in plasma
Aβ40 however, which has prompted initiation of a Phase II
study of ponezumab in patients with CAA (predominantly
composed of Aβ40) (Burstein et al., 2013).
There are still more mAbs in Phase I/II development yet
to reach Phase III trials, which show promise. These include
BIIB037/aducanumab (Biogen), LY3002813 (Eli Lilly),
MEDI1814 (AstraZeneca) and SAR228810 (Sanofi).
53.3.1.6.9 BIIB037/ADUCANUMAB
BIIB037/aducanumab (Biogen) has been developed by ‘reverse
translational medicine’, in that it is a naturally occurring fully
human IgG1 mAb against Aβ, acquired from cognitively
healthy elderly donors. Phase Ib trial in biomarker-positive
participants with prodromal or mild AD (amyloid-PET) is
under way, and Biogen recently announced results of pre-
specified interim analyses. They reported a dose- and time-
dependent reduction in brain Aβ (florbetapir-PET) at 26 and 54
weeks, which corresponded with a significant slowing of dete-
rioration in clinical measures (MMSE and CDR-SB). For the
MMSE, the placebo group declined by 3.1 points at 12 months,
compared with 0.6 points in the highest-dose group (p < 0.05).
For the CDR-SB, the change in score was 2.0 (placebo) and 0.6
(for 10 mg/kg aducanumab), respectively (p < 0.05).
The incidence of ARIA-E was quite high, ranging from 5
to 55%, and was highest in APOE ε4 carriers and at higher
doses. Most participants with ARIA were asymptomatic or
reported mild, transient symptoms only, and treatment was
continued at lower doses. APOE ε4 carriers treated with
the highest dose (10 mg/kg) were most likely to discontinue
treatment (35%). The other most common AE reported was
headache, in 22% of the intervention group compared with
5% of placebo. Biogen plans a Phase III trial in the near future
(Biogen Press Release, 2015).
53.3.1.6.10 LY3002813
LY3002813 binds to a pyroglutamate-bound form of Aβ
(p3-42), which promotes formation of oligomers and
Drug treatments in development for Alzheimer’s disease 565
aggregation into plaque, and is more resistant to clear-
ance than Aβ42 (Gunn et al., 2010). In preclinical studies,
the murine equivalent, mE8, has been shown to clear Aβ
plaques without causing microhaemorrhage (Demattos
et al., 2012). A Phase I study in prodromal or mild AD with
florbetapir PET screening on entry was commenced in 2013,
with results expected in 2015.
Other companies no doubt also have mAbs under devel-
opment, as these approaches target the core of the amyloid
hypothesis. Failure would cast an even greater shadow over
this anti-amyloid approach, although a role in prevention is
still possible even if therapy of established AD is unsuccessful.
53.3.1.7 Polyclonal antibodies
Human immunoglobulin contains polyclonal anti-Aβ
antibodies (IgG and IgM classes) that bind to both oligo-
meric and fibrillar Aβ and three companies have trialled
human immunoglobulin infusions for the treatment of
AD (Octagam, Octapharma; Gamunex, Grifols Biologicals;
Gammagard, Dexter Healthcare). Intravenous immuno-
globulin preparations are already utilized for a range of
other immune-mediated conditions, and it has been pre-
viously observed that individuals treated with immuno-
globulin therapy for other reasons have a reduced risk of
subsequent AD (Fillit et al., 2009).
53.3.1.7.1 GAMMAGARD
The most advanced agent in trials is Gammagard (Baxter),
which was tested in two Phase III trials. The first was
run in conjunction with the U.S. ADCS group and tested
Gammagard, 400 or 200 mg/kg against placebo over 18
months (n = 390, mild-to-moderate AD). Unfortunately, the
study failed to show a difference in its primary (cognitive)
end points, although there were some trends to improve-
ment in pre-specified subgroups (moderate AD, APOE
ε4 carriers) and dose-dependent biomarker responses
(decrease in CSF Aβ42). Following the release of these out-
comes, the second Phase III trials were terminated.
53.3.1.7.2 OCTAGAM
Octapharma’s agent Octagam has completed Phase II tri-
als in MCI patients, with initial results suggesting reduced
atrophy over 12 months. However, no cognitive differences
emerged and no further trials have been announced. The
Grifols Biologicals agent, Gamunex, is currently still in
Phase II/III, estimated to run to 2016.
53.3.1.8 New modes of delivery of
immunotherapy
A significant drawback of immunotherapy is the need to
infuse the treatment, usually intravenously. Aβ fragments
delivered mucosally (e.g. via the nose) have elicited an anti-
body response in mice, avoiding the need for parenteral
administration. An oral Aβ vaccine is also being developed,
but efficacy is not yet in the public domain.
566 Dementia
Other methods of delivery of Aβ, or mAbs, include uti-
lizing filamentous viral bacteriophages and modifying an
adenovirus to include a ‘payload’ of antigen or antibody.
53.3.1.9 Other immunotherapies
Anti-Aβ DNA vaccination is a promising approach that is
being trialled. Additionally, an antibody has been devel-
oped from a subject with the British APP mutation that
interacts with various β-pleated protein sheets. This anti-
body potentially targets both amyloid and tau (as neurofi-
brillary tangles) as both are β-sheets and it may thus have
benefits beyond those of individual anti-amyloid or anti-tau
therapies (Lambracht-Washington et al., 2013).
53.3.1.9.1 GRANULOCYTE-MACROPHAGE COLONY-
STIMULATING FACTOR (GM-CSF) AND
GRANULOCYTE COLONY–STIMULATING
FACTOR (G-CSF)
Sargramostim and Filgrastim/Neupogen are synthetic
preparations of the haemopoietic growth factors, GM-CSF
and G-CSF. These agents are indicated for bone marrow
stimulation post-transplant in haematological malignan-
cies. These agents are proposed to enhance the innate
immune system, thereby stimulating microglia to take up
and clear Aβ. Second, as soluble Aβ in the peripheral cir-
culation binds to circulating erythrocytes (via complement
opsonin 3b), they may also increase peripheral clearance by
promoting erythropoiesis (Boyd et al., 2010).
Observational data suggest that haematology patients
treated with G-CSF + GM-CSF have better cognitive out-
comes than those on G-CSF alone (Jim et al., 2012). A pilot
study of eight mild-to-moderate AD patients treated with
G-CSF for 5 days showed improvements on a single epi-
sodic memory task, but no change in CSF Aβ1–42 (Sanchez-
Ramos et al., 2012). Sarmograstin/GM-CSF is currently
in several Phase II trials in patients with AD, MCI and
Parkinson’s disease (PD).
53.3.1.10 Amyloid aggregation inhibitors
53.3.1.10.1 TRAMIPROSATE
Glycosaminoglycans (GAGS) are components of proteo-
glycans, which are incorporated into the amyloid plaque.
Tramiprosate (Alzhemed) is a GAG-mimetic patented vari-
ant of taurine that binds to Aβ and inhibits fibril formation.
In vitro, tramiprosate binds soluble Aβ, inhibits aggregation
and neurotoxicity. In a Phase II trial, tramiprosate reduced
brain levels of Aβ42 but did not improve cognition scores
compared to placebo (Aisen et al., 2006). The drug pro-
ceeded to an 18-month Phase III trial in mild-to-moderate
AD, which was negative on primary end points. There was
a trend towards slowing of decline on the ADAS-Cog but
no difference in the CDR-SB. There was with significant
reduction in hippocampal atrophy in participants tak-
ing tramiprosate, but there are no other biomarker results
(Aisen et al., 2011). It has not been tested in preclinical or
prodromal AD, but tramiprosate is currently available over
the counter as a supplement to assist memory (Vivimind) in
the United States.
53.3.1.10.2 ELND005/ADZ-103/SCYLLO-INOSITOL
ELND005/ADZ-103/Scyllo-inositol is related to the natu-
rally occurring inositol (found in fruit) that binds to and
inhibits neurotoxic oligomeric Aβ42, and prevents aggrega-
tion and plaque formation. It also lowers brain myo-inositol
levels, which are higher in AD, Down’s Syndrome and bipo-
lar disorder, and correlate with behavioural and psycho-
logical symptoms of dementia (BPSD) (Shinno et al., 2007).
In transgenic mice, ELND005 reduces Aβ plaque burden
and improves learning deficits (Salloway et al., 2011). In
a Phase II trial, 353 patients with mild-to-­moderate AD
received 500, 2000 or 4000 mg daily or placebo for 78 weeks.
Increased infections and deaths were seen in the higher-
dose groups and these were terminated early. At 500 mg,
treatment with ELND005 was deemed safe, but did not
result in any significant difference in cognition or function
(NTB, ADCS-ADL) overall. It was however measureable in
CSF, and CSF Aβ42 level decreased significantly (p = 0.009).
There were significant differences in NTB scores when the
mild AD group were analysed separately, and interestingly,
this group also had slightly less emergence of neuropsychi-
atric symptoms on the NPI (Neuropsychiatric Inventory). It
is unclear whether these effects may be due to the drug’s AD
disease-modifying properties or due to the lowering of myo-
inositol. Further Phase II trials have looked at ELND005’s
role in treatment of neuropsychiatric symptoms in bipolar
disorder (add-on therapy, terminated early due to financial
reasons) Down’s syndrome and in moderate–to-severe AD
(n = 400, 12 + 18 weeks, still recruiting). Results presented
from the study in Down’s syndrome (n = 23, ELND005 250
mg/500 mg/placebo for 4 weeks) have been presented. A
greater proportion of those on the high-dose regime par-
ticipants showed improvements in NPI score than with
low-dose or placebo – although the numbers overall were
very small (7/8 compared with 0/4 and 1/3, respectively)
(Transition Therapeutics Media Release, 2014).
53.3.1.10.3 CURCUMIN
Curcumin is found in the spice turmeric and has antioxi-
dant, anti-inflammatory and anti-aggregation properties.
Curcumin binds Aβ and reduces amyloid plaque burden
(Garcia-Alloza et al., 2007) and tau aggregation in mice (Ma
et al., 2013). A Phase II trial in AD was negative, with some
gastrointestinal adverse symptoms, and it failed to show any
biomarker changes (Ringman et al., 2012). However, a trial of
curcurmin in combination with exercise (aerobic and non-
aerobic yoga) is in progress in MCI, with clinical, blood and
fludeoxyglucose-PET (FDG-PET) biomarker end points.
53.3.1.10.4 PBT-2
Aβ binds copper and zinc and some metal-chelating com-
pounds affect Aβ aggregation, particularly into the most toxic

oligomeric species. Original studies with clioquinol, a ­copper–
zinc chelator, showed reduced Aβ deposition in a mouse
model of AD (Cherny et al., 2001). A structural analogue,
PBT-2, has completed a 12-week Phase II trial in 78 subjects
(­placebo, 50 mg and 250 mg daily) (Lannfelt et al., 2008). The
trial was not powered for cognitive end points but did show a
significant benefit of the 250 mg dose, compared to placebo,
on verbal fluency and working memory. There was also a
highly significant (p = 0.0060) reduction in CSF Aβ42 with the
250 mg dose. A subsequent Phase III trial was completed in
42 prodromal AD patients over 12 months (MCI with a posi-
tive 11C-PiB PET scan). Results presented to date indicate that
there was no difference seen in the primary outcome (PiB PET
binding). The active group did have a reduction in PiB stan-
dardized uptake value ratio (SUVR) (Aβ burden), although
unusually, the SUVR went down in the placebo group as well.
There was a trend to reduction in hippocampal atrophy with
treatment; however, cognitive outcomes were also negative.
The drug was safe and well-tolerated; however, it is unclear
whether it will have the opportunity to go on to larger trials
better powered for clinical benefits.
53.3.1.10.5 COLOSTRININ
Colostrinin is a proline-rich polypeptide found in sheep
colostrum, which affects amyloid aggregation and may pre-
vent apoptosis of neurones. A small open-label study sug-
gests possible clinical benefit and the peptide components of
colostrinin are under investigation (Janusz and Zabłocka,
2010). Like curcumin, it may be favourably regarded due to
its ‘nutraceutical’ categorization.
53.3.1.10.6 CARVEDILOL
Carvedilol is a nonselective antagonist of the α- and
β-adrenergic receptors.It is currently indicated for man-
agement of congestive heart failure, ischaemic heart dis-
ease/angina and hypertension. In TgCRND8 and Tg2576
transgenic mouse models of AD, carvedilol attenuates Aβ
oligomerization and formation of fibrillar plaques, as well as
preserving dendritic spine density and attenuating special
memory deterioration (Wang et al., 2011). Trials in humans
(mild AD) are under way, with cognitive and CSF-Aβ out-
come measures.
53.3.1.11 Other anti-amyloid approaches
53.3.1.11.1 APOE ε4 GENE MODULATION
The association between APOE ε4 and AD risk has led
to early phase trials of agents that modulate or reduce ε4
expression or activity. One group of agents that inhibit
APOE ε4 domain interactions looks promising, but large
human trials are awaited (Chen et al., 2011).
53.3.1.11.2 BEXAROTENE (TARGRETIN)
Bexarotene is already FDA approved for use in humans, for
cutaneous T-cell lymphoma. It gathered interest in 2012
when a preclinical study reported clearance of amyloid
Drug treatments in development for Alzheimer’s disease 567
plaques in mice by 50% within 72 hours (Cramer et al.,
2012). Subsequent attempts to replicate these findings have
met with varied success although two have corroborated an
effect on soluble Aβ (Veeraraghavalu et al., 2013). Bexarotene
acts on the retinoid X receptor to increase ApoE levels and
promote ApoE lipidation, both of which assist with ApoE-
mediated trafficking of Aβ. However, its benefit may vary
according to APOE genotype – i.e. it appears to correct the
pathological loss-of-function of APOE ε4 but make little
difference in mice expressing APOE ε3 (Tai et al., 2014).
A Phase I trial in healthy adults, and a Phase IIa trial
(BEATAD) is currently under way, the latter using change
in amyloid (florbetapir PET) as the primary outcome.
Importantly, it has been known to cause lipid and triglyceride
abnormalities and pancreatitis, so safety monitoring is critical.
53.3.1.11.3 PHENSERINE AND POSIPHEN
Phenserine has both cholinesterase-inhibiting and anti-
amyloid effects (reduces APP expression) and preclinical
results were promising (Lahiri et al., 2007). Subsequent
Phase II and III trials were negative (albeit trends to cogni-
tive and CSF benefits), and it was withdrawn from devel-
opment (Winblad et al., 2010). Its positive enantiomer,
Posiphen, is currently under evaluation. It does not cause
cholinergic effects, potentially enabling higher doses to be
used. In a Phase I study, treatment with Posiphen resulted
in significant CSF biomarker improvements (Maccecchini
et al., 2012). A 10-day course of Posiphen in MCI patients
led to normalization of CSF tau- and p-tau levels. Posiphen
also lowers α-synuclein, which also makes it a compound of
interest for PD (Ross et al., 2013).
53.3.1.11.4 CHF 5074
A NSAID-derivative initially promoted as a γ-secretase
modulator, CHF 5074 is now understood to have several
additional mechanisms of action, activating microglia and
reducing aberrant cell cycle events. A 12-week Phase II
trial in 96 participants with MCI showed improvements
in CSF measures of inflammation (CD40l and TNF-
α) and trends to cognitive benefits in APOE ε4 carriers.
Withdrawals due to diarrhoea occurred in both Phases I
and II (Ross et al., 2013). The Phase II has been extended
(open label) to 90 weeks.
53.3.1.11.5 PQ912 (PROBIODRUG AG)
PQ912 is a small-molecule antagonist of glutamyl cyclase,
which generates the aggregation-prone and neurotoxic
pyroglutamate Aβ (see Section 53.3.1.7.8). Phase I trials have
suggested that it is well-tolerated, but there are no data on
efficacy to date (Perez-Garmendia et al., 2013).
53.3.1.11.6 LEVETIRACETAM
Levetiracetam is an anticonvulsant medication that has
shown cognitive benefits in AD patients with seizures
(Cumbo et al., 2010). MCI subjects treated with leveti-
racetam demonstrated improved memory performance
and reduced pathological neuronal hyperactivity in the
568 Dementia
hippocampus (Bakker et al., 2012). Recently, levetirace-
tam has been shown to act on synaptic vesicle protein 2A
(SV2A), which regulates neuronal endocytosis. In APOE
ε4 carriers, there is enhanced endocytosis of BACE1
and APP within endosomes, which provides ideal con-
ditions for BACE1 cleavage of APP to Aβ40 and Aβ42.
Modification of SVA2 activity via levetiracetam in trans-
genic mice suppresses this APOE ε4-dependent increase
in Aβ40 and Aβ42 production (Rhinn et al., 2013). Two
early phase studies of levetiracetam on cognition and epi-
leptiform activity in AD are currently recruiting, one of
which is targeting early-onset AD (age at symptom onset
<70 years).
53.3.1.11.7 CT1812 (Cognition Therapeutics)
In vitro studies suggest that binding of Aβ oligomers to spe-
cific receptors at neuronal synapses may be an important
step leading to loss of neuronal function in AD. CT1812 is
a small molecule antagonist at sigma-2/PGRMC1 that dis-
places binding of Aβ oligomers from neurones in vitro, and
restores cognition n AD transgenic mice. It is currently in
early phase studies in humans.
53.3.1.11.8 CSF DRAINAGE/COGNISHUNT™
It is possible that continuous CSF drainage will remove Aβ
from the brain, essentially creating an Aβ gradient. A ran-
domized controlled trial (RCT) of 215 subjects utilized a
sham (occluded) shunt as the control arm. At 9 months,
there was no significant difference in cognitive or global end
points between the two groups. There were 12 CNS infec-
tions. It is unlikely that this approach will be subjected to
further trials (Silverberg et al., 2008).
53.3.2 TAU
By 2050, there will be 600 million people with significant
tau pathology (BRAAK stage II or above) – not all with AD.
Anti-tau therapy could have widespread application for
people with AD, some FTLDs and MCI.
53.3.2.1 Anti-tau immunotherapy
A number of potential targets exist for immunotherapy
against tau, including the microtubule-binding region
of tau and the pathogenic p-tau (as opposed to non-­
phosphorylated tau).
53.3.2.1.1 ACI-35
AC Immune recently announced it will begin human tri-
als of ACI-35, a liposome vaccine containing synthetic
p-tau fragments within a lipid bilayer. In tau transgenic
mice, vaccination with ACI-35 resulted in generation of IgG
antibodies against p-tau, without T-cell actuation, gliosis
or increasing inflammation. The antibodies produced were
able to reduce soluble and aggregated tau in vitro (Theunis
et al., 2013). A Phase I trial in humans (mild-to-moderate
AD) is currently under way.
AADvac-1 is another active vaccine against pathological
tau fragments (Axon Neuroscience) that is also in Phase I
development.
53.3.2.2 Anti-aggregation approaches for
tau
53.3.2.2.1 METHYLTHIOMINIUM CHLORIDE
(REMBER/TRX0014) AND TRX0237
There has been a completed trial of the first therapeutic agent
targeting tau, utilizing a drug derived from the dye used to
stain neurofibrillary tangles in neuropathological stud-
ies. The agent primarily inhibits tau aggregation, although
other reported effects include antioxidant and increasing Aβ
clearance. The 84-week Phase II study in 321 subjects showed
significant benefits, compared to placebo, in the cognitive
(ADAS-Cog) and global (CDR) primary end points but only
for the lower doses (Wischik et al., 2014). The 100 mg (high-
dose) formulation may have had formulation deficiencies
(cross-linking with the gelatine capsule), which have sub-
sequently been addressed. Neuroimaging end points were
also promising, including single-photon emission computed
tomography (SPECT) in 125 subjects (with no decline in per-
fusion seen with the 60 mg dose, compared to a decline in
the placebo group) and FDG-PET in 19 subjects (improved
metabolism in the actively treated group). The agent is poorly
absorbed and diarrhoea occurred in some treated subjects.
TRx0237 is the second-generation formulation of
Rember, which is reported to have improved bioavailabil-
ity and tolerability. It is currently in Phase III for mild-to-
moderate AD, mild dementia (all-cause, MMSE > 20) and
behavioural variant FTD.
53.3.2.3 Targeting tau
hyperphosphorylation
Several phosphorylation inhibitors have been developed, as
have agents that dephosphorylate tau.
53.3.2.3.1 TIDEGLUSIB
Tideglusib is an inhibitor of glycogen synthase kinase 3
(GSK-3), which phosphyorylates tau. In mice, it reduced p-tau
and neurodegeneration, and improved memory deficits. It
has undergone Phase II human trials for AD and progressive
supranuclear palsy (PSP), a tauopathy. Unfortunately both
applications failed in their primary end points (subanalysis
at lower dose in mild AD suggested slight benefit) and its
development has been discontinued (Lovestone et al., 2014;
Tolosa et al., 2014).
53.3.2.3.2 LITHIUM
Lithium inhibits tau phosphorylation via GSK-3 and may
have other beneficial roles including improving mitochon-
drial function, increasing levels of neurotrophins (e.g.
brain-derived neurotrophic factor [BDNF]) and reduc-
ing apoptosis (Forlenza et al., 2012). Some observational

studies have also suggested a reduced incidence of demen-
tia in patients with bipolar affective disorder treated with
lithium, compared with other agents (Gerhard et al., 2015).
Several small open-label or case–control studies in mild-to-
moderate AD have not shown benefit; however, a small RCT
in amnestic MCI (n = 45) showed lower conversion to AD
compared with placebo, which correlated with reductions
in CSF p-tau levels (Forlenza et al., 2012).
53.3.2.3.3 SELENIUM
Selenium (as sodium selenate) activates the enzyme PP2A
phosphatase, which dephosphorylates tau. It is shown to
lower levels of p-tau and total tau and improve memory
and learning in transgenic mice (Corcoran et al., 2010). It
is being tested against placebo and vitamin E in a Phase III
prevention study in cognitively healthy men (PREADVISE,
n = 7547); however, no results have been presented as yet.
A small 24-week Phase IIa trial (n = 40) was completed in
Australia but sodium selenate at doses of 10 mg and 320 μg
showed no effect on CSF biomarkers including both total
and p-tau (VEL015- Velacor).
53.3.2.3.4 METFORMIN
The insulin-sensitizing antidiabetic drug, metformin is
also a PP2A phosphatase agonist. It may also reduce AD
risk by improving glucose sensitivity and metabolic profile
(see Section 53.2.8); however in vitro results are conflict-
ing, as it may also increase BACE1 transcription. A trial
of metformin in MCI (n = 80) is recently completed (as yet
unpublished) and another in MCI and AD is in progress
(Yarchoan and Arnold, 2014).
53.3.2.3.5 ABT-957 (ABBVIE)
The enzyme calpain is involved in a number of pathways to
neurodegeneration, including mediating Aβ-induced neu-
rotoxicity and activating the tau kinase, cyclin-dependent
kinase 5 (CDK5). It may also be involved in pathologi-
cal cleavage pathways of the α-synuclein protein in Lewy
body disorders. Inhibition of calpain in tau transgenic mice
reduced hyperphosphorylation of tau and prevented neuro-
degeneration (Rao et al., 2014). ABT-957, a calpain antago-
nist, began Phase I trials in 2014.
53.3.2.4 Enhancing microtubular stability
53.3.2.4.1 EPOTHILONE D
Epothilone D (BMS-241027, Bristol-Myers Squibb) clears
tau pathology and improves cognition and behaviour in
transgenic tauopathy mice (Barten et al., 2012), but a Phase I
study was terminated early due to lack of target engagement.
53.3.2.4.2 TPI 287
TPI 287 (Cortice Biosciences) is a derivative from the taxane
family of cancer drugs. It is in Phase I for AD, and other
tauopathies including corticobasal degeneration (CBD)
and PSP.
Drug treatments in development for Alzheimer’s disease 569
53.3.3 NEURONES AND SYNAPSES
53.3.3.1 Neurotrophic therapies
53.3.3.1.1 NERVE GROWTH FACTOR
The first trial of NGF via direct intraventricular injection
into the CSF was halted due to a high proportion of sub-
jects experiencing intense axial (back) pain. This may have
been due to the presence of NGF receptors in the spinal
cord (Eriksdotter Jönhagen et al., 1998). A variation on this
direct neurorestorative approach was examined in a Phase I
trial in eight patients with mild AD (Tuszynski et al., 2005).
Fibroblasts were extracted from their fingers, genetically
modified to express human NGF, then injected directly
back into the cholinergic nucleus basalis of their forebrain.
After a mean follow-up of 22 months in six subjects, no long-
term adverse effects were seen but two (non-anaesthetized)
subjects moved abruptly during the procedure, causing
subcortical haemorrhage. All subsequent procedures were
performed under general anaesthesia. The MMSE and
ADAS-Cog showed improvements in the rate of decline and
serial FDG-PET scans showed significant (p < 0.05) wide-
spread increases in metabolism after the procedure. Brain
autopsy from one subject showed robust growth responses
to the NGF expression.
A more recent variation on this theme involved ste-
reotactic implantation of an encapsulated cell biodelivery
device containing engineered retinal pigment cells into
the basal forebrain. In a small Phase I study (n = 6) in AD
patients, the procedure was reported as ‘safe, well-tolerated
and feasible’, with cognitive (CDR, instrumental activities
of daily living [IADLs]) and biomarker (CSF Aβ 1–42, hip-
pocampal atrophy) improvements seen in 50% of partici-
pants (Ferreira et al., 2015).
CERE-110/AAV2-NGF (Ceregene/Sangiamo) uses a viral
vector that expresses human NGF, which is injected into the
nucleus basalis of Meynert. In Phase I (mild-to-moderate
AD, n = 6), it was well-tolerated and cognitive improve-
ments were reported, as well as increases in brain metabo-
lism using FDG-PET. The technique is currently in Phase II.
53.3.3.1.2 XALIPRODEN
Xaliproden is a neurotrophic factor enhancer and 5-HT1A
agonist that demonstrated neuroprotective and neuro-
restorative effects in preclinical studies. It proceeded to
large Phase III clinical trials (>1300 patients each) in sub-
jects with AD. Results were negative, although a smaller
substudy (n = 329) showed less hippocampal atrophy in the
active group (Porzner et al., 2009).
53.3.3.1.3 CEREBROLYSIN
A peptide mixture extracted from pig brains, Cerebrolysin
has neurotrophic activity (increases pro-NGF) and
reduced Aβ deposition in animal models. A recent meta-
analysis of six RCTs in mild- and moderate-AD subjects
(n = 784) compared Cerebrolysin (30 mL intravenous
infusion daily for 4 weeks) with measures at 4 weeks and
570 Dementia
6 months. By standardizing outcome scales from the dif-
ferent studies, they found benefit for cerebrolysin in global
clinical change at week 4 (odds ratio [OR] 3.32, 95% CI
1.20–9.21) and 6 months (OR 4.98, 95% CI 1.37–18.13).
However, a significant cognitive function benefit was seen
at week 4 only (standardized mean difference −0.40, 95%
CI −0.66to −0.13) but not at 6 months (not reported). AEs
profile was similar to placebo, and it has been studied
both as monotherapy and in combination with ChEI. A
Cochrane review of RCTs in vascular dementia (six stud-
ies, n = 597) also was supportive, although also benefits
over placebo were of modest magnitude only (one-point
difference in MMSE, four-point difference in ADAS-Cog).
It is commercially available for treatment of AD in several
countries and is being trialled in acute traumatic brain
injury and stroke (Alvarez et al., 2006, 2011; Chen et al.,
2013; Gauthier et al., 2014).
53.3.3.1.4 T-817MA
T-817MA is an oral neurotrophic agent that promote neu-
rite growth and protects synapses against Aβ-induced neu-
rotoxicity (Takamura et al., 2014). A large Phase IIa trial
(n = 373) showed trends to improved cognition and func-
tion, which will be tested in another trial as add-on therapy
in AD (Schneider et al., 2013).
53.3.3.2 Stem cell therapies
Stem cells are self-renewing cells that can replicate and
differentiate to produce other diverse cell types. Stem cell
therapy provides neural progenitor cells, with the aim of
replacing damaged nerves (neurogenesis). Its proposed
applications in the CNS include treatment of nerve injury
(e.g. spinal cord injury) and neurodegenerative disorders
(e.g. PD, AD). For comprehensive reviews, see Antigoni
Ekonomou (2010), Fan et al. (2014) and Li et al. (2015).
Stem cells may be derived from several sources, includ-
ing neural stem cells (NSCs) from mature or foetal brain
tissue, mesenchymal stem cells (MSCs) from umbilical
cord blood or bone marrow and cells from the developing
embryo (embryonic stem cells [ESCs]). Somatic cells may
also be treated to reprogramme their activity to produce
pluripotent stem cells. With stem cell therapy, there are
inherent risks of immune rejection (with donor or non-self
cells) and development of tumours (with pluripotent cell
lines) (Antigoni Ekonomou, 2010; Li et al., 2015).
Endogenous NSCs are also present in adult brains, and
ongoing neurogenesis occurs in select regions, including
the hippocampus. However, these cells are few in number
and this activity is reduced in neurodegenerative disease.
Treatments or factors shown to restore or promote this
neurogenesis in vitro and in animal models include allo-
pregnanolone (an endogenous neurosteroid), and intrinsic
factors such as environment and physical activity (Li et al.,
2015).
Research with foetal and ESCs poses great ethical and
supply challenges, and use of this tissue is tightly regulated.
53.3.3.2.1 STEM CELL THERAPY IN OTHER CENTRAL
NERVOUS SYSTEM DISEASES
Early human studies in animal models and humans with
PD grafted (postmitotic) foetal dopaminergic neurones into
the striatum. While this achieved clinical improvement in
some subjects, lack of availability of foetal tissue has limited
its utility (Antigoni Ekonomou, 2010).
Under strict guidelines, ESCs for research have been
sourced from in vitro fertilization programmes. A trial of
ESCs (oligodendrocyte progenitor cells [OPCs], OPC1) to
treat neurologically complete thoracic spinal cord injury
was commenced in 2010, following promising preclini-
cal findings in rats. Only 5 of the planned 10 participants
were recruited, and the study sponsor, Genen, discon-
tinued this field of development. Their stem cell therapy
portfolio has been purchased and is being expanded
through Asterias Biotherapeutics. Although no results
have been published, they report successful delivery of
OPC1 cells, with no serious AEs, and potential radio-
logical benefits, although no measurable neurological
improvements were seen. A subsequent Phase I/IIa esca-
lating dose study in cervical cord injury is to recruit in
2015 (Asterias Biotherapeutics, 2015).
For multiple sclerosis, autologous bone marrow-derived
haemopoietic stem cells have also been used as an add-on
to immunosuppression to mitigate immune-mediated neu-
ropathology. Both radiological and clinical benefits are
reported, although larger RCTs are required (Burt et al.,
2015).
53.3.3.2.2 STEM CELL THERAPY IN ALZHEIMER’S
DISEASE
There is evidence for benefit of NSC and MSC therapies
in animal models of AD, including reduction of expres-
sion of APP, BACE1 and Aβ; attenuation of BACE1 and
γ-secretase activity; increased expression of BDNF and
neprilysin (enhancing degradation of Aβ); reduction in
pro-inflammatory cytokines and inflammation; improve-
ment in cholinergic transmission and reversal of mem-
ory deficits (Yun et al., 2013; Li et al., 2015). However,
the unfriendly microenvironment may compromise the
survival and ‘successful’ differentiation of the NSCs into
neurones. In AD, presence of APP and Aβ fragments may
result in reduced NSC proliferation, reduced neurogen-
esis, and preferential production of astrocytes. Provision
of additional neurotrophins, e.g. BDNF, glial-derived
neurotrophic factor (GDNF) and vascular endothelial
growth factor (VEGF) may counter these negative effects
(Li et al., 2015).
There are no current trials of NSCs or ESCs in humans
with AD, although a Phase I trial of intravenous infusion
of human umbilical cord blood-derived MSCs in 30 AD
participants has commenced in China. Outcomes are safety
(AEs) and cognitive (ADAS-Cog and Clinician’s Interview
Based Impression Of Change [CIBIC]). Results are expected
by end of 2015.

53.3.4 INSULIN-SENSITIZING
TREATMENTS AND PPAR-γ
AGONISTS
Several therapeutic approaches to improving insulin and
IGF signalling in AD are currently in clinical trials.
53.3.4.1 PPAR-γ agonists
The thiazolidinedione (TZD) group of PPAR-γ receptor ago-
nists (glitazones), increase tissue sensitivity to glucose, reg-
ulate lipid metabolism and increase mitochondrial activity,
as well as reducing inflammatory responses by inhibiting
nuclear factor-κB and downregulating BACE1 promotion
(Gold et al., 2010). At low doses, they may also effect amy-
loid clearance by increasing LRP1 expression (Moon et al.,
2012).
53.3.4.1.1 ROSIGLITAZONE
Rosiglitazone is a PPAR-γ agonist that increases peripheral
insulin sensitivity and is approved for clinical use in type
2 (T2DM). In transgenic mice, it decreases Aβ42 plaque
burden, mitigates Aβ-associated inflammation, synaptic
dysfunction and cognition. In Phase II (n = 323), cognitive
benefits were seen in APOE ε4-negative individuals, but not
in APOE ε4 carriers. Subsequently a large Phase III study
(n = 693) stratified by APOE ε4 status was negative (Gold
et al., 2010). Side effects included peripheral oedema and
cardiac failure.
53.3.4.1.2 PIOGLITAZONE
Pioglitazone is another PPAR-γ agonist that is approved for
use in T2DM that has been trialled in AD. It has been tested
in MCI and AD with small Phase I/II trials and has shown
positive results in diabetics, but not in non-diabetics. In one
open-label study of AD patients with T2DM, pioglitazone
15–30 mg improved regional cerebral blood flow, stabilised
plasma Aβ40/42 ratio and improved cognition (Sato et al.,
2011). Pioglitazone is currently being tested at low doses
(0.8 mg daily about 2% of the therapeutic dose in diabetes) in
a large multicentre study of cognitively normal individuals
aimed at preventing progression to MCI (TOMMORROW
Study). Aiming to enrol 5800 participants, this study will
assign individuals to intervention or placebo according to
their genetic risk for AD using APOE and TOMM40 geno-
types. The primary end point will be the time to conversion
to MCI due to AD.
This trial is administering pioglitazone at doses much
lower than that usually prescribed for diabetes, suggest-
ing that it aims to target the LRP1 hypothesis (Moon et al.,
2012) rather than insulin resistance.
53.3.4.1.3 MSDC-0160
MCDC-0160 (Metabolic Solutions) is a novel oral insulin-
sensitizer that acts at the mitochondrial target of thiazoli-
dinedione (mTOT) receptor in the inner mitochondrial
membrane. mTOT coordinates carbohydrate, lipid and
Drug treatments in development for Alzheimer’s disease 571
amino acid metabolism, improving insulin signalling
and pancreatic β-cell function. It also influences metabo-
lism to favour ‘brown fat’ (calorie burning) and decrease
‘white fat’ (calorie storing). A small Phase IIa study in
mild-to-moderate AD (n = 29), MCDC-0160 maintained
or increased glucose metabolism using FDG-PET in ante-
rior and posterior cingulate, parietal lateral temporal
and medial temporal cortices (regions affected by AD)
(Shah et al., 2014). It is also being assessed for benefit as
an alternative insulin-sensitizer in diabetes, and in PD,
where it may have neuroprotective effects on dopaminer-
gic neurones.
53.3.4.2 Glucagon-like peptide-1 (GLP-1)
analogues and GLP-1 receptor
agonists
Incretin hormones are released by the gut in response to oral
ingestion of glucose. They act to facilitate insulin signalling,
but also have neurotrophic and anti-inflammatory effects
(McClean and Hölscher, 2014). A number of GLP-1 ago-
nists or analogues are currently approved for use in T2DM,
including liraglutide (Victoza), exendin-4 (Exenatide/
Byetta) and lixisenatide (Lyxumia).
53.3.4.2.1 LIRAGLUTIDE
Liraglutide is a GLP-1 receptor agonist currently approved
for T2DM. In APP/PS1 mice, liraglutide reduced Aβ plaque
load and inflammation by one-third, while increasing IDE
levels and improving object recognition and memory per-
formance (McClean and Hölscher, 2014). A Phase IIb study
in mild AD (Dubois criteria, MMSE > 22, CDR global score
0.5–1) is currently recruiting, to test liraglutide (1.8 mg sub-
cutaneous injection daily) against placebo. It will run for
12 months, with primary outcome measure change in brain
metabolism using FDG-PET. Secondary measures include
change in cognitive ADAS exec, MRI volumes, microglial
activation and CSF markers.
53.3.4.2.2 EXENATIDE
Exendin-4 (Byetta) is a GLP-1 analogue, derived from the
venom of the Gila monster, a shy Central American lizard
that can survive long periods of fasting.
In AD transgenic (3xTg-AD) mice, exendin-4 signifi-
cantly reduced brain Aβ levels (Li et al., 2010) and in rats
with experimental hyperglycaemia and oxidative stress
Exendin-4 downregulates GSK-3β, reducing tau hyperphos-
phorylation (Chen et al., 2012) and improving cognition.
A Phase II trial of Exendin-4 (twice daily subcutaneous
injections) in AD (MMSE > 20, n = 230) is under way. This
trial uses CSF Aβ for participant screening and as a second-
ary outcome measure.
53.3.4.2.3 INTRANASAL INSULIN (DETEMIR,
LEVEMIR, HUMULIN, NOVOLIN)
Improved brain insulin signalling correlates with mem-
ory function in healthy adults, AD and MCI (Freiherr
572 Dementia
et al., 2013). The challenge has been to deliver insulin
effectively to the brain, without causing peripheral effects.
Several small trials of intranasal delivery of insulin (vari-
ous formulations) have been conducted (Benedict et al.,
2004; Reger et al., 2008; Craft et al., 2012). One Phase I
clinical trial in MCI (n = 64) or early AD (n = 40) par-
ticipants administered 20 or 40 IU of intranasal insulin
over 4 months. The treatments were well-tolerated and
they showed improvements in primary efficacy measures
(ADAS-Cog and ADCS-ADL) over placebo. Subsets also
had CSF (n = 23) and FDG PET (n = 40). FDG hypome-
tabolism was attenuated in the treatment groups, and
although CSF = Aβ did not differ at group level, change in
CSF = Aβ42 and Aβ42/tau ratio correlated with change in
cognitive performance (Craft et al., 2012). A Phase II/III
study of intranasal insulin in AD and aMCI is currently
recruiting (n = 240, the ‘Study of Nasal Insulin in the Fight
against Forgetfulness, SNIFF’).
53.3.5 NEUROTRANSMITTERS AND
RECEPTORS
Most therapies directed at neurotransmitters and their
receptors are symptomatic rather than disease modify-
ing, although the distinction between these two classes of
effects is less clear than originally thought. Modifying syn-
aptic activity may have neuroprotective effects, although
it has been difficult to demonstrate this with the ChEIs.
Several new neurotransmitter approaches are being tri-
alled and some may ultimately improve symptoms in
the short term while also having longer-term effects on
neurodegeneration.
53.3.5.1 Histamine 3 (H3) receptor
antagonists
The H3 receptor is preserved even in severe AD, and
drugs that antagonize it increase levels of acetylcholine,
noradrenaline and dopamine in the cingulate cortex and
hippocampus. Several compounds are being evaluated for
cognitive benefits through H3 receptor antagonism, which
improves cognition, attention and alertness in animal
models (Vohora and Bhowmik, 2012). GSK239512IT has
undergone a Phase II study (mild-to-moderate AD, MMSE
16–24, 16 weeks, n = 196), which demonstrated modest but
significant improvement in episodic memory performance
(but not executive function or ADAS-Cog). Side effects
included headache, dizziness and sleep disturbance (Grove
et al., 2014).
A Phase II trial of the Sanofi compound SAR110894
(mild-to-moderate AD, MMSE 15–25, n = 290, 24 weeks)
was negative in all primary and secondary end points,
except for a significant improvement in functional score
(ADCS-ADL) compared with placebo.
A Phase II study of the Abbot H3 antagonist, ABT-288,
in mild-to-moderate AD versus placebo and active placebo
(donepezil) was terminated prematurely following a futility
analysis.
Both MK0249 (Merck) and PF-03654746 (Pfizer) have
been studied in AD, schizophrenia and attention-deficit
hyperactivity disorder (ADHD), all with negative findings
on cognition. It is unclear whether they will be developed
further.
53.3.5.1.1 5-HT6 RECEPTOR ANTAGONISM
5-HT6 receptor is localized almost exclusively in the CNS,
particularly in the cerebral cortex and hippocampus.
Antagonism enhances cholinergic and glutamatergic neu-
rotransmission and may be complementary as adjunct ther-
apies to ChEIs (Upton et al., 2008).
Two agents, RVT-101 (formerly SB-742457) (Axovant,
formerly GSK) and LU AE58054/idalopirdine (Lundbeck)
both led to improvements in cognition and global function,
with stronger findings in moderate-to-severe AD, and when
used as add-on therapy with donepezil. Lundbeck is test-
ing idalopirdine in three large Phase III trials (n ~ 2500 in
total) in AD as adjunct to ChEIs. GSK tested SB-742457 to
Phase II. Under Axovant, SB-742457 has been renamed and
will be tested to Phase III in mild-to-moderate AD, again as
add-on to donepezil. Trials in Lewy body dementia are also
planned.
A Pfizer agent, PF-05212377, is currently being tested
in Phase II as add-on therapy to donepezil in patients with
mild-to-moderate AD with neuropsychiatric symptoms.
There are also at least four other 5-TH6 antagonists in
Phase I (Schneider, 2014).
α-Amino-3-hydroxy-5-methyl-4-
53.3.5.2 
isoxazolepropionic acid (AMPA)
receptor modulation
Reduction in number of the glutamatergic AMPA recep-
tors is an early finding in AD, accompanied by loss of den-
dritic spines and synapses. Modulation of AMPA receptor
function is suggested to improve alertness and concentra-
tion, facilitate long-term potentiation (required for memory
encoding) and they have been postulated as beneficial in
AD, ADHD and sleep disorders.
Eli Lilly’s LY451395 was tested to Phase II after preclini-
cal studies demonstrated reversal of age-associated memory
deficits in mice; however in humans with mild-to-moderate
AD, there was no benefit seen in cognition or neuropsychi-
atric symptoms.
Cortex Pharmaceuticals have developed many
‘AMPAkines’, including several that have been discontinued –
CX-516/Ampalex (lack of efficacy), CX-691/Farampator
(inconsistent results). CX717 was rejected by FDA for AD
due to toxicity concerns but was subsequently trialled in
Europe for respiratory depression. CX1632, acquired by
Servier S47445, is being tested as an add-on to donepezil in
patients with mild-to-moderate AD with depressive symp-
toms (Aisen et al., 2012).

53.3.5.3 Acetylcholinesterase inhibition
53.3.5.3.1 HUPERZINE-A
Huperzine-A is derived from the club moss, Huperzia
serrata. A traditional Chinese remedy for fever and
inflammation, Huperzine-A, is a potent inhibitor of acetyl-
cholinesterase. In animal models, it also reduces soluble and
insoluble β-amyloid, reduces tau hyperphosphorylation and
decreases levels of iron (implicated in free radical formation
and oxidative damage) (Huang et al., 2014) Several trials
in China in the 1990s suggested cognitive benefits in AD,
and different formulations have since been tested to Phase
II, with varying results (Yang et al., 2013). Huperzine-A is
approved for treatment of AD in China and is available over
the counter as a neutraceutical in the United States. Given
that its mechanism of action is similar to that of the FDA-
approved ChEIs, it is not recommended for use in combina-
tion with any of these agents.
53.3.5.3.2 LADOSTIGIL
Ladostigil is an inhibitor of acetylcholinesterase that
also inhibits monoamine oxidase A and B (MAO-A and
-B) and has neuroprotective and antioxidant properties
(Weinreb et al., 2012). It is currently in a Phase IIb trial in
MCI (n = 200). Interim results announced in a media release
in 2014 asserted no safety concerns, with positive efficacy
trends. Final results will be reported in 2016.
53.3.5.4 Nicotinic receptor agonists and
modulators
Galantamine, a ChEI used in AD, also has nicotinic recep-
tor activity. Several nicotinic agents (predominantly act-
ing on the α7-nicotinic receptor) have been developed for
AD. These agents may have other neurotransmitter benefits
beyond increasing levels of acetylcholine.
53.3.5.4.1 ENCENICLINE/EVP-6124
Encenicline/EVP-6124 is an α7 receptor potentiator that is
believed to increase the receptor’s responsiveness to acetyl-
choline. It was well-tolerated in Phase I and II, and cognitive
and functional benefits were seen at higher doses (ADAS-
Cog and CDR-SB, respectively). It proceeded to Phase III
trials (COGNITIV AD) in mild-to-moderate AD (with or
without ChEIs), and schizophrenia (Deardorff et al., 2015).
These studies were placed on hold in 2015 due to severe gas-
trointestinal side effects in AD participants. Interestingly,
the two Phase III studies in participants with schizophre-
nia continued to completion, with no severe gastrointesti-
nal effects reported. Unfortunately, however, neither study
showed positive results on the co-primary endpoints of cog-
nition or function.
53.3.5.4.2 ABT-126
ABT-126 (ABBVie) is another α7 nicotinic receptor ­agonist,
which has been tested in a Phase II study, high and low
Drug treatments in development for Alzheimer’s disease 573
dose, head-to-head with donepezil and placebo (n = 274,
mild-to-moderate AD, MMSE 10–24, 12 weeks). It was well-
tolerated, and there were trends to cognitive benefit with
high-dose ABT-126 that were similar in magnitude to the
donepezil group (ADAS-Cog mean difference [standard
error]: −1.2 [0.9], p = 0.09 versus −1.4 [0.9], p = 0.06) (Gault
et al., 2013).
53.3.5.4.3 TC-1734/AZD3480
One agent, TC-1734/AZD3480, a selective agonist of the
α4β2 and α2β2 receptors progressed to Phase II trials.
A large Phase IIb study was negative in its primary out-
come, but showed modest effects in moderate (but not
mild) AD, comparable with donepezil (Frölich et al., 2011).
Subsequent head-to-head study with donepezil did not
evidence superiority, however, and development has been
discontinued.
53.3.5.4.4 GLN-1062 (MEMOGAIN)
GLN-1062 is a pro-drug of the ChEI, galantamine, with
improved bioavailability in the brain (>15 fold), without the
same dose-limiting side effects seen with the others within
this class (Maelicke et al., 2010). A Phase Ia in young and
elderly healthy subjects compared GLN-1062 to donepezil
10 mg and galantamine 16 mg. Nausea was reported with
galantamine at 16 mg, but GLN-1062 was well-tolerated
up to the highest dose (44 mg). Also, GLN-1062 improved
vigilance and short-term memory performance in the both
young and elderly healthy volunteers, compared with done-
pezil and galantamine, which had no effect (Neurodyn
media release, 2014).
53.3.5.5 Muscarinic receptor agonists
53.3.5.5.1 AF267B
M1 muscarinic agonists such as AF267B increase non-­
amyloidogenic APP processing (promote production of
sAPPα over Aβ). In a mouse model AF267B attenuated both
plaque and tangle formation (Salloway et al., 2008). It went
to Phase I in AD and in Sjögren’s syndrome (dry mouth) but
no further trials have been registered.
53.3.5.5.2 MK-7622
Merck has a muscarinic agonist, MK-7622, in Phase II cur-
rently, as an adjunct to donepezil in mild-to-moderate AD.
Multiple dose regimes will be assessed, with change in
ADAS-Cog11 the primary clinical end points.
Earlier trials with direct muscarinic receptor agonists
were abandoned largely due to unacceptable adverse effects
(these drugs included milameline, xanomeline and talsa-
clidine). There are several muscarinic receptor subtypes
and it is possible that an effective therapy with an accept-
able adverse effects profile will emerge. The Anavex agent,
ANAVEX2-73 has both M1 agonist and sigma-1 agonist
properties (see Section 53.3.7.2).
574 Dementia
53.3.6 ANTI-INFLAMMATORY THERAPIES
53.3.6.1 Non-steroidal anti-inflammatory
drugs
Alzheimer recognized the presence of activated microg-
lia cells around plaques and tangles and many other
markers of inflammation have been documented. Large
epidemiological studies have demonstrated a lower
prevalence of AD in long-term users of NSAIDs and
this led to a large number of therapeutic trials of these
agents in AD, from 1993 to 2004. All were negative and
any further development of existing agents (including
steroids, NSAIDs and hydroxychloroquine) is unlikely
(Woodward, 2007).
53.3.6.1.1 ETANERCEPT
Involvement of the pro-inflammatory cytokine tumour
necrosis factor-α (TNF-α) in the pathogenesis of AD has
long been suspected. Etanercept is a biological antagonist
of TNF-α and when delivered by perispinal administration
it improved cognitive function in a small number of cases
from a single centre (Tobinick and Gross, 2008). It is pos-
sible that perispinal delivery may not be necessary; a sub-
sequent Phase II trial of subcutaneous etanercept (50 mg
weekly) versus placebo (n = 41) also showed reduced rate of
decline in cognition and ADLs at 6 months. Further trials
are suggested (Holmes et al., 2014).
53.3.6.1.2 MASITINIB
Masitinib is a selective tyrosine kinase inhibitor that influ-
ences the differentiation and activation of mast cells, which
are involved inflammatory processes throughout the body
and within the CNS. It has also been applied in inflamma-
tory disorders such as asthma and rheumatoid arthritis. In
a small Phase II study (n = 34) in mild-t-moderate AD as
adjunct therapy, there were significant differences seen in
ADAS-Cog, ADCS-ADL and MMSE compared with pla-
cebo. However, AEs were more common (65% versus 38%
in placebo) with oedema, rash and gastrointestinal symp-
toms most frequent (Piette et al., 2011). A Phase III trial has
commenced.
53.3.7 MITOCHONDRIAL AGENTS
53.3.7.1 Latrepirdine (dimebon)
Latrepirdine was developed as an antihistamine (5HT6
antagonist) but also is a weak ChEI, a weak NMDA antag-
onist, and improves mitochondrial function. A Phase
II trial (n = 193) in AD was overwhelmingly positive for
the primary and all secondary end points at 6 months,
and also after an additional 6-month blinded extension
(Doody et al., 2008). However, the drug failed to meet any
of its end points in two large Phase III trials and has been
discontinued.
53.3.7.2 ANAVEX2-73 (Anavex Life Sciences
Corp.)
ANAVEX2-73 (tetrahydro-N, N-dimethyl-2, 2-diphenyl-
3-furanmethanamine) is a mixed muscarinic receptor
ligand and a sigma-1 receptor (s1R) agonist.
M1-4 agonists preferentially activate the neuroprotec-
tive/non-amyloidogenic pathway (see Section 53.3.5.5).
The σ1 protein is a molecular chaperone, located on the
endoplasmic reticulum (ER) at sites in communication
with mitochondria. It regulates calcium exchange between
ER and mitochondria and is important for regulation of
metabolism, production of reactive oxygen species and
cell apoptosis. Promoting σ1 activity has beneficial effects
on Ca 2+ homeostasis and signal transduction and protects
mitochondrial function (Lahmy et al., 2013, 2015).
In preclinical trials, ANAVEX2-73 was shown to be
protective against oxidative stress and mitochondrial
dysfunction, reduced tau hyperphosphorylation and led
to memory and neuroprotective benefits (Lahmy et al.,
2015). A Phase I study in healthy controls has been com-
pleted, and a Phase II two-phase crossover study of oral
and intravenous ANAVEX2-73 in mild-to-moderate AD is
recruiting.
53.3.8 ANTIOXIDANTS
Α-TOCOPHEROL (VITAMIN E)
53.3.8.1 
Following encouraging results from a trial of the antioxi-
dant Vitamin E in patients with moderate-to-severe AD
(Sano et al., 1997), there was a negative trial of Vitamin E
in subjects with MCI – the therapy did not delay progres-
sion to AD over 3 years (Petersen et al., 2005). Vitamin E
has been retested alone and in combination with meman-
tine in mild-to-moderate AD. Improvements in ADCS-
ADL (function) and caregiver time were noted, and a trend
to improvement in ADAS-Cog but not MMSE or NPI.
Intriguingly, memantine was no better than placebo in this
group, and the combination of Vitamin E and memantine
did worse still. At doses to 2000 IU, the rates of AEs and
discontinuation was similar across all groups (Dysken et al.,
2014). Concern about increased mortality risk of Vitamin E
at high doses has limited study of this antioxidant as an AD
therapy (Miller et al., 2005).
53.3.8.2 RESVERATROL
Resveratrol is a polyphenolic compound present in seeds
and skin of many plants, including grapes and berries. It is
also found in dark chocolate, tea and red wine.
As a potent antioxidant and a direct free radical scav-
enger, resveratrol may also have other neuroprotective
effects, including reducing iron accumulation and decreas-
ing production of Aβ (Rege et al., 2014). In cognitively nor-
mal obese humans, it induces metabolic changes similar to

the effect of caloric restriction (activates ­sirtuin-1, lowers
blood pressure [BP], improves glucose tolerance, reduces
inflammatory markers) and improves brain glucose
metabolism, functional connectivity and cognitive mea-
sures. In AD (Phase II, MMSE 14–26, n = 119, 12 months),
resveratrol altered CSF Aβ40 and reduced brain vol-
umes, but had no effect on CSF Aβ42, p-tau, hippocam-
pal volume or cognition. A large six-arm Phase IV trial of
dietary modification, which includes resveratrol in over-
weight MCI participants (body mass index [BMI] 25-35)
is ongoing.
53.3.9 OTHER AGENTS
53.3.9.1 Phosphodiesterase inhibition
The cyclic nucleotide PDEs incorporate 11 families of
enzymes (over 100 variants) that break down cyclic adenos-
ine monophosphate (cAMP) and cyclic guanosine mono-
phosphate (cGMP), two second messengers, that regulate
diverse cellular processes by promoting gene transcription.
The expression of different PDE isoforms varies between
tissues, including with the CNS, and as such, several rep-
resent potential targets in AD. Dependent on isoform and
site, either symptomatic or disease-modifying effects are
suggested (García-Osta et al., 2012).
53.3.9.1.1 PF-04447943
The Pfizer drug PF-04447943 is a high affinity inhibitor
of PDE-9A and this action should elevate cGMP, in turn
improving synaptic function and stabilizing vulnerable
synapses. Although preclinical data were promising, trials
to Phase II have not shown any difference in cognition or
function (Heckman et al., 2014).
53.3.9.1.2 CILOSTAZOL
The PDE-3 inhibitor Cilostazol, is a vasodilator currently
available for treatment of peripheral vascular disease.
PDE-3 is also upregulated in cerebral vessels in AD and
CAA. In mouse models Cilostazol improved Aβ clearance
by promoting arterial pulsation-driven perivascular drain-
age (Maki et al., 2014). It has shown some efficacy in early-
phase trials, but data are mixed (Heckman et al., 2014).
53.3.9.1.3 MK-0952
PDE-4 has been a target of interest in AD, as inhibiting PDE-4
leads to increased availability of cAMP, important in mediat-
ing step in the consolidation of long-term memory. However,
many PDE-4 inhibitors to date have caused dose-limiting
nausea and vomiting. Merck has developed MK-0952 a PDE-4
inhibitor, which was well-tolerated in animal models and did
improve memory. Phase II trials were initiated in 2006, but no
results have been published (Heckman et al., 2014).
53.3.9.1.4 HT-0712
HT-0712 is another PDE-4 inhibitor that has positive effects
on memory in preclinical studies. In a Phase IIa study in
Drug treatments in development for Alzheimer’s disease 575
elderly subjects with ‘age-associated memory impairment’,
it was well-tolerated and led to improvements in long-term,
but not short-term memory. No results have been published;
however, it is listed as still being in development according
to the Dart NeuroScience (2014) website.
The α-secretase activator Etazolate/EHT-0202, described
in (Section 53.3.1.3.1), also inhibits PDE-4.
53.3.9.2 Statins (3-hydroxy-3-
methylglutaryl-coenzyme A [HMG-
CoA] reductase inhibitors)
A significantly lower prevalence of AD in those using statins
(HMG-CoA reductase inhibitors) has been found in most
epidemiological studies, irrespective of cholesterol levels.
Statins affect APP processing by γ-secretase so any efficacy
in AD could be due to decreased Aβ production. Despite
epidemiological findings, a Cochrane review of statin ther-
apy for dementia (three trials included 748 participants) did
not identify any cognitive benefits in treatment of possible
or probable AD (McGuinness et al., 2014).
53.3.9.2.1 ATORVASTATIN
A small study of atorvastatin in 63 individuals showed some
promising results (Sparks et al., 2005) but a large Phase III
trial using the 80 mg dose for those with AD (LeaDe trial)
(Jones et al., 2008) was negative.
53.3.9.2.2 SIMVASTATIN
Simvastatin is one of the most highly lipophilic of the HMG-
CoA reductase inhibitors and so can pass the BBB. Early stud-
ies of simvastatin in AD suggested some disease-modifying
effects, with alterations in CSF biomarkers seen (Simons
et al., 2002; Sjögren et al., 2003). However, a subsequent large
trial in mild-to-moderate AD had no benefit on symptom
progression, despite lowering cholesterol (Sano et al., 2011).
Statins may still be of benefit when applied in cognitively
normal individuals. A small Phase IV study (normal con-
trols, n = 23) compared 12 weeks’ treatment with simvastatin
against pravastatin, which is less lipophilic and does not
cross the BBB). Simvastatin lowered CSF p-tau, but did not
alter Aβ isoforms (Riekse et al., 2006). A 4-month trial study
of simvastatin versus placebo (n = 57) for 4 months showed
no difference in CSF biomarkers, but did not improve verbal
fluency and working memory in treated subjects (Carlsson
et al., 2008). Further trials in cognitively normal individu-
als and prodromal AD are in progress. Statins may yet also
have a role as add-on therapy, but only positive trial results
could support this usage.
53.3.9.3 CONTINUOUS POSITIVE AIRWAYS
PRESSURE (CPAP)
Observational studies suggest links between sleep-­
disordered breathing and dementia risk, as well as with
cardiovascular and cerebrovascular disease. Obstructive
sleep apnoea (OSA) causes chronic intermittent hypoxia
576 Dementia
and increase oxidative stress, which are each associated
with increased β-amyloid and p-tau in animal models.
Untreated OSA and excessive daytime sleepiness are asso-
ciated with increased prevalence of cognitive impairment
(particularly attention and executive function) and risk of
future cognitive decline. Further, in one study of cognitively
normal elderly, severity of sleep-disordered breathing cor-
related with CSF Aβ and tau, although the directions and
significance varied by APOE genotype (Osorio et al., 2014).
A trial of CPAP in AD patients with OSA improved mem-
ory, executive function and processing speed (Ancoli-Israel
et al., 2008), although there were no biomarker outcome
measures. Two further trials in AD and one in MCI have
been commenced. As well as attempting to confirm cog-
nitive benefits of CPAP in AD, they will collect biomarker
measures (neuroimaging and CSF) to look for evidence of
disease modification.
53.3.9.4 NILVADIPINE
Nilvadipine is a dihydropyridine calcium channel inhibitor
that is in clinical use as an antihypertensive medication in
Europe and Japan. In an open-label study of 55 AD partici-
pants, nilvadipine had benefits on cognition over 6 weeks
treatment (Kennelly et al., 2011). In a small study of hyper-
tensive MCI participants, nilvadipine warded off cognitive
decline and improved cerebral blood flow (Hanyu et al.,
2007). A large multicentre trial in mild-to-moderate AD
(n = 500) is ongoing.
53.3.9.5 REPETITIVE TRANSCRANIAL MAGNETIC
STIMULATION (rTMS)
Transcranial magnetic stimulation is a technique, which
can non-invasively measure cortical activity, with altera-
tions in AD seen in accordance with underlying neu-
rodegeneration. Preliminary studies also suggest that
administered repetitively, rTMS can also influence corti-
cal excitability and neuroplasticity, although larger tri-
als are required to confirm these results (Nardone et al.,
2014).
53.3.9.3 Hormone therapy
Driven by observational evidence in population stud-
ies (females) and studies of treatments for prostate cancer
(males), the potential therapeutic role for hormones in those
with AD has led to several trials. Hormone replacement
therapy has not been effective for the treatment of AD in
females and most recently the ‘COSTAR’ study of tamoxifen/
raloxifene was negative. Leuprolide, which affects levels of
luteinizing hormone (Casadesus et al., 2004) was ineffective
in two large 52-week Phase III trials conducted by Voyager
Pharmaceuticals despite earlier promising Phase II results.
Dehydroepiandrosterone (DHEA) dione has also been
trialled in AD subjects, and again results were negative. It
appears very unlikely that any hormonal therapy for AD
will be available within the next decade.
Elevated levels of the glucocorticoid hormone cortisol
are associated with cognitive dysfunction and may be neu-
rotoxic. Xanamem (UE2343) inhibits 11β-hydroxysteroid
dehydrogenase type 1 (11β-HSD1), which converts inactive
cortisone into the active cortisol. Preclinical trials suggest
benefits on cognition and Aβ plaque deposition, and the
drug is now in Phase II (XanADu) in mild AD (MMSE
20-26, CDR 0.5-1.0). Co-primary endpoints include the
ADCOMS cognitive composite score and the ADAS-Cog.
53.3.9.4 Homocysteine-lowering therapies
Homocysteine levels are higher in AD patients than in age-
matched controls (Seshadri et al., 2002) and this may relate
to reduced DNA repair or cerebrovascular effects of homo-
cysteine, but trials of the homocysteine-lowering agents,
folate and vitamins B12 and B6, in AD have been negative
(Kwok et al., 2011).
53.3.9.5 Neutraceuticals and medical foods
There are several ‘neutralceuticals’ or medical foods cur-
rently in development or commercially available for AD.
According to FDA, medical foods are ‘… formulated to
be consumed … under the supervision of a physician …
for the specific dietary management of a disease for which
distinctive nutritional requirements, based on recognized
scientific principles, are established …’ Notably, medi-
cal foods are not required to undergo pre-market FDA
approval (FDA, 2016).
53.3.9.5.1 SOUVENAID
Souvenaid, containing Fortasyn Connect, is a medical food
rich in precursors and cofactors for formation of neuronal
membranes, including choline, phospholipids, docosahexae-
noic acid (DHA), folic acid and selenium. A multicentre
‘proof-of-concept trial’ (n = 225, mild AD, 12 weeks) showed
benefit in one (Wechsler Memory Scale – Revised), but not
another co-primary end point (ADAS-Cog) (Kamphuis et al.,
2011a). Two subsequent trials were performed, the Souvenir
II (mild AD, 24 weeks, n = 259) and S-Connect (mild-to-
moderate AD, on conventional treatment, 24 weeks, n = 527)
studies. Souvenir II demonstrated significant benefits over
placebo in its primary end point, the NTB memory function
Z-score (p = 0.02, Cohen’s d = 0.21). It also showed improved
electroencephalogram (EEG) functional connectivity mea-
sures with Souvenaid treatment (Scheltens et al., 2012). By
contrast, the S-Connect study did not demonstrate any dif-
ference in ADAS-Cog in mild-to-moderate AD on cholines-
terase treatment (Shah et al., 2013).
The treatment is usually well-tolerated. Weight gain
is reported, however, this is a benefit as development of
dementia in AD is commonly associated with weight loss.
In Souvenir I, post hoc analyses reported greatest functional
benefits in those with lower pretreatment BMI (Kamphuis
et al., 2011b)

A small study has tested Souvenaid in behavioural
variant FTD, with reported improvements in behavioural
symptoms and social cognition skills (Pardini et al., 2015).
Souvenaid is also being evaluated in prodromal AD: the
LipiDiDiet study has recruited around 300 participants and
the results of the 2-year trial, with cognitive (NTB, ADAS-
Cog), functional (ADCS-ADL), neuroimaging (MRI), blood
and CSF biomarkers outcomes (Freund-Levi et al., 2012),
will be reported in 2015.
53.3.9.5.2 KETOSYN (AXONA/AC-1202) AND AC-1204
In AD there is impaired uptake and utilization of glucose
in vulnerable brain regions. AC-1202 and AC-1204 are
formulations of caprylic acid (found in coconut oil) and
medium-chain triglycerides, which are converted in the
liver to ‘ketone bodies’ (β-hydroxobutyrate, acetoacete and
acetone). These compounds cross the BBB and can provide
an alternative energy source for mitochondrial metabolism,
even with a carbohydrate-rich diet.
A large multicentre Phase II trial of AC-1202 (n = 152,
mild-to-moderate AD) showed cognitive differences ini-
tially (at 45 days) but these did not persist to study end
(90 days). However, in pre-specified analyses stratified by
ε4 status, there were five-point differences seen in ADAS-
Cog in ε4 non-carriers at 90 days (p = 0.008) and cogni-
tive improvement correlated with higher serum levels of
the ketone body, β-hydroxobutyrate. Unfortunately, 23% of
the active group discontinued from the trial, with gastro-
intestinal adverse effects in common (diarrhoea, dyspepsia,
flatulence) (Henderson et al., 2009). Instead of pursuing
a Phase III trial, AC-1202 has been brought to market as a
medical food under the tradename Axona.
NOURISH AD, a Phase II/III trial of AC-1204 (a
­follow-up formulation of AC-1202) is under way in mild-to-­
moderate AD (n = 480, 26 weeks).
53.3.9.5.3 EPIGALLOCATECHIN-3-GALLATE (ECCG)
EGCG is the main biologically active polyphenol in green
tea. In vitro, it has numerous beneficial attributes, includ-
ing antioxidant, anti-inflammatory and antiatherogenic
properties. It also influences growth-factor-mediated
pathways, protein kinase pathways, has anti-aggregation
effects on Aβ and possibly promotes α-secretase activ-
ity. Unfortunately, its in vivo effects are less consistent,
which may be due to inability to attain therapeutic con-
centrations within the brain (Mereles and Hunstein,
2011). A pilot study in Down’s syndrome (n = 3 1, age < 29
years, 3 months’ treatment) resulted in better immediate
and working memory performance, but poorer executive
function (psychomotor speed) (De la Torre and Dierssen,
2012).
EGCG is currently in Phase II/III in AD patients with
and without concomitant donepezil therapy. It is also being
tested at Phase II/III in Down’s syndrome and multiple sys-
tem atrophy.
Drug treatments in development for Alzheimer’s disease 577
53.3.9.5.4 DOCOSAHEXAENOIC ACID
DHA is the most abundant long-chain fatty acid in the
brain. Epidemiological evidence suggest that high DHA
consumption is associated with lower risk of AD, and in
animal models, DHA lowers amyloid and p-tau levels. It
is suggested that it may improve cardiovascular health as
well as influencing AD pathology. However, a large ran-
domized, double-blind, placebo-controlled trial of DHA
in mild-to-moderate AD (n = 402, MMSE 14–26) showed
no effect on cognitive decline overall, although there was
a suggestion of benefit in APOE ε4 non-carriers, with
slower cognitive decline seen in this subgroup (Quinn
et al., 2010).
DHA/Omega 3 is being tested in the large secondary
prevention Multi-domain Alzheimer Preventive Trial
(MAPT) – which also includes a multi-domain behavioural
intervention arm (nutritional, physical and cognitive train-
ing) (Ousset, 2010).
53.3.9.5.5 GINKGO BILOBA/EGB761
Ginkgo biloba is a traditional Chinese medicine that has
multiple suggested mechanisms of action in AD includ-
ing improving mitochondrial metabolism, inhibiting Aβ
aggregation and reducing blood viscosity/increasing perfu-
sion. A recent meta-analysis of seven RCTs of Ginkgo biloba
extract EGb761 in AD (n = 2684) suggested symptomatic
benefit, although a large study (n = 2854) of its use in demen-
tia prevention was negative (Vellas et al., 2012; Gauthier and
Schlaefke, 2014).
53.3.9.6 Newer symptomatic treatments
in behavioural and psychological
symptoms of dementia
53.3.9.6.1 RO40602522/RG1577
RO40602522 (Evotech AG/Roche) is a centrally act-
ing inhibitor of MAO-B, an enzyme that inactivates
monoamines such as dopamine. MAO-B expression is
higher in AD, which may contribute to neurodegenera-
tion, as its activity generates reactive oxygen species. In
addition, reduced dopaminergic function in AD has
been linked with behavioural symptoms including apa-
thy and ADL impairment. It is currently being tested in
Phase II in AD as an adjunct to a ChEI or memantine
(Mayflower RoAD, MMSE 13–20), with change in the
ADAS-Cog-11 (cognitive behaviour subscale) the primary
outcome measure.
53.3.9.6.2 BREXIPIPRAZOLE/OPC-34712
Brexipiprazole/OPC-34712 is a quinolinone partial ago-
nist of the dopamine receptor D2, related to the atypi-
cal antipsychotic aripiprazole. It also has partial agonist
effects against serotonin 5-HT1a receptors. Its primary
indication is in schizophrenia and as add-on therapy in
578 Dementia
depression; however, it is also being tested in two Phase
III studies for symptoms of agitation in moderate-to-
severe AD.
53.3.9.6.3 AVP-923/NUEDEXTRA (AVANIR)
AVP-923/Nuedextra (Avanir) is a combination of dextro-
methorphan (a weak NMDA antagonist) and quinidine (an
antiarrhythmic that increases the bioavailability of dextro-
methorphan). It is currently also in evaluation for pseudo-
bulbar effect in multiple sclerosis and motor neurone disease,
dyskinesia in PD and neuropathic pain. A Phase II study
tested its efficacy against agitation in AD, with benefit on the
NPI aggression/agitation domain.
53.3.9.6.4 PRAZOCIN
Prazocin is an α-1 adrenoreceptor antagonist, which has
vasodilatory effects on vascular smooth muscle. It is in
clinical use for hypertension and benign prostatic hyper-
trophy. In APP23 transgenic mice, prazocin mediated an
anti-­inflammatory response and improved memory deficits
(Katsouri et al., 2013). α-1Adrenergic blockade may also atten-
uate Aβ-mediated cerebral vasoconstriction and improve
cerebral perfusion (Haase et al., 2013). Administration of
prazocin 1–6 mg daily in probable AD with agitation/aggres-
sion (n = 22) resulted in significant improvements in NPI,
Brief Psychiatric Rating Scale (BPRS) and CGIC. A larger AD
trial for agitation (target n = 120) is recruiting.
53.3.9.6.5 CIRCADIN/MELATONIN
Melatonin secretion from the pineal gland declines in
AD, with sleep–wake cycle disturbance and nocturnal
awakening a common contributor to carer fatigue. In
addition to restoring sleep–wake phase, in animal mod-
els, melatonin reduces Aβ aggregation/oligomerization,
inhibits tau hyperphosphorylation, regulates α-secretase
(to promote non-amyloidogenic pathway) and has anti-
oxidant properties (Zhang et al., 2015). Early small open-
label or placebo-controlled trials have hinted at cognitive
benefits of melatonin, although a large trial was negative
for improvement in sleep. More recently, a Phase II study
of prolonged-release melatonin as add-on to donepezil
(+/− memantine) in mild-to-moderate AD (n = 80) dem-
onstrated significant positive effects on cognition and
sleep, most marked in those reporting poor sleep at study
outset (Wade et al., 2014). Circadin is a slow release mela-
tonin preparation.
53.4 THE NEAR FUTURE: THERAPIES IN
DEMENTIA
Despite a number of high-profile disappointments, there
remain many extremely promising treatments that may yet
make the jump into clinical use. Application of therapies
that have already survived Phase III for other indications
may ‘fast-track’ drugs for AD to become available within
the next few years (e.g. liraglutide, exendin-4, levetirace-
tam). Availability and affordability are likely to be limiting
factors in the uptake of new therapies.
The application of therapeutics for AD is complex and
depends not only on disease stage and severity but also on
individual clinical (e.g. diabetic or non-diabetic) or phar-
macogenomic differences (e.g. some, like levetiracetam,
may work in APOE ε4 carriers but not in non-carriers).
Life course risk factors including physical activity, cogni-
tive reserve and diet are also being assessed in several large,
randomized clinical trials internationally, results of which
ultimately may have even greater impact on dementia prev-
alence than pharmacological therapies. In addition, the fre-
quent presence of multiple neuropathologies in those with
dementia (Scheltens et al., 2012) may necessitate multiple
therapeutic agents targeting the individual pathologies.
Indeed, it may be as important to target the contributory
pathologies as the clinical features.
AD therapy may be used similarly to therapies for
other chronic diseases – a mixture of disease-modifying
and symptomatic therapies used both in combination and
sequentially, over the course of the disease.
The prospect of applying preventative or preclinical
interventions in AD is tantalizing. However, dementia prev-
alence rates are likely to continue to increase worldwide,
even once disease-modifying agents become available.
Continued efforts into identifying and implementing novel
approaches for symptoms and behaviour in AD dementia
also remain imperative.
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 (a) (b)

(c) (d)

Figure 11.1 Diffusion tensor imaging provides quantitative measures of (a) apparent diffusion coefficient (ADC) and
(b) ­fractional anisotropy (FA). Brighter signal means more average diffusion and more constrained diffusion for ADC and FA,
respectively. Note that grey and white matter do not differ in ADC but have very different FA values, such that FA provides
a map of the myelinated axons of white matter. By calculating the tensor information, the direction of diffusion can be
­determined in each voxel (c), from which tracts can be reconstructed (d). Panel (c) shows the principal diffusion direction in
the region including the genu of the corpus callosum depicted by the red box in panel (b). In panel (d), a tract of the forceps
minor (yellow) has been reconstructed by placing a single ‘seed’ voxel (blue) in the genu of the corpus callosum.
Figure 12.2 Typical pattern of 11C-PiB binding in AD. Representative sagittal and transaxial [11C]PiB PET images over-
layed on their respective MRI in a healthy elderly control subject (HC) (left) compared with an Alzheimer’s disease (AD)
patient (right). 11C-PiB retention is observed in frontal, temporal and parietal cortices as well as in the posterior cingulate/
precuneus areas, with relative sparing of occipital and sensorimotor cortex.
Figure 12.3 Aβ imaging in Alzheimer’s disease. Representative parametric sagittal, transaxial and coronal PET images
of Alzheimer’s disease (AD) patients assessed with either [11C]PiB, [18F]florbetaben, [18F]flutemetamol, [18F]florbetapir or
[18F]NAV4694. All AD patients harboured high Aβ burdens in the brain, reflected in marked radiotracer retention in
cortical and subcortical grey matter areas. [18F]Florbetapir (Amyvid®); [18F]flutemetamol (Vizamyl®) and [18F]florbetaben
(Neuraceq®) have already been approved for clinical use by the FDA and EMA.
 PiB- HC

Misfolded
proteins PiB- MCI

PD

α-syn

PiB- DLB

PiB+ HC

PiB+ MCI

Aβ PiB+ DLB

AD

tau

FTLD

PrPsc spCJD

Figure 12.5 Aβ imaging in ageing and dementia. Representative 40–70 min post-injection transaxial 11C-PiB images along
the spectrum of some of the misfolded proteins associated with neurodegenerative diseases, encompassing the different
patterns of 11C-PiB retention in the brain, with – from top to bottom – a 73-year-old healthy PiB-negative control (PiB-HC)
subject (mini mental state examination [MMSE] 30), 83-year-old PiB-negative subject with mild cognitive impairment (PiB-
MCI) (MMSE 28), 61-year-old PiB-negative Parkinson’s disease (PD) patient (MMSE 27), 69-year-old PiB-negative patient
with dementia with Lewy Bodies (DLB; MMSE 24), 77-year-old PiB-positive healthy control (PiB+ HC) subject (MMSE 28),
82-year-old PiB-positive subject with mild cognitive impairment (PiB+ MCI) (MMSE 28), 78-year-old PiB-positive DLB
patient (PiB+ DLB) (MMSE 19), 76-year-old Alzheimer’s disease (AD) patient (MMSE 21), 59-year-old patient with fronto-
temporal lobe degeneration (FTLD; MMSE 20) and 59-year-old PiB-negative patient with confirmed sporadic Creutzfeldt-
Jakob disease (spCJD). PET images show clear differences when comparing cortical PiB retention in PiB-negative HC,
MCI, PD, spCJD and FTLD with PiB-positive HC, MCI, DLB or AD patients. Only non-specific PiB binding in white matter
is observed in PiB-negative HC, MCI, PD, spCJD and FTLD compared with PiB binding in cortical areas of AD and DLB
patients. All images are scaled to the same standardized uptake value ratio (SUVR) maximum.
 HC AD

18F-flutemetamol 18F-flutemetamol
L R R L L R R L

PET-SUVRpons PET-SUVRpons
1.2 1.2
0.9 0.9
RT.LAT LT.LAT SUP INF RT.LAT LT.LAT SUP INF
0.7 0.7
0.4 0.4

RT.MED LT.MED POST ANT RT.MED LT.MED POST ANT

18F-THK5117 18F-THK5117
L R R L L R R L

PET-SUVRCbCtx PET-SUVRCbCtx
2.0 2.0
1.6 1.6
RT.LAT LT.LAT SUP INF RT.LAT LT.LAT SUP INF
1.2 1.2
0.8 0.8

RT.MED LT.MED POST ANT RT.MED LT.MED POST ANT

Figure 12.6 Aβ and tau imaging in ageing and dementia. Surface display PET images of the respective Aβ ([18F]flute-
metamol, top row) and tau ([18F]THK5117, bottom row) burden in an age-matched healthy control (HC) and an Alzheimer’s
disease (AD) patient.
 Aβ production
Preclinical
Aβ aggregation
Aβ clearance (immunotherapy) ACI-24
Tau aggregation or phosphorylation Phenylthiazolylhydrazide
Cholinergic drugs
Anti-Aβ antibodies Phase 1
Others Rhodanines

RS-0406 Minocycline
Affitope AD-01*

Phase 2
GSK-933776 AL-208*
Affitope AD-02
SEN-1269 AL-108* Anti-tau
PF-04360365
MABT-5102A antibodies
ACC-001 MTC/LMT*
AN-1792* Phase 3 Nicotinamide
UB-311 IVIg
CAD-106 Valproate* N-031112
SP-233 Bapineuzumab (NP-12)* N-744
ELND-005
Solanezumab Phase 4 Lithium*
R-1450 NGF
PBT1* Tramiprosate* Donepezil† Antioxidants

Rivastigmine† SB-742457
Peptidic anti- EGCg
V-950 PBT2* Statins
aggregants Galantamine† PRX-03140*
NIC5-15 Tarenflurbil* Memantine† BDNF
Latrepirdine PUFAs*
E-2012*
Semagacestat TTP-488
Bryostatin-1 Phenserine*
Exebryl-1 Rosiglitazone* PF-04447943
MK-0752* EHT-0202*
EVP-6124
BMS-708163 Huperzine-A* Ladostigil
CHF-5074
AF-102B*
NGXsc Pioglitazone* AZD-3480*
CTS-21166* ABT-089* Talsaclidine* AF-267B

PF-3084014* M-30
GSM-1
Begacestat* Memoquin
Anti-β-secretase antibodies

BBS1

Figure 55.3 Drug development in Alzheimer’s disease: drugs being investigated for Alzheimer’s disease therapy,
reported according to the most advanced phase of study and main therapeutic properties (including data from studies
in vitro and animal models). Aβ, amyloid-β; BBS1, anti-β-site antibodies; BDNF, brain-derived neurotrophic factor; EGCg,
­epigallocatechin-3-gallate; IVIg, intravenous immunoglobulin; LMT, leuco-methylthioninium; MTC, methylthioninium chlo-
ride; NGF, nerve growth factor; NGXsc, NGX series compounds; PUFAs, polyunsaturated fatty acids; GSM, γ-secretase
modulator; RCT, randomized controlled trial. *RCTs in Alzheimer’s disease not ongoing. †Drugs approved for the treat-
ment of Alzheimer’s disease. (Reprinted from The Lancet Neurology, 9, Mangialasche, F. et al., Alzheimer’s disease: Clinical
trials and drug development, 702–716, 2010, with permission from Elsevier.)
 Odds ratio of dementia
< 0.67 300
0.67–0.83 Miles
0.83–0.91
0.91–0.95
0.95–1.05
1.05–1.1
1.1–1.2
1.2–1.5
> 1.5

North

(a) (b)

Figure 55.7 Age-adjusted odds ratio of dementia in male (a) and female (b) Swedish twins with twin-level random effects
(likely to capture genetic and shared environmental variance) removed. (From Russ, T.C. et al., Epidemiology, 26, 263–270,
2015a. With permission.)
 Odds ratio of dementia
< 0.67
0.67–0.83
0.83–0.91
0.91–0.95
0.95–1.05
1.05–1.1
1.1–1.2
1.2–1.5
>1.5

(a) (b)

100
Miles

North

(c) (d)

Figure 55.8 Age-adjusted odds ratio of dementia in the SMS1932 cohort: childhood – males (a), females (b); adulthood –
males (c), females (d). (From Russ, T.C. et al., Epidemiology, 26, 263–270, 2015a. With permission.)
 Newcastle categorization of the major CV lesions
associated with cognitive impairment
I II III IV V VI

Large infarct or Multiple small or Strategic Cerebral Cerebral CV lesions

several infarcts microinfarcts infarcts hypoperfusion haemorrhage with AD pathology

Multi-infarct White matter Thalamus Hippocampal Lobar Mixed

dementia lesions hippocampus sclerosis ICH dementia
basal forebrain SAH

Figure 59.2 Schematic diagram of different cerebrovascular pathologies associated with dementia. The proposed
Newcastle categorization includes six subtypes (Kalaria et al., 2004). In all of the subtypes, the age of the vascular
lesion(s) should correspond with the time when disease began. The post-stroke cases are usually included in subtypes
I–III. While these may not be different from other published subtypes (Jellinger, 2008), they are practical and simple
to use. Cases with extensive white matter (WM) disease in the absence of significant other features are included under
SVD. Subtype I may result from large vessel occlusion (atherothromboembolism), artery-to-artery embolism or car-
dioembolism. Subtype II usually involves descriptions of arteriosclerosis, lipohyalinosis, hypertensive, arteriosclerotic,
amyloid or collagen angiopathy. Subtypes I–II and V may result from aneurysms, arterial dissections, arteriovenous
malformations and various forms of arteritis (vasculitis). CAA, cerebral amyloid angiopathy; ICH, intracerebral haemor-
rhage; SAH, subarachnoid haemorrhage. (Original diagram courtesy of Dr K Nagata, Akita, Japan.)
 (a) (b)

(c) (d)

(e) (f )

Figure 59.4 Pathological features associated with SVD in VaD. Panels show examples of lacunes, small infarcts and micro-
infarcts: (a) typical cavitated lacunar lesions (arrow) in the putamen of a 65-year-old man. (b) Multiple infarcts in the basal
­ganglias of an 80-year-old man with vascular and neurofibrillary pathology. (c)–(e) Cerebral microvessels with variable
hyalinosis, perivascular rarefaction, microinfarcts and perivascular spaces in three different cases. Moderate gliosis in the
­surrounding region is also evident in case in (c); (f) small cortical infarct in a VaD case with severe CAA. A ­penetrating
­arteriole with CAA is seen in the middle of the infarct (arrow). Magnification bar: (a) = 1 cm, (b), (f) = 500 μm; (c), (d) = 100 μm,
(e) = 200 μm.
 (a) (b)

(c) (d)

Figure 59.5 WM lesions visualized by conventional histopathological staining in an 85-year-old man diagnosed with vascular
encephalopathy. (a) >75% stenosis in the internal carotid artery 8 mm above the bifurcation. The narrowed lumen (arrow) is
seen. (b) WM rarefaction and myelin loss in the medial temporal lobe but sparing of U fibres; (c), post-mortem T2W magnetic
resonance image of a formalin-fixed block from the parietal lobe. Area of hypersignal can be seen in the WM (*); (d), H&E
stained section from the block in (c) showingsevere deep WM ­pallor in the area of hypertensity (*). A small cortical infract is
also seen (arrow). Magnification bar: (a) = 500 mm, (b) = 400 μm, (c) = 1 cm, (d) = 500 μm.
 (a) (b) (d) (e)

50 μm 50 μm 20 μm

(c) (f )

50 μm 20 μm

100 μm 50 μm

Figure 62.1 Lewy bodies and Lewy pathologies in Parkinson’s disease. (a) and (b) Haematoxylin and eosin stained classic
Lewy bodies in pigmented dopaminergic neurones of the substantia nigra showing the typical core and halo structure.
Scale in (b) is equivalent for (a). (c)–(f). α-Synuclein immunoreactive pathologies showing (c) and (e) mature Lewy bodies,
(c) and (d) pale bodies and neuronal aggregates and (f) astrocytes containing aggregates.
Figure 65.2 Fluorodeoxyglucose positron emission tomography (FDG-PET) scan from a patient with FTD whose structural
imaging did not show convincing evidence of disproportionate frontal atrophy. Note the clear evidence of asymmetric
frontal hypometabolism (arrows).
 (a)

(b)

(c)

Figure 65.3 Use of electroencephalography (EEG) in the investigation of suspected FTD. This 63-year-old male presented
with marked changes in personality and comportment, typical of those seen in FTD, that had evolved over the preceding
8 months. FDG-PET, shown as a parametric map of hypometabolism (a), revealed a marked prefrontal hypometabolism.
His EEG was grossly abnormal with a considerable delta-wave activity (b). This is not compatible with FTD. His diagnosis
was presumed to be an autoimmune encephalitis, and after treatment with high-dose methylprednisolone both his FTD-like
behavior and EEG (c) improved dramatically.
 Primary progressive aphasia (PPA)

Sporadic PPA Familial PPA

GRN-associated C9orf72-associated
svPPA nfvPPA IvPPA
aphasia aphasia

Pathological subtypes

FTLD-TDP FTLD-TDP FTLD-TDP FTLD-tau FTLD-tau FTLD-tau Alzheimer

Type A Type B Type C CBD/PSP Pick’s GGT pathology

Figure 69.1 Clinico-pathological and clinico-genetic associations in primary progressive aphasia (PPA). PPA as a syndrome
has heterogeneous genetic and pathological associations. However, the importance of subtyping PPA is indicated by the
third row of boxes, which show in a schematic manner the pathological associations with semantic variant PPA (svPPA),
nonfluent variant PPA (nfvPPA), logopenic PPA (lvPPA) and with the familial progranulin (GRN)-associated or C9orf72-
associated form of PPA, where one pathological subtype tends to dominate. Each of the pathological subtypes are indi-
cated by a separate coloured box: frontotemporal lobar degeneration – TAR DNA binding protein (FTLD-TDP) types A to
C, FTLD-tau (CBD, corticobasal degeneration; PSP, progressive supranuclear palsy; GGT, globular glial tauopathy; and
Pick’s disease) and Alzheimer pathology.
Figure 69.2 Regional percentage differences in cortical thickness in posterior cortical atrophy (PCA) (N = 48) compared
with typical amnestic Alzheimer’s disease (tAD; N = 30) for the left and right hemispheres. The colour scale represents
magnitude of cortical thickness difference. Red and yellow (positive values) represent lower cortical ­thickness in PCA
subjects compared with tAD, whereas dark to light blue (negative values) represents greater cortical thickness. (From
Lehmann, M., et al., Cereb. Cortex, 21, 2122–2132, 2011a.)

Vitamins and complementary therapies used to
treat Alzheimer’s disease
DENNIS CHANG, GENEVIEVE Z. STEINER, DILIP GHOSH AND ALAN BENSOUSSAN
54.1 INTRODUCTION
Alzheimer’s disease (AD) is the most common form of
dementia, a leading cause of mental and physical disabil-
ity in elderly people. Current pharmaceutical manage-
ment of AD offers only modest short-term symptomatic
relief and does not satisfactorily consider the magnitude
of the disease burden on patients and the community as
a whole. Acetylcholinesterase (AChE) inhibitors or gluta-
mate receptor antagonists are typically used to manage the
behavioural and psychological symptoms of AD, but there
is limited evidence on their efficacy for patients beyond the
first 6–12 months (Madhusoodanan and Ting, 2014) (see
Chapter 52).
Complementary and alternative medicine (CAM) is used
extensively worldwide, with a national survey conducted by
the National Center for Complementary and Alternative
Medicine (NCCAM) estimating approximately 33.2% of
adults and 11.6% of children in the United States having
used or use some form of CAM (Black et al., 2015; Clarke et
al., 2015). Worldwide prevalence of CAM use is estimated to
be up to 74.8% (Frass et al., 2012).
Treatment of ageing-related disorders with CAM dates
back to 5000 years in ancient China, where herbal remedies
were used to boost memory function and increase longevity.
The common forms of CAM for AD include herbal medicine
(e.g. Western herbal medicine, Chinese herbal medicine,
Ayurvedic medicine), vitamins and dietary supplements
(e.g. fish oil), acupuncture, aromatherapy, mind–body ther-
apy (e.g. meditation, tai chi, yoga), physical therapies (e.g.
chiropractic, reflexology, remedial massage), music therapy
and combined and light therapy (Table 54.1).
This chapter focuses on the scientific evidence support-
ing the use of herbal medicine, vitamins and fish oil in the
management of AD.
54
54.2 HERBAL MEDICINE FOR AD
Herbal medicines have been used widely across many cul-
tures to improve memory function and manage behav-
ioural and psychological symptoms. Specific herbs that
have attracted most attention include Ginkgo biloba,
Bacopa monnieri, Huperzia serrata, Panax ginseng,
Curcuma longa, Melissa officinalis and Camellia sinensis.
The mechanisms of action, adverse effects and herb–drug
interactions of these herbal medicines for AD are summa-
rized in Table 54.2.
Unlike pharmaceutical agents, herbal medicines often
contain multiple bioactive components that can affect
several therapeutic targets for diseases with multifacto-
rial/multisystem pathophysiological components, such as
dementia. In addition, the complex chemical mixtures of
herbal medicines enhance therapeutic efficacy by facili-
tating synergistic action (e.g. constituents interacting to
improve their solubility and hence bioavailability) (Yang
et al., 2014).
54.2.1 GINKGO BILOBA
Ginkgo biloba leaf extract (from the ginkgo tree in China) is
one of the most studied herbs. The principal active compo-
nents in ginkgo are flavonol glycosides (e.g. quercetin and
kaempferol) and terpenoids (e.g. ginkgolide and bilobalide).
Preclinical studies demonstrate that ginkgo can decrease
oxygen radical discharge and pro-inflammatory functions of
macrophages (antioxidant and anti-inflammatory), reduce
corticosteroid production (anti-anxiety), increase glucose
uptake and utilization and ATP production, improve blood
flow by increasing red blood cell deformability, decrease red
cell aggregation, induce nitric oxide production and inhibit
platelet activating factor receptors (Chan et al., 2007). In
587
588 Dementia

Table 54.1 Overview of common vitamins and memory loss and mental impairment. Besides HupA’s
complementary therapies for the treatment of Alzheimer’s well-known AChE inhibiting property, other pharmaco-
disease logical effects include antioxidant activity, anti-β-amyloid
Herbal medicine Ginkgo biloba peptide fragmentation, inhibition of oxygen-glucose
deprivation and N-methyl d-aspartate (NMDA) receptor
Huperzia serrata (Huperzine A)
antagonism (Howes and Houghton, 2003) (Table 54.2).
Bacopa monnieri
Recent meta-analyses suggest that HupA can improve
Curcuma longa
cognition and behaviour in patients with AD (Yang et
Panax ginseng al., 2013; Xing et al., 2014), in particular, HupA improved
Melissa officinalis cognitive function and activities of daily living, com-
Camellia sinensis (tea) pared to placebo (Yang et al., 2013); quality of life was
Vitamins and Vitamin C and E not evaluated in these studies. While these findings are
dietary Vitamin B and folic acid positive and consistent with earlier reports (Wang et al.,
supplements Vitamin D 2009), they should be interpreted with caution due to the
Fish oil poor methodological quality, small sample sizes and short
Souvenaid® intervention periods of the included trials. More rigorous
Other Acupuncture randomized controlled trials (RCTs) are needed to con-
complementary Aromatherapy firm the clinical effectiveness of HupA.
therapies Physical therapy (chiropractic,
reflexology, remedial massage, 54.2.3 BACOPA MONNIERI
therapeutic touch)
Mind–body therapy (meditation, Bacopa monnieri (Brahmi) is an Indian Ayurvedic medi-
tai chi, yoga, qigong) cine used for the management of a range of psychological
Music therapy conditions (e.g. anxiety, attention) (Russo and Borrelli,
Combined melatonin and light 2005). Brahmi is marketed in western countries as a mem-
therapy ory enhancing agent, with effects attributable to two major
constituents: saponins, bacosides A and B. Brahmi has been
shown to have neuroprotective effects and can enhance
healthy young adults, ginkgo has been shown to improve cognition in animal dementia models (Saini et al., 2012).
speed of processing, working memory and executive func- The exact mechanisms for these actions remain unclear;
tion (Kennedy et al., 2007). however, it has been suggested that neuropharmacological/­
Despite recent evidence, the efficacy of ginkgo as nootropic actions of Brahmi are induced by antioxidant
a cognitive enhancer for dementia remains controver- effects via metal chelation at the initiation level and also
sial. This is primarily because early clinical trials dem- as a lipid peroxidation chain action breaker and modula-
onstrated inconsistent effects on memory, attention and tion of cholinergic system via reversing acetylcholine (ACh)
anxiety (for a review see Birks and Evans, 2009); however, depletion, reducing choline acetylase activity and decreas-
the use of self-report questionnaires in these early studies ing muscarinic receptor binding (Stough et al., 2008; Aguiar
raises concerns about the reliability of results (Howes and
and Borowski, 2013).
Houghton, 2003). Three recently published meta-analyses
(Gauthier and Schlaefke, 2012; Yang et al., 2014; Tan et al., Human trials suggest that Brahmi can enhance cogni-
2015) indicate that treatment with EGb761® (a standardized tion in older adults, but there is limited evidence for its
ginkgo extract preparation) stabilized or reduced the decline effectiveness in AD. Two double-blind placebo-controlled
process in cognition, function and behaviour, with limited studies examining the acute effects (320 and 640 mg) of
adverse effects in patients with cognitive impairment and Brahmi (KeenMind ® – CDRI 08) demonstrated improved
dementia, compared to placebo. Importantly, one review cognition, compared to placebo (Downey et al., 2013;
found these effects were most notable in patients with neu- Benson et al., 2014). A 12-week study on 98 older adults
ropsychiatric symptoms (Tan et al., 2015). However, a 5-year showed improved verbal learning, memory acquisition and
randomized, double-blind, placebo-controlled trial of EGb retention with 300 mg/day of Brahmi, compared to placebo
761 did not show any reduction in risk of progression to AD (Morgan and Stevens, 2010). Two systematic reviews also
for adults with memory complaints (Vellas et al., 2012).
concluded that Brahmi can improve attention and memory
(Pase et al., 2012; Kongkeaw et al., 2014); however, inconsis-
54.2.2 HUPERZIA SERRATA tent measures used by the included trials make it difficult
to ascertain whether Brahmi can enhance other aspects of
Huperzine A (HupA) is an alkaloid derived from the club cognition. For instance, another 12-week trial on 72 adults
moss, Huperzia serrata. It is a licensed anti-AD drug in (aged 35–60 years) found that Brahmi (450 mg/day) did
China (hence, most clinical trials of HupA have been not affect cognition, but did show a trend towards decreas-
conducted and published in China) and is sold over the ing anxiety, compared to placebo (Sathyanarayanan et al.,
counter as a dietary supplement in the United States for 2013). Further studies are required to ascertain the effective
 Vitamins and complementary therapies used to treat Alzheimer’s disease 589

Table 54.2 Mechanisms of action, adverse effects and herb–drug interactions of commonly used herbs for Alzheimer’s
disease

Herb Possible mechanisms of action Adverse effects Herb–drug interaction

Ginkgo Decrease oxygen radical discharge
biloba and pro-inflammatory functions of
macrophages, reduce corticosteroid
production, increase glucose uptake
and utilization and ATP production,
improve blood flow by increasing
red blood cell deformability,
decrease red cell aggregation,
induce nitric oxide production,
inhibit platelet activating factors
Huperzia Anti-cholinesterase, anti-oxidant,
serrata anti-β-amyloid peptide fragment,
(Huperzine A) inhibition of oxygen-glucose
deprivation, muscaric receptor
antagonism
Bacopa Enhance nerve impulse transmission,
monnieri improve memory and cognition
Curcuma Antioxidant, anti-inflammatory,
longa cholesterol-lowering properties,
block aggregation and fibril
formation
Panax Stimulating central cholinergic and
ginseng dopaminergic receptors, stimulating
hypothalamic–pituitary–adrenal axis
Melissa Nicotinic and muscarinic binding
officinalis properties, strong antioxidant effect
Camellia The phenolic compounds (especially
sinensis epigallocatechin gallate [EGCG])
(tea) have antioxidant effects
Dizziness, tinnitus,
headache, nausea,
vomiting, diarrhoea,
headache, weakness,
restlessness and skin rash,
etc.
Nausea, vomiting, anorexia,
diarrhoea, hyperactivity,
insomnia, indigestion and
mild abdominal pain
Therapeutic doses are not
associated with major
adverse effects
No significant side effects
reported
Insomnia, diarrhoea,
headache, tremor and
skin eruptions
No significant side effects,
may cause drowsiness
No significant side effects,
excessive caffeine may
lead to agitation, tremors
and insomnia
Possess antiplatelet activity,
caution when used with
anticoagulant and
antiplatelet agents (such as
warfarin)
May cause additive effects
when used with other
anticholinesterase agents
such as donepezil
Slightly sedative effect; caution
when used with other known
sedatives, inhibits the effect
of thyroid-suppressant drugs.
Possess anticoagulant or
antiplatelet activity, caution
when used with anticoagulant
and antiplatelet medications
Combination of
antidepressants and ginseng
may induce mania, caution
when used with anti-diabetic
drugs as ginseng may reduce
fasting blood glucose levels
Caution when used together
with sedatives, anti-anxiety
drugs, narcotic pain relievers
(e.g. codeine), antihistamines
Caution when used with
theophylline and ephedrine

dosage range, the effects of long-term administration and
potential therapeutic effects of Brahmi for AD.
54.2.4 CURCUMA LONGA
The perennial herb Curcuma longa (turmeric) contains three
structurally closely-related chemical components – c­ urcumin,
demethoxycurcumin and bisdemethoxycurcumin – which
together are commonly referred to as ‘curcumin’ or ‘curcumi-
noids’ (Goel et al., 2008). Commercially available ‘curcumin’
is widely promoted for its anti-inflammatory properties
(Jurenka, 2009).
In Ayurvedic medicine, turmeric is a well-documented
treatment for many diseases (e.g. asthma, respiratory
allergy, liver disorders, anorexia, rheumatism, diabetic
wounds, cough and sinusitis) and neurodegenerative dis-
orders (Goel et al., 2008). Data from animal and in vitro
studies suggest that curcuminoids possess antioxidant,
anti-inflammatory and cholesterol-lowering properties, all
of which are key processes associated with the pathogenesis
of AD (Ringman et al., 2005). Furthermore, curcuminoids
directly bind to small β-amyloid species to block aggrega-
tion and fibril formation supporting the rationale for cur-
cuminoids to be used therapeutically for AD (Yang et al.,
2005). However, evidence from rigorous AD studies is lack-
ing, with only two double-blind RCTs conducted (Baum
et al., 2008; Ringman et al., 2005), both of which showed
no difference in cognition between placebo and curcumin
590 Dementia
treatment. The discrepancy between in vitro and in vivo
findings and human trials may be due to the low bioavail-
ability of curcumin as a result of low absorption and rapid
hepatic and intestinal metabolization (Brondino et al.,
2014). Novel formulations have attempted to remedy this,
for instance, a recent double-blind RCT using a solid lipid
curcumin formulation (Longvida®) in healthy older adults
demonstrated improved sustained attention and working
memory with acute administration (1 hour and 3 hours)
and improved working memory, mood enhancement and
lowered total and low-density lipoprotein (LDL) cholesterol
with chronic administration (4 weeks) (Cox et al., 2014).
Several large scale clinical trials are underway or soon to
be completed and other new formulas aimed at increas-
ing the bioavailability of curcumin are being developed.
The upcoming results will help to determine if curcumin
has therapeutic value for the treatment and prevention of
dementia.
54.2.5 PANAX GINSENG
Panax ginseng (ginseng) root has been used to manage AD
in many Asian countries. The principal bioactive compo-
nents of ginseng are ginsenosides, which have antioxidant,
anti-inflammatory and anti-apoptotic effects (Radad et
al., 2006). In vitro studies have demonstrated that ginsen-
oside Rg3 promotes β-amyloid peptide degradation through
enhanced gene expression (Yang et al., 2009) and ginsen-
oside retinoblastoma 1 (Rb1) can ameliorate AD pathology
by suppressing phosphorylated tau protein expression and
upregulating brain-derived neurotrophic factor (BDNF)
(Wang et al., 2013).
Most of the cognitive effects of ginseng have been stud-
ied in animals and healthy individuals. Some data suggest
that ginseng modestly improves thinking and working
memory in healthy volunteers (Kennedy and Scholey,
2003a; Reay et al., 2006). Two small open-label trials dem-
onstrated potential therapeutic benefits of ginseng for AD,
with both studies evidencing improved Alzheimer’s Disease
Assessment Scale-cognitive subscale (ADAS-cog) scores
after 12 weeks of treatment with ginseng, compared to pla-
cebo (Heo et al., 2008; Lee et al., 2008). Ginseng has also
demonstrated clinical benefits when combined with ginkgo
in improving cognitive function in humans (Wesnes et al.,
2000; Kennedy et al., 2001; Yakoot et al., 2013). Large-scale,
long-term studies using standardized extracts are required
to determine the clinical efficacy of ginseng therapy in AD.
54.2.6 MELISSA OFFICINALIS
Melissa officinalis (from the lemon balm plant) binds to
both nicotinic and muscarinic ACh receptors in the central
nervous system (Perry et al., 1999; Kennedy et al., 2003b)
and has strong antioxidant properties (Dastmalchi et al.,
2008); both of which are desirable in the management of
AD. Human studies have shown that lemon balm extract
can modulate mood and cognitive performance when
administered to young, healthy volunteers (Kennedy et al.,
2003b). In mild-to-moderate AD patients, 16 weeks of treat-
ment with lemon balm extract significantly improved cog-
nitive function and reduced agitation, compared to placebo
(Akhondzadeh et al., 2003). However, a more recent double-
blind RCT that compared lemon balm oil aromatherapy
to donepezil and placebo in 81 patients with probable or
possible AD found no difference between placebo and the
two interventions in reducing agitation (Burns et al., 2011).
Interestingly, an 18%–37% improvement in agitation and
neuropsychiatric symptoms was noted in all treatment
groups suggesting that touch and interaction may be help-
ful for treating agitation in AD patients. More experiments
are required to establish whether lemon balm is of value in
the management of agitation and cognitive decline in AD.
54.2.7 CAMELLIA SINENSIS (TEA)
Data from animal and epidemiological studies suggests
that drinking tea (mostly green tea) may help to protect
the brain against ageing. An inverse correlation between
tea consumption and the incidence of AD and other neu-
rodegenerative diseases (e.g. Parkinson’s disease) has been
reported (Sharangi, 2009). The chief bioactive components
of tea are caffeine, amino acids (e.g. l-Theanine) and poly-
phenols (antioxidants) (Sharangi, 2009). In particular, its
main c­atechin polyphenol constituent, epigallocatechin
(EGCG), has demonstrated neuroprotective/neurorescue
properties (Mandel et al., 2008) with in vitro studies evi-
dencing anti-amyloidogenic properties of EGCG (Hyung
et al., 2013) and in vivo work in mice dementia model
showing improved cognition and less β-amyloid deposition
(Hassaan et al., 2014). A recent meta-analysis of human acute
studies indicates that tea increases multisensory attentional
outcomes in healthy adults (Camfield et al., 2014). Further,
a human cross-­sectional study assessing the effect of green
tea on cognition in elderly Japanese participants, reported
that green tea consumption of two or more cups (100 mL/
cup/day) reduced the prevalence of cognitive impairments
(Kuriyama et al., 2006). Further research is required to
ascertain whether tea can be used to delay AD progression
and improve cognition in this cohort.
54.3 FISH OILS FOR AD
A high dietary omega-6/omega-3 polyunsaturated fatty acid
(PUFA) ratio has been associated with an increased risk of
dementia (Loef and Walach, 2013). While there is a growing
body of evidence suggesting that omega-6 PUFAs promote
inflammation and disease processes (Lawrence, 2013), it has
been suggested that the neuroprotective effects of omega-3
PUFAs are attributable to reduced cardiovascular risk fac-
tors (e.g. triglyceridemia) (Schilling et al., 2014), attenuation
of the inflammation process and reduction of amyloid pro-
duction and increased clearance (Fotuhi et al., 2009).
 Vitamins and complementary therapies used to treat Alzheimer’s disease 591
Data from animal and cross-sectional epidemiological
studies have demonstrated that long-chain omega-3 PUFAs,
including docosahexaenoic acid (DHA) and eicosapentae-
noic acid (EPA), may protect against cognitive decline and
dementia (Conquer et al., 2000; Heude et al., 2003; Tully
et al., 2003). For example, the Framingham Heart Study
showed a 47% reduction in the risk of developing all-cause
dementia with higher DHA intake (levels of approximately
0.18 g/day) (Schaefer et al., 2006) and that older individuals
with high (c.f. low) red blood cell DHA levels had greater
white matter volumes and those with high DHA and EPA
levels had better visual memory, executive function and
abstract thinking abilities than those with low levels (Tan
et al., 2012).
Although omega-3 PUFAs may play a role in pre-
venting the development of dementia and even revers-
ing aspects of cognitive decline (such as mild cognitive
impairment [MCI]), there is limited evidence on the effi-
cacy of omega-3s as a treatment for patients who have
already developed dementia (Cederholm et al., 2013). For
instance, a double-blind 18 month RCT of DHA on 295
patients with mild-to-moderate AD did not slow down
the rate of cognitive and functional decline compared
to placebo (Quinn et al., 2010). A 24-week double-blind
RCT found that 1.8 g/day of omega-3 PUFAs improved
ADAS-cog scores in participants with MCI but not AD,
compared to placebo (Chiu et al., 2008). Another 24-week
intervention did not delay the rate of cognitive decline (on
Mini-Mental State Examination [MMSE] and ADAS-cog)
compared to placebo, but positive effects were observed in
a subgroup with very mild AD (MMSE > 27) (Freund-Levi
et al., 2006). Findings suggest that a diet rich in omega-3
and low in omega-6 PUFAs may help to prevent cognitive
decline and dementia in older age (Martínez-Lapiscina
et al., 2013).
54.4 VITAMINS FOR AD
54.4.1 VITAMIN E AND VITAMIN C
A consistent body of work indicates that oxygen free radi-
cals are involved in the pathological processes of AD
(Ferreiro et al., 2012; Padurariu et al., 2013). This oxidative
stress hypothesis (Markesbery, 1997) has led to interest in
the use of antioxidants, such as vitamins E and C, for the
treatment of AD.
While lower plasma levels of vitamins C and E are
observed in AD (Lopes da Silva et al., 2014) and in vitro
studies have shown that vitamin C can decrease β-amyloid
generation and AChE activity (Heo et al., 2013), longitu-
dinal epidemiological studies do not consistently show
that habitual dietary vitamin C and E supplementa-
tion will reduce risk of dementia (Crichton et al., 2013).
Furthermore, evidence from clinical trials of vitamin E is
inconsistent (Farina et al., 2012), with some even suggesting
adverse effects (Ames and Ritchie, 2007). For example, 800
IU/day treatment with vitamin E (c.f. placebo) for 6 months
was only effective in reducing oxidative stress in some AD
patients. For those that were not responsive, a detrimen-
tal decline in cognition was observed (Lloret et al., 2009).
However, in a recent study involving 613 patients with
mild-to-moderate AD, treatment with 2000 IU/day of vita-
min E resulted in slower functional decline than placebo
(Dysken et al., 2014). Currently, there are no published
clinical trials on a vitamin C intervention for dementia, but
it has been suggested that maintaining healthy vitamin C
levels (rather than consuming additional supplements) can
protect against cognitive decline and AD (Harrison, 2012;
Harrison et al., 2014).
54.4.2 B VITAMINS AND FOLATE
Data from retrospective case-controlled studies and pro-
spective cohort studies suggest that elevated serum total
homocysteine level is a potential risk factor for cognitive
decline and dementia (Clark, 2008), with high levels associ-
ated with increased risk of endothelial cell injury, inflam-
matory processes in blood vessels, ischemia and brain
infarcts (Morris, 2003, 2012). Homocysteine serum lev-
els can be lowered by vitamins B12, B6 and folate, which
convert homocysteine to methionine and cysteine, respec-
tively. This homocysteine hypothesis of dementia has led to
considerable interest in using B vitamins and folate for the
treatment/prevention of AD (Clark, 2008).
Evidence for this therapeutic approach from clinical
trials has not been consistent. Several systematic reviews
(Balk et al., 2007; Vogel et al., 2009; Dangour et al., 2010;
Wald et al., 2010; Ford and Almeider, 2012) have concluded
that B vitamins cannot effectively slow down cognitive
decline. However, this may be due to the low method-
ological quality and short duration of the included trials.
For example, a more recent and rigorously designed study
supplemented 900 older adults with 400 µg folate + 100 µg
vitamin B12 for 24 months found improved ­immediate
and delayed memory performance compared to placebo
(Walker et al., 2012). Another study supplemented 818
older adults with 800 µg/day of folic acid or placebo for
3 years and found increased memory, information pro-
cessing speed and sensorimotor speed with folic acid
treatment, compared to placebo (Durga et al., 2007). High
quality studies on AD cohorts are also lacking at present.
One double-blind RCT of high dose folate, vitamin B6 and
B12 on 409 patients with mild-to-moderate AD found that
treatment reduced homocysteine serum levels, but did
not slow cognitive decline, compared to placebo (Aisen
et al., 2008). The same pattern of results was observed in
a smaller 26-week study (Sun et al., 2007). Furthermore,
adverse effects have been noted, with a large cohort study
on 1354 adults demonstrating that high serum folate lev-
els were related to impaired cognition (Moore et al., 2014).
These inconsistent findings, together with the potential
for adverse effects indicates that, although homocysteine
592 Dementia
and B-vitamins share common biochemical pathways,
further research is required to demonstrate their efficacy
in treating AD.
54.4.3 VITAMIN D
Vitamin D plays an important role in brain development
and function; however, despite several cohort s­tudies
showing a relationship between vitamin D deficiency
and cognitive decline and dementia, the mechanism
is not well understood (McCann and Ames, 2008). A
recent longitudinal study tracked 1658 elderly adults for
approximately 5.6 years and found that vitamin D defi-
ciency was associated with a substantially increased risk
of all-cause dementia and AD (Littlejohns et al., 2014).
A longitudinal study in women found that lower vita-
min D dietary intake was associated with a greater risk
of developing AD (Annweiler et al., 2012). Even in the
absence of dementia, vitamin D insufficiency is related
to a decline in ­cognitive function (van der Schaft et al.,
2013; Annweiler et al., 2015). Clinical trials examining the
efficacy of vitamin D supplementation for patients with
AD are currently ­lacking. Furthermore, due to the high
prevalence of ­hypovitaminosis D in older persons, those
at risk should be tested for low serum 25-hydroxycholecal-
ciferol (25-OH-D3) concentration and receive supplemen-
tation if necessary (McCann and Ames, 2008; Annweiler
et al., 2015).
54.4.4 SOUVENAID®
Souvenaid ® is a medical nutrition drink specifically designed
to target the complex metabolic biochemical changes seen
in AD. The formula contains precursors and cofactors that
promote synaptic formation, protection, function and opti-
mize brain metabolic activity including uridine monophos-
phate, choline, phospholipids, EPA, DHA and vitamins E,
C, B12, B6, folic acid and selenium.
Although work on the efficacy of this nutritional
approach as a treatment for mild-to-moderate AD is in
its infancy, current evidence shows modest improve-
ments in cognition, most notably memory. Treatment for
12 weeks with Souvenaid ® compared to control, improved
delayed verbal recall in patients with mild AD (Scheltens
et al., 2010) and a similar study showed improved memory
scores and electroencephalograph (EEG) delta band func-
tional connectivity (Scheltens et al., 2012) over a 24-week
period. Improved ADAS-cog scores were noted for AD
patients treated for 12 weeks relative to placebo; however,
improvement was only apparent for those with high base-
line scores (Kamphuis et al., 2011). Furthermore, a large
24-week trial of Souvenaid did not slow cognitive decline
in patients with mild-to-moderate AD compared to a con-
trol group (Shah et al., 2013). Additional clinical trials
with longer intervention periods are required to validate
this approach.
54.5 OTHER COMPLEMENTARY
THERAPIES FOR AD
Other complementary therapies have been used to treat
AD and other dementias and/or alleviate associated symp-
toms. These interventions include, but are not limited to,
acupuncture, chiropractic, reflexology, remedial massage,
therapeutic touch, aromatherapy, mind–body therapy (e.g.
meditation, qigong exercise), music therapy, Montessori-
based activities, exercise programmes, combined melatonin
and light therapy (Table 54.1). One report argued that the
most important aspect of CAM for dementia was to take an
individualized approach that emphasized the therapeutic
relationship together with the choice of CAM (Teut et al.,
2013). For example, a trial of one-to-one Montessori-based
activities reduced anxiety in 44 dementia patients, com-
pared to baseline (van der Ploeg et al., 2013). Interestingly, a
similar effect was observed during non-personalized social
contact, suggesting that activities promoting social contact
can also have positive outcomes. Some evidence exists for
the efficacy of other CAM therapies in dementia; for exam-
ple, acupuncture has been shown to improve sleep quality
(Kwok et al., 2013) and yoga can improve physical health,
depression and problem behaviours in dementia patients
(Fan and Chen, 2011). However, more rigorous scientific
research is needed to evaluate the effectiveness of these
other treatments.
54.6 CONCLUSIONS
Due to the poor efficacy and tolerability of approved anti-
dementia pharmaceutical therapies, it is imperative that
potentially suitable complementary medicines and thera-
pies be thoroughly examined and validated, if appropriate.
The pathogenesis and pathophysiology of AD is complex
and diverse. Interventions need to take into account multiple
factors including chronic inflammation, increased free rad-
ical production, glucose energy substrate hypometabolism
and reduced synaptic density and vascular integrity. Where
conventional pharmaceutical treatments typically follow a
single-target method, complementary interventions, such
as herbal medicines and multivitamin supplementation can
contain multiple active components and have the capacity
to affect multiple targets. This makes CAMs ideal thera-
pies for disorders (including dementia) with multifactorial/
multisystem pathophysiological components. Furthermore,
treatments that can target inflammation are of high impor-
tance (Lim et al., 2013).
A large proportion of the existing evidence support-
ing the use of CAM for AD comes from animal and
in vitro studies and epidemiological data. Unfortunately,
clinical trials of these interventions frequently produce
disappointing and inconsistent results due to poor meth-
odologies, small sample sizes and short intervention
 Vitamins and complementary therapies used to treat Alzheimer’s disease 593
periods. Large scale, randomized, double-blind, placebo-­
controlled trials are needed to evaluate the effectiveness
and safety of these interventions. In addition, some tra-
ditional medical systems such as Chinese and Ayurvedic
medicine emphasize health maintenance and disease
prevention, which is currently not the primary focus of
western medicine. Hence, further research that assesses
the protective and preventive effects of these medicines
should also be carried out.
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Prevention of Alzheimer’s disease and
Alzheimer’s dementia
TOM C. RUSS, KAREN RITCHIE AND CRAIG W. RITCHIE
55.1 INTRODUCTION
There is now consensus that a substantial proportion of
cases of dementia is potentially preventable. With this
agreed, the discussion has centred on the extent to which
the risk of developing Alzheimer’s disease (ADis) could be
reduced and exactly which risk factors should be the focus of
public health attention. At this point, it is worth making the
distinction – widely accepted in the clinical and academic
community – between ADis (a pathological process) and
Alzheimer’s dementia (ADem, the clinical dementia syn-
drome associated with ADis). This chapter will discuss what
prevention (or risk reduction) means in the context of both
disease and dementia, which will lead us on to consider
the life course approach in dementia epidemiology. This
approach hypothesizes that risk and protective factors from
all stages of life – from before conception to late life – may be
important in affecting dementia risk. Following these theo-
retical considerations, we will report the current research
evidence for the prevention of ADis and ADem, summarize
the policy recommendations that have been made worldwide
and consider whether public health interventions in other
domains, for example cardiovascular disease, may have had
additional positive impact on dementia risk.
55.2 WHAT DO WE MEAN BY
PREVENTION?
Much of the scientific literature in this area uses a phrase
like ‘dementia prevention’ to refer to reducing the preva-
lence of dementia in a specific population. However, more
recently some concerns have been expressed about this use
of language, which highlights a frequent confusion between
598
55
a description at the level of the population and one at the
level of the individual. In his classic paper ‘Sick individuals
and sick populations’, Geoffrey Rose distinguishes between
factors which affect the incidence of a disease in a popu-
lation and those which affect whether an individual will
develop the disease (Rose, 1985). For example, if a public
health intervention succeeds in reducing a risk factor in the
population (such as shifting the population distribution of
systolic blood pressure to the left – i.e. more like the Kenyan
nomads than the London civil servants in Figure 55.1) this
may reduce the incidence of dementia. However, even in
the lower risk population as a whole, there will still be indi-
viduals with ‘high’ levels of the risk factor and, thus, still
at increased risk. Indeed, an individual with an optimized
risk factor profile may still develop dementia, assuming that
this single risk factor is not, on its own, a sufficient cause.
Alternatively, the individual may unsuccessfully attempt to
reduce this risk factor, even though the population mean of
the risk factor and the incidence of dementia both reduce.
The individual in this case might meet talk of ‘prevention’
with consternation – they reduced their level of the risk fac-
tor but still developed dementia; or they tried and failed to
diminish the risk factor, thus failing to prevent dementia.
Does this mean they are in some way responsible for devel-
oping the disease? It is clear that we must be very careful,
both in our thinking and our language here. Indeed, some
have called for us to talk in terms of ‘risk reduction’ rather
than ‘prevention.’ However, there is a clear and important
difference between these concepts – risk reduction strategies
would focus on the exposure variable thought to be associ-
ated with the outcome, whereas prevention implies a focus
on reducing the frequency or incidence of the outcome,
which may be achieved not only by risk reduction but also
specific – perhaps pharmacological – interventions. ‘Risk’ in
the former sense could potentially be reduced but is unlikely
to be eliminated completely. Notwithstanding these caveats,
 Prevention of Alzheimer’s disease and Alzheimer’s dementia 599

for simplicity we will continue to use the term ‘prevention’ Braak, 1997). The search for ADis decades before demen-
in this chapter. tia is expected to develop is the specific focus of projects
The distinctions between ADis and ADem as well as like PREVENT (Ritchie and Ritchie, 2012; Ritchie et al.,
between ‘risk reduction’ and ‘prevention’ outlined above are 2013). These projects hypothesize that earlier life disease
relevant when we consider the usual definitions of types of will be a more specific indicator of later dementia than it
prevention. Prevention has traditionally been divided into has been shown to be – in multiple projects – in later life.
primary, secondary and tertiary prevention and Figure 55.2 Indeed, the Religious Orders Study and the Memory and
outlines how this distinction applies to ADis and ADem. Aging Project found that a third of people who died with-
However, defining these categories closely relies on the out dementia had sufficient neuropathological changes to
natural history of the condition in question being under- be classified as ADis with intermediate certainty (Bennett
stood and, thus, a few words about this might be helpful et al., 2006). This and other evidence including a neuropatho-
here. ADis has been widely considered a condition of later logical series from the Medical Research Council Cognitive
life. However, this is not the complete picture and emerg- Function and Ageing Study (MRC CFAS) (Wharton et al.,
ing evidence points to ADis in fact having its genesis in 2011) suggests that ADis (neuropathological changes in the
midlife or even earlier, with ADem being a manifestation brain) and ADem (cognitive and functional decline) are not
of this disease typically reserved for people in later life. identical but, rather, are two related, parallel phenomena.
For example, unselected autopsy samples of adults aged Three recent Cochrane Diagnostic Test Accuracy Reviews
25 years and older showed that ADis was commonly pres- highlighted this as they demonstrated that amyloid-β lev-
ent in individuals decades before the usual age of clini- els (a core pathological lesion in ADis) whether measured
cal onset of symptoms (Braak and Braak, 1991; Braak and in cerebrospinal fluid (CSF) (Ritchie et al., 2014) or using
positron emission tomography (PET) imaging (Zhang
et al., 2014; Smailagic et al., 2015) had very low specificity
30

Kenyan nomads
London civil servants
but better sensitivity for later ADem in populations with
mild cognitive impairment (MCI). Indeed, the data sup-
20

porting the use of biomarkers for the diagnosis of dementia

in general are limited and variable in quality (Noel-Storr et
%

al., 2013). In essence, you may need Alzheimer’s pathology

10

to get ADem, but you can have Alzheimer’s pathology and

still enjoy normal cognitive health well into later life. For
this reason, it is imperative always to be clear whether we
0

60 80 100 120 140 160 180 200

are referring to ADis or ADem – an essential distinction
Systolic blood pressure (mm Hg)
that the abbreviation AD frequently obscures.
Primary prevention refers to preventing a ­ condition
Figure 55.1 Distributions of systolic blood pressure in developing in the first place in healthy people. If the neu-
middle-aged men in two populations. (Redrawn from ropathological changes of ADis begin in midlife this
Rose, G., International. Journal of Epidemiology, 1985 by means that implementing primary prevention measures
permission of Oxford University Press). would need to begin earlier than that. Therefore, it would

Primary prevention Secondary prevention Tertiary prevention

Identification: Identification: Identification:
Extent of Alzheimer’s disease pathology

Genetic risks Biomarker abnormalities Clinical symptoms

Clinical risks Clinical symptoms Functional impairment
Risk of Alzheimer’s dementia

e.g. head injury/diabetes Genetic and clinical risks

Intervention:
Intervention: Intervention: Specific pharmacology
Risk reduction Risk reduction Psychosocial
Enhanced nutritional and interventions and support
Who leads: lifestyle modifications Risk reduction
The individual Specific pharmacology Enhanced nutritional and
Public health lifestyle modifications
Education Who leads:
The individual Who leads:
Public health The individual
Education The individual’s family
Primary care Primary care
Specialists Specialists
Social services
The third sector

Life course

Figure 55.2 Primary, secondary and tertiary prevention of Alzheimer’s disease and dementia.
600 Dementia

be helpful from a methodological point of view to have a
reliable method to identify early brain changes of ADis
in vivo, in order to identify those people in whose brains
not even the very early stages of ADis are detectable. Many
­middle-aged people with no symptoms of dementia are in
fact likely to have early ADis and considered therefore ‘at
risk’ of developing ADem. Thus, primary prevention initia-
tives would have to go ‘upstream’ and begin in early adult-
hood, if not even earlier in life.
Because of the long, clinically silent latent period of
ADis, rather than representing primary prevention endeav-
ours, many midlife intervention studies would probably fall
under our definition of secondary prevention. In the con-
text of dementia, the aim of secondary prevention initiatives
is to prevent or delay the clinical onset of ADem in indi-
viduals who already have the pathological changes of ADis
in their brain. There is evidence that delaying the clinical
onset of symptoms would have substantial effects on the
number of people with dementia by compressing morbidity,
therefore increasing the number of years spent disease-free
(Brookmeyer et al., 1998; Brookmeyer et al., 2007; Ritchie
et al., 2015).
Tertiary prevention refers to attempts to modify the dis-
ease and its symptomatic course once it has become symp-
tomatically apparent so that patients do not progress to later,
higher morbidity stages of the condition. In the context of
dementia, this would mean both disease-modifying treat-
ments targeting individuals who have already shown cog-
nitive and/or functional decline (for simplicity, we would
also include those labelled as having ‘MCI’ in this category)
as well as pharmacological treatments targeting symptom
profiles and psychosocial interventions. Disappointingly,
though there have been a large number of studies targeting
disease modification over the last two decades in this popu-
lation, they have been predominantly negative (Figure 55.3)
(Mangialasche et al., 2010; Schneider et al., 2014). Perhaps
this stands to reason when we consider the patho-clinical
course being proposed for ADis, whereby people with even
mild ADem may in fact have very severe ADis, which has
been occult (using current technologies) for decades. In

Aβ production
Preclinical
Aβ aggregation
Aβ clearance (immunotherapy) ACI-24
Tau aggregation or phosphorylation Phenylthiazolylhydrazide
Cholinergic drugs
Anti-Aβ antibodies Phase 1
Others Rhodanines

RS-0406 Minocycline
Affitope AD-01*

Phase 2
GSK-933776 AL-208*
Affitope AD-02
SEN-1269 AL-108* Anti-tau
PF-04360365
MABT-5102A antibodies
ACC-001 MTC/LMT*
AN-1792* Phase 3 Nicotinamide
UB-311 IVIg
CAD-106 Valproate* N-031112
SP-233 Bapineuzumab (NP-12)* N-744
ELND-005
Solanezumab Phase 4 Lithium*
R-1450 NGF
PBT1* Tramiprosate* Donepezil† Antioxidants

Rivastigmine† SB-742457
Peptidic anti- EGCg
V-950 PBT2* Statins
aggregants Galantamine† PRX-03140*
NIC5-15 Tarenflurbil* Memantine† BDNF
Latrepirdine PUFAs*
E-2012*
Semagacestat TTP-488
Bryostatin-1 Phenserine*
Exebryl-1 Rosiglitazone* PF-04447943
MK-0752* EHT-0202*
EVP-6124
BMS-708163 Huperzine-A* Ladostigil
CHF-5074
AF-102B*
NGXsc Pioglitazone* AZD-3480*
CTS-21166* ABT-089* Talsaclidine* AF-267B

PF-3084014* M-30
GSM-1
Begacestat* Memoquin
Anti-β-secretase antibodies

BBS1

Figure 55.3 (See colour insert.) Drug development in Alzheimer’s disease: drugs being investigated for Alzheimer’s
disease therapy, reported according to the most advanced phase of study and main therapeutic properties (including data
from studies in vitro and animal models). Aβ, amyloid-β; BBS1, anti-β-site antibodies; BDNF, brain-derived neurotrophic
factor; EGCg, ­epigallocatechin-3-gallate; IVIg, intravenous immunoglobulin; LMT, leuco-methylthioninium; MTC, methyl-
thioninium chloride; NGF, nerve growth factor; NGXsc, NGX series compounds; PUFAs, polyunsaturated fatty acids; GSM,
γ-secretase modulator; RCT, randomized controlled trial. *RCTs in Alzheimer’s disease not ongoing. †Drugs approved for
the treatment of Alzheimer’s disease. (Reprinted from The Lancet Neurology, 9, Mangialasche, F. et al., Alzheimer’s dis-
ease: Clinical trials and drug development, 702–716, 2010, with permission from Elsevier.)
 Prevention of Alzheimer’s disease and Alzheimer’s dementia 601
effect, people with ADem already have end-stage brain
failure with multiple concurrent pathological processes
being relevant. Therefore, a single targeted approach to one
pathology is highly unlikely to produce substantial clinical
benefit. There has been much interest recently in findings
presented at the 2015 Alzheimer’s Association International
Conference that a sample of participants in the negative
phase 3 trials of solanezumab (Doody et al., 2014; Siemers
et al., 2016) with mild ADem who were allocated during
the double-blind phase to the treatment group have subse-
quently declined more slowly than participants who were
in the control group, despite both groups receiving the
treatment after the end of the trials (Liu-Seifert et al., 2015).
However, while this single positive finding is encouraging,
the effect remains small and merely maintained people in
a state of dementia without recovery to an earlier phase of
the clinical syndrome. Moreover, these findings will require
corroboration in further ongoing trials and, practically
speaking, it is unlikely that an expensive treatment admin-
istered as an infusion would become widely used in clinical
practice, particularly given the small effect size. However,
if asymptomatic people showing evidence of ADis could
be identified using what will come to be known as ‘partner
diagnostics’, the impact of disease modification for second-
ary prevention is likely to be much more meaningful and
therefore cost-effective.
55.3 THE ORIGINS OF DEMENTIA
We have already seen that ADis begins years, or even
decades, before ADem. In addition to the pathological
evidence cited above, there is also a great deal of evidence
from prospective cohort studies of the association between
midlife risk factors and later dementia. Furthermore,
findings from intervention studies in late life in people
with dementia – including those looking at medication
(Mangialasche et al., 2010) or risk factor modification
(McGuinness et al., 2009; McGuinness et al., 2014) – have
been uniformly disappointing. More recent studies in older
people who are free from dementia though have shown that
dietary, clinical, lifestyle and brain training may reduce the
rate of brain failure (e.g. the Finnish Geriatric Intervention
Study to Prevent Cognitive Impairment and Disability
[FINGER] [Ngandu et al., 2015] and the Mediterranean-
DASH Intervention for Neurodegenerative Delay [MIND]
[Morris et al., 2015]) optimistically pointing to the message
that ‘it is never too late to prevent dementia.’ However, the
failures in people with established dementia adds weight
to the idea that ADem represents the later stages of a long
process and that the logical thing to do is to intervene at
an earlier stage and/or younger age when the brain is better
preserved. Indeed, many people speculate that the secret to
therapeutic success in ADis is to intervene earlier, when the
brain is in a state more amenable to preservation of func-
tion. This ties in to the observation that the most important
risk factor for dementia – by far – is ageing and, thus, in
order to understand dementia properly (and to have any
hope of preventing it) we must understand brain ageing
much better (Brayne, 2007).
One possible time point to intervene is before someone
develops the clinical symptoms of ADem – commonly
­cognitive changes (predominantly memory) and functional
decline. However, one question we have not yet addressed is
what influences the timing of the clinical onset of demen-
tia? We have already seen that a large proportion of people
without dementia have ADis in their brains. Why do they
not have any symptoms of dementia? A relevant theory
answering this question is that of cognitive reserve – that
certain people’s brains are more resilient to the pathologi-
cal changes of ageing and ADis (Stern, 2012). This concept
includes the overlapping ideas of brain reserve and cognitive
reserve. The former primarily reflects structural differences,
for example numbers of neurones, whereas the latter refers to
a more active process in which the brain adapts to compen-
sate for age- or disease-related changes by altering or opti-
mizing its function. Support for the idea of cognitive reserve
comes from the association between lower educational and
occupational attainment and increased dementia risk, sug-
gesting that brain changes resulting from positive learning
and occupational experiences could render the brain less
susceptible to insult (Valenzuela and Sachdev, 2006). A cor-
ollary of the ability of being able to tolerate more pathology
before the clinical onset of dementia (i.e. people with greater
cognitive reserve) is that such people decline more rapidly
after diagnosis, analogous to a dam being broken – the dam
in question being built through the person’s life through
education (Stern et al., 1995, 1999). Further biological sup-
port for the concept of cognitive reserve can be found in
the observation that people with dementia with greater edu-
cational attainment show decreased parietotemporal blood
flow on PET scans compared to people with dementia with
the same levels of clinical symptoms but who left school at a
younger age (Stern et al., 1992). A linked finding is that lev-
els of neuropathology do not seem to relate well to levels of
clinical symptoms. This is particularly the case for amyloid,
though tau levels in the brain may relate better to symptoms
(Arriagada et al., 1992).
The growing consensus that a longer period of an indi-
vidual’s life may be relevant to their dementia risk has led to
the widespread application, as with many chronic diseases,
of the life course paradigm of epidemiology to ADis (Ben-
Shlomo and Kuh, 2002; Whalley et al., 2006). This simply
suggests that factors from all stages of development – i.e. at
any point in the life course – may influence (either increase
or decrease) an individual’s probability of developing demen-
tia. Risk may be accumulated over time or a particular factor
may influence risk only at a particular point in time (a critical
period) or more at one point in time than at other times (a
sensitive period). Figure 55.4 depicts hypothetical life course
influences on brain ageing with several critical periods. An
advantage of this life course approach is that it provides a
framework to help disentangle the genetic and epigenetic
602 Dementia

ICV

Spectrum of High GM
educa
age-related Low e tion
cognitive function du cation
since birth
WM

Small birth size Education

Epigenetic influences
Intrauterine environment Socioeconomic status Lifestyle
Placental function Nutrition Cardiovascular
Maternal nutrition Education risk and disease
Genetic influences

First trimester Second trimester Third trimester 0 4 8 12 16 20 30 40 50 60 70 80 Age (years)

Prenatal period Childhood/adolescence Adulthood Old age

Figure 55.4 Hypothesized model on the origins and life course of brain ageing. Several ‘critical periods’ (prenatal period,
childhood/adolescence, adulthood and old age) are identified during which an individual is at greatest risk of damage if
exposed to putative risk factors. Normal development of intracranial volume (ICV) and brain volume (grey matter [GM] and
white matter [WM]) is presented for these critical periods, and the possible different risk factors influencing brain develop-
ment throughout these periods are described. Allegedly, genetics and epigenetic influences could alter brain structure
and function throughout life, but their impact would probably fade with age. In addition, the spectrum of age-related
cognitive ability from birth to old age is presented in this figure, with a schematic view of our findings that small birth size
is related to poor cognitive functioning only in those with lower educational levels. (From Muller, M. et al., Pediatrics, 134,
761–770, 2014. With permission.)

factors as well as complex gene–­environment interactions,
which most probably work together to ­determine dementia
risk. It also lays the foundation for interventions – p
­ rincipally
at a public-health level – ­ targeting groups and focusing
resources with modification of risks during critical or sensi-
tive periods as based on the evidence.
A concrete example supporting the application of the
life course paradigm in dementia is the association between
physical stature and dementia. Maximal height is attained
in the first two decades of life and, in addition to being
influenced by genes, is regarded as a marker of early life
experience, including illness, adversity, nutrition and psy-
chosocial stress (Batty et al., 2006). Thus, height could be
considered a proxy for these factors. The fact that shorter
height is associated with an increased risk of dementia
leads one to conclude that such early life adversities may
influence the individual’s subsequent risk of developing
dementia (Russ et al., 2014). Another measure that captures
relevant exposures throughout the life course is pulmonary
function (estimated by a variety of spirometric measures,
including forced expiratory volume, forced vital capacity
and peak expiratory flow), which is influenced by smoking,
illness and socioeconomic deprivation at various stages of
life. Figure 55.5 shows four different possible trajectories of
pulmonary function throughout the life course: (A) ‘­normal’
growth and decline; (B) reduced maximal lung function as
a result of impaired pre- or post-natal growth leading to a
greater risk of later disability and mortality from chronic
respiratory disease in spite of a normal rate of decline; (C)
normal growth but accelerated decline and, consequently,
premature disability and death from chronic respiratory
disease (scenarios A–C could also be complicated by epi-
sodes of reversible impairments in pulmonary function
[D]) (Strachan and Sheikh, 2004). The association between
poorer lung function and increased dementia risk further
supports the life course perspective in dementia and points
to the possible importance of these factors in the develop-
ment of the disease (Russ et al., 2015b). However, the picture
is more complicated here. While it is difficult to imagine how
shorter height might, in itself, affect dementia risk, poorer
 Prevention of Alzheimer’s disease and Alzheimer’s dementia 603

Not to scale Not to scale

Level of lung function

Level of lung function

A A
Level below Level below B
which which
symptoms symptoms
may occur may occur

Birth 10 20 30 40 50 60 70 80 Birth 10 20 30 40 50 60 70 80

Age in years Age in years

Not to scale Not to scale

Level of lung function

Level of lung function

A A
Level below B Level below D B
which which D
symptoms C symptoms C
may occur may occur

Birth 10 20 30 40 50 60 70 80 Birth 10 20 30 40 50 60 70 80

Age in years Age in years

Figure 55.5 Schematic representation of the life course of pulmonary function measurements. (Adapted and redrawn
from Figure 10.2 in Kuh, D. et al., A Life Course Approach to Chronic Disease Epidemiology, 2004, by permission of Oxford
University Press.)

lung function could plausibly be a risk factor in its own right,
affecting the brain through hypoxia, reduced oxygenation of
brain tissues with the associated hypercapnic state leading to
a lower brain pH, which is known to drive amyloid-β aggre-
gation (Atwood et al., 1998), as well as a risk marker because
of the factors mentioned above which influence it.
We have seen that the life course paradigm suggests that
risk and protective factors from all periods of life are poten-
tially relevant. Until recently, there has been no evidence
directly linking birth parameters with brain ageing. An indi-
rect link can be inferred from the influence of birthweight
(and parental social class) on cognitive function at the age of
11 years (Shenkin et al., 2001), which, in turn, is a risk fac-
tor for dementia, possibly more so for vascular dementia than
ADem (Whalley et al., 2000; McGurn et al., 2008). However,
a recent retrospective cohort study as part of the Age Gene/
Environment Susceptibility (AGES)–Reykjavik study in
Iceland demonstrated that lower birthweight was associated
with slower processing speed and poorer executive function
at the aged of 75 years, but only in those with lower educa-
tional attainment (Muller et al., 2014). It can be seen that
there are complex interplays between cognition, education
and socioeconomic status that need to be carefully unpicked,
but this finding that the birthweight – hypothesized to be a
measure of the intrauterine environment – is related to cog-
nitive function in later life is an exciting one which echoes
other such findings in the area of ‘foetal origins of adult dis-
eases’ (Barker, 1990; Calkins and Devaskar, 2011).
Of course, in an ideal world, one would study the early
life origins of dementia with direct measure of the factors
of interest in early life, repeated measures throughout life
and sufficiently long follow-up for a large number of people
to develop ADem. Clearly, such a prospective design is cur-
rently unfeasible. Thus, alternative strategies must be found
for different aspects of the methodology. One possibility is a
retrospective design (as in the AGES–Rekjavik study [Muller
et al., 2014]), in which individuals who are already older
(either an aged cohort or a group of people with dementia for
whom matched controls can be found) for whom relevant
data, by coincidence, were recorded earlier in life – either
routinely, as is the case for birthweight, or because they were
part of an earlier study which is still accessible, for example
the Lothian and Aberdeen Birth Cohort studies, the Nun
study or the Aberdeen children of the 1950s cohort (Deary
et al., 2009; Leon et al., 2006; Snowdon, 2011; Whalley et al.,
2011; Deary et al., 2012). An alternative solution to the same
problem is to measure a proxy for something that happened
earlier in life, as in the studies of height and lung function
mentioned above (Russ et al., 2014; Russ et al., 2015b).
Follow-up is often limited by economic resources and one
solution to this is ‘passive’ follow-up using electronic health
records, which allows a large number of people to be fol-
lowed up for a long time for relatively little money. There are
understandably some concerns that this may lead to under-
ascertainment of dementia cases (in addition to the univer-
sal under-diagnosis in the community), but the evidence
604 Dementia
suggests that using multiple sources is likely to be adequate
for epidemiological purposes, especially if the ascertainment
or otherwise is not related to the exposure under study and
particularly in certain contexts, for example universal health-
care (Knopman et al., 2011). Indeed, this is the approach
being taken by large cohort studies such as UK Biobank
(N = 500,000) (Sudlow et al., 2015). A final possibility is not
waiting until people develop ADem but to identify those who
have ADis through the use of biomarkers, for example struc-
tural and functional imaging, neuropsychological testing and
CSF measures. This is the approach taken in the European
Prevention of Alzheimer’s Dementia (EPAD) project, which
will be described in Section 55.5 (Ritchie et al., 2015).
55.4 PRIMARY PREVENTION
We defined primary prevention above as attempting to prevent
ADis developing in the first place and suggested that many
midlife prevention studies were, in fact, studying secondary
prevention – the prevention of ADem in people who already
had ADis. That said, primary prevention can be considered at
two levels: the individual and the population. Individual-level
risk factors could potentially be targeted at any stage of the
life course and, indeed, could be the focus of population-wide
public health interventions. Population-level risk factors, on
the other hand, have been relatively understudied and in this
chapter we will focus on environmental risk factors and a geo-
graphical approach through disease mapping.
55.4.1 INDIVIDUAL-LEVEL RISK FACTORS
A group at the University of California, San Francisco sys-
tematically reviewed the literature in relation to seven poten-
tially modifiable individual-level risk factors for ADis: in
early life, educational attainment; in midlife, hypertension
and obesity; and throughout the life course, diabetes, smok-
ing, depression and physical inactivity (Barnes and Yaffe,
2011). They estimated that approximately half of ADem
cases worldwide could be attributed to these risk factors
and that a 10% reduction in each risk factors could prevent
a million cases worldwide; a 25% reduction would prevent
three million cases. A more recent paper took into account
the fact that these seven risk factors are not independent: in
these models, eliminating all the risk factors would prevent
28.2% cases of ADem worldwide (Norton et al., 2014). More
reasonable estimates of 10% or 20% reduction in risk factors
could result in the prevention 8.3% or 15.3% cases world-
wide by 2050. Findings from such modelling studies do not
necessarily translate into the real world where factors like
confounding, bias and reverse causality are likely to com-
plicate the association between risk factor and dementia.
Unmeasured confounders may be the real causal risk fac-
tors and so altering these measured risk factors might have
no effect on dementia risk. Bias, the consequence of selec-
tive mortality or incomplete follow-up, could also mean
that the results in the real world might not be as hopeful
as the report suggests. Finally, and probably most relevant
to dementia given what we know of its natural history, the
possibility that the early stages of the condition might influ-
ence the risk factors and so produce spurious associations
(reverse causality) must be very carefully considered in all
work on dementia prevention.
In line with the life course paradigm of epidemiology
­outlined above, some of the risk factors just mentioned
seemed to be most important at particular stages of life:
educational attainment in early life; and hypertension
and obesity in midlife. Related to education, we have also
seen above that lower early life intelligence is associated
with an increased risk of dementia in later life, possibly
more so for vascular dementia than ADem (Whalley et al.,
2000; McGurn et al., 2008). These findings come from the
Aberdeen and Lothian Birth Cohort studies, which were
made possible by the discovery in the 1990s of the results
of intelligence tests sat by all 11-year olds in Scotland in
the summers of 1932 and 1947, which allowed these indi-
viduals to be followed up in later life (Scottish Council for
Research in Education, 1933; Scottish Council for Research
in Education, 1949; Deary et al., 2009; Whalley et al., 2011;
Deary et al., 2012). A similarly serendipitous discovery led
to the Nun study, which linked early life linguistic ability
inferred from autobiographies written by the nuns shortly
before taking their religious vows with later life measures
(Snowdon, 2011). The measures of linguistic ability used
were ‘idea density’ and ‘grammatical complexity.’ Lower lev-
els of both measures – particularly the former – were associ-
ated with poorer cognition in later life and an increased risk
of pathologically confirmed ADem (Snowdon et al., 1996;
Riley et al., 2005). These studies have caught the imagination
of the wider world and have both inspired plays – ‘Still Life
Dreaming’ by the Spare Tyre Theatre Company about the
Aberdeen and Lothian Birth Cohort Studies and ‘27’ by the
National Theatre of Scotland and the Royal Lyceum Theatre,
Edinburgh, about the Nun study, both first performed in
2011 in Edinburgh.
In midlife, raised blood pressure or body mass index
(BMI) seem to be the most important risk factors for demen-
tia. However, both of these physical parameters change over
the life course, which can complicate the interpretation of
their association with dementia risk. Blood pressure, for
example, decreases in the years preceding a diagnosis of
dementia (Skoog et al., 1996). This could lead one to the erro-
neous conclusion that lower blood pressure in later life was
a risk factor for dementia when this relationship is, in fact,
an example of the reverse causality mentioned above. The
relationship observed between trajectories of blood pressure
and later dementia risk is more complex still and affected by
treatment with antihypertensive drugs (Figure 55.6) (Joas
et al., 2012). The association between BMI and dementia
may be even more complex. An association between being
underweight and an increased risk of dementia was recently
reported from a large study of two million patients in pri-
mary care (Qizilbash et al., 2015) and this finding seems to

Mean age of sample*
45 51 57 69
180
Systolic blood pressure mm Hg
160
140
120
100
1968 1974 1980 1992
Time
No history of antihypertensive treatment:
Dementia cases
Non-dementia cases
History of antihypertensive treatment:
Dementia cases
Non-dementia cases
Figure 55.6 Trajectories of systolic blood pressure from
1968–1969 to 2005–2006 among those with and without
dementia in 2000–2006 and stratified by antihypertensive
treatment between 1968 and 1992. The trajectories are
adjusted for age, education, cardiovascular disease, dia-
betes mellitus, smoking, stroke and body mass index. The
predicted trajectories show the mean when the continu-
ous confounders are mean centred and the categorical
confounders are set to 0. *The age axis shows the mean
age of the study sample (N = 707). Dashed line indicates
dementia cases; solid line, non-dementia cases. (From
Joas, E. et al., Blood pressure trajectories from midlife to
late life in relation to dementia in women followed for 37
years, Hypertension, 59, 796–801, 2012.)
have been replicated in the Whitehall I Study (Kivimaki
et al., 2015). Since this contradicts the received opinion
that raised BMI is associated with dementia risk (Daviglus
et al., 2010a, 2010b; Prince et al., 2014), there has been a
great deal of speculation regarding this finding. Suggested
explanations have included the possibility that investigators
conflated midlife and late-life BMI measurement by includ-
ing individuals aged 40–80 years at baseline in the study
(Strand et al., 2015) and the hypothesis that the focus should
be on weight loss rather than absolute BMI in relation to
dementia (van der Burg et al., 2015). The latter point seems
to be supported by the finding that different trajectories in
BMI can be seen in those who go on to develop dementia
compared to those who do not (Gustafson et al., 2012).
55.4.2 ENVIRONMENTAL RISK FACTORS
A new area of research interest is investigating risk factors
for dementia through a geographical approach, which has
been fruitful in other areas of medicine. It is now estab-
lished that the geographical distribution of dementia risk is
Prevention of Alzheimer’s disease and Alzheimer’s dementia 605
not random and varies from location to location (Whalley,
77 2012). A recent systematic review summarized the pub-
lished literature based on within-study comparisons (thus
removing the possibility that any differences might result
from methodological differences between studies) and con-
cluded that there was evidence at all geographical scales for
geographical variation in dementia prevalence and inci-
dence (Russ et al., 2012). However, the review highlighted
the dearth of large-scale (i.e. small area) studies, which
are likely to be the most informative in terms of shedding
light on the possible causes for this geographical variation.
More recently, researchers using data from the Dementia in
Swedish Twins study (HARMONY) conducted a small area
Bayesian disease mapping study and reported two-to-three-
2000 2005
fold higher odds of dementia in the north of Sweden com-
pared to the south after the removal of genetic variance and
the influence of factors shared within families (Figure 55.7)
– suggesting that this variation is the result of one or more,
as yet unidentified, unshared environmental risk factors
(Russ et al., 2015a). Indeed, the importance of the influ-
ence of environmental differences between children from
the same family has been described as ‘[o]ne of the most
importance findings that has emerged from human behav-
ioral genetics’ (Plomin and Daniels, 2011). A complemen-
tary disease mapping study in the United Kingdom using a
narrow age cohort of people born in 1921 (the 1932 Scottish
Mental Survey cohort) passively followed up over eight
decades showed no variation in dementia odds based on the
county of the school participants attended aged 11 years but
substantial variation, following a broadly similar pattern to
that seen in Sweden, based on residential location after the
age of 60 years (Figure 55.8) (Russ et al., 2015a).
This clear geographical variation in dementia risk
observed in two countries, showing broadly similar pat-
terns invites speculation as to the mechanism underlying
the variation. This is being actively investigated, but there
are several possible environmental factors that may be
related. Vitamin D has been linked to dementia and cog-
nitive decline through a variety of mechanisms including
clearance of amyloid-β protein and cerebrovascular changes
(Balion et al., 2012; Annweiler et al., 2013; Littlejohns et al.,
2014; Annweiler et al., 2015). One of the factors which influ-
ence vitamin D levels is latitude, with individuals living
at higher latitudes having lower serum levels (Brouwer-
Brolsma et al., 2013). Thus, vitamin D could be a plausible
mechanism explaining part of the higher dementia risk seen
further north in both countries. Another possibility is the
micronutrient selenium which has been linked to cogni-
tive impairment and ADem (Loef et al., 2011; Berr et al.,
2012). Selenium levels in the soil are lower in the north of
Sweden than the south and so could plausibly explain some
of the observed results (Parkman and Hultberg, 2002).
There is also interest in ambient air pollution, particularly
particulate matter with an aerodynamic diameter of less
than 2.5 μm (PM2.5), which may be associated with loss of
white matter that might represent accelerated brain ageing
(Chen et al., 2015). Clearly much more detailed research is
606 Dementia

Odds ratio of dementia

< 0.67
300
0.67–0.83 Miles
0.83–0.91
0.91–0.95
0.95–1.05
1.05–1.1
1.1–1.2
1.2–1.5
> 1.5

North

(a) (b)

Figure 55.7 (See colour insert.) Age-adjusted odds ratio of dementia in male (a) and female (b) Swedish twins with
twin-level random effects (likely to capture genetic and shared environmental variance) removed. (From Russ, T.C. et al.,
Epidemiology, 26, 263–270, 2015a. With permission.)

Odds ratio of dementia

< 0.67
0.67–0.83
0.83–0.91
0.91–0.95
0.95–1.05
1.05–1.1
1.1–1.2
1.2–1.5
>1.5

(a) (b)

100
Miles

North

(c) (d)

Figure 55.8 (See colour insert.) Age-adjusted odds ratio of dementia in the SMS1932 cohort: childhood – males (a),
females (b); adulthood – males (c), females (d). (From Russ, T.C. et al., Epidemiology, 26, 263–270, 2015a. With permission.)
 Prevention of Alzheimer’s disease and Alzheimer’s dementia 607
required to clarify the mechanisms behind the observed
geographical variation in dementia risk but it seems to be
a fruitful avenue to pursue alongside more well-established
efforts such as cardiovascular disease risk.
55.5 SECONDARY PREVENTION
(INTERVENING IN MIDLIFE)
In Figure 55.2, we outlined the concept of secondary pre-
vention as it applies to ADis and ADem. That is, that, in
contrast to people with advanced, symptomatic disease,
people with evidence of disease but no (or minimal)
symptoms may derive maximal benefit from disease-
modifying interventions or combinations of interven-
tions. The benefit is likely to be maximal because of two
facts: first, the disease processes will be at an earlier phase
and therefore more likely to be susceptible to interven-
tion; second, since dementia is recognized as being the
end point of brain failure with multiple pathological pro-
cesses contributing to the clinical phenotype, specific
interventions lead to little, if any, net clinical benefit. It is
highly unlikely that all neurodegenerative disease pathol-
ogies emerge s­imultaneously – it is much more likely
that this is a sequential process. If this sequence could be
defined empirically, it would be possible to target the most
upstream, potentially triggering process, which could
fundamentally affect the disease course and therefore lead
to maximal (clinical) benefit.
The EPAD project has been designed to optimize the
proof-of-concept testing of novel interventions (predomi-
nantly pharmacological) for the secondary prevention of
ADem. It is a single trials platform that benefits from access
to numerous pre-existing ‘parent’ cohorts across Europe
and the development of a new EPAD longitudinal cohort
study of over 6000 research participants.
This work poses three major challenges: first, we need
empirically derived models of disease in the ‘second-
ary prevention’ population. How do you assess research
participants from a biological and clinical perspective
to derive data which can be used to improve disease
models – which biomarkers? How does one measure cog-
nition in preclinical populations in a way which captures
underlying brain impairment? What other features may
be relevant to optimize these models? Second, how do you
take these ­so-derived probability models and apply them
to the study population to stratify probability of decline
necessary in the placebo group to drive effect in the proof-
of-concept clinical trial? Third, how, in the absence of
either of these in the first instance, can you create the
simulations necessary for adaptive trial designs to test the
interventions? These three challenges are being addressed
in the EPAD project (Ritchie et al., 2015; Vaudano et al.,
2015). This Innovative Medicines Initiative funded pub-
lic–private partnership will develop a longitudinal cohort
study of 6000 people (at any given time) who do not have
dementia and are willing to participate in a clinical trial
for the secondary prevention of ADem. Every partici-
pant will be fully characterized biologically and clinically
(including PET-amyloid imaging, CSF- and blood-based
biomarkers in addition to a bespoke cognitive outcome
measure, the EPAD Clinical Evaluation). Thus, partici-
pants in EPAD will act as a ‘readiness cohort’ for the trial.
The cohort will also generate a vast amount of data for
improved disease modelling in this secondary prevention
population. For example, it will be possible to create indi-
vidualized ‘probability scores’ based on the three dimen-
sions of risk factors, biomarker expression of disease and
clinical expression of disease. Using these probability
scores, it will then be possible to identify subpopulations
with evidence of the target pathology relevant to the pro-
posed therapy and who are most likely to decline during
the proposed time course for the trial. The trial is per-
petual with new drugs or combinations of drugs being
brought into the project on a regular basis and arms being
closed as they show futility or success and thereafter grad-
uation to phase 3 confirmatory studies. The trial itself will
use adaptive methodologies to optimize selection of sub-
jects to interventions showing (during the course of the
study) the greatest likelihood of successful graduation to
phase 3 confirmatory trials. Within the same programme,
the EPAD project will aim to control numerous factors
that have probably conspired to create the disappoint-
ments seen in recent attempts at drug development for
disease modification. These include knowledge of every
subject’s disease status pre-baseline to reduce screen fail-
ures to a minimum, the collection of run-in data from the
longitudinal cohort study to be used analytically to mea-
sure the post-randomization effect of drugs and to select
those which appear promising, the continuous updat-
ing of disease models from all trial and cohort data and
finally the establishment of a dedicated network of EPAD
Trial Delivery Centres to ensure the highest standards of
data quality to minimize measurement bias.
While EPAD focuses on single and combinational phar-
macological approaches, other (non-­ pharmacological)
multimodal approaches are already showing great prom-
ise. One such study of people at risk of developing clini-
cal dementia is the FINGER study (Kivipelto et al., 2013;
Ngandu et al., 2014). Preliminary results from the first 2
years of follow-up were recently published and they indi-
cated that a multidomain intervention (focusing on diet,
exercise, cognitive training and vascular risk monitoring)
resulted in slower decline in the intervention group than
in the group receiving general health advice (Ngandu
et al., 2015). This finding that a simple, non-invasive
intervention could have an effect on the rate of cognitive
decline in individuals at risk of developing dementia is
very encouraging. Results from another trial (prevention
of dementia by intensive vascular care [PreDIVA]) inves-
tigating whether intensive vascular care in older adults
could decrease dementia incidence are awaited with inter-
est (Richard et al., 2009).
608 Dementia
55.6 POLICY CONTEXT
There have been a number of national and international
statements on dementia prevention in recent years and it
would be useful to summarize their conclusions to provide
context for the foregoing consideration. In 2010, the US
National Institutes of Health held a State-of-the-Science
conference on ‘Preventing Alzheimer’s disease and cogni-
tive decline’ (Daviglus et al., 2010a, 2010b). Their conclu-
sions were not optimistic: ‘Currently, no evidence of even
moderate scientific quality exists to support the associa-
tion of any modifiable factor … with reduced risk for ADis’
(Daviglus et al., 2010b). However, they did make a number
of recommendations for future research, including robust
definitions of the outcome used in dementia studies, involv-
ing caregivers in estimating daily function and institut-
ing robust new p ­ opulation-based cohort studies as well as
using existing cohort studies, for example of cardiovascular
disease risk factors, participants in which are now reach-
ing later life. A few years later, following the G8 dementia
summit in London, a group of international experts issued
a more optimistic statement entitled simply ‘Dementia
(Including Alzheimer’s ­disease) can be prevented’. They
concluded that more work was needed to discover modifi-
able risk factors for dementia but, importantly, that ‘there
is already sufficient evidence to justify immediate action …
[i.e.] tell people that adopting a healthy lifestyle may help
to ward off dementia as it does for other diseases’ (Smith
and Yaffe, 2014). The authors estimated that approximately
half of ADem cases could be attributed to known risk fac-
tors and that instituting public health measures including
smoking cessation, adopting the Mediterranean diet, pre-
venting obesity and diabetes, avoiding excessive alcohol
consumption and treating hypertension could prevent one
in five predicted new cases over the next decade. The opti-
mism of the Blackfriars Consensus on brain health and
dementia (Lincoln et al., 2014; Public Health England, UK
Health Forum, 2014), which came out around the same time
was fuelled by reports of decreasing prevalence of dementia
over time (but approximately stable absolute numbers due
to demographic change), which will be discussed in more
detail in Section 55.7. The focus of this report was the overlap
in aetiology between vascular risk and dementia and con-
cluded that ‘the scientific evidence is evolving rapidly and
sufficient to justify considered action and further research
on dementia risk reduction, both by reducing the modifi-
able risk factors and improving the recognized protective
factors” (Public Health England, UK Health Forum, 2014).
They too called for more population-based cohort studies
(both new and existing cohorts) and highlighted the MRC-
funded Dementias Platform UK (DPUK) and the European
Union Joint Programme on Neurodegenerative Disorders
(JPND) in this regard.
Possibly the most important document in this area is
Alzheimer’s Disease International’s (ADI) World Alzheimer
Report 2014, which focused entirely on risk reduction
(Prince et al., 2014). This report reviewed the evidence
for risk factors for dementia under the broad headings of
developmental and early life factors, psychological factors,
lifestyle-related factors and cardiovascular disease risk fac-
tors. They concluded from their systematic review of the lit-
erature that there was strong evidence for potentially causal
associations between low educational attainment, midlife
hypertension and smoking and diabetes (both at any stage
of life) with dementia. There was also evidence for associa-
tions between physical and cognitive activity and dementia
risk, but this was less secure and the possibility of reverse
causality still remains. They concluded that two mecha-
nisms underlying dementia development could be cognitive
(or brain) reserve and vascular pathology.
A more recent systematic review and Delphi consensus
study came to similar conclusions to the ADI report, finding
support for midlife hypertension and obesity, depression,
physical inactivity, diabetes, hyperlipidaemia and smoking
(Deckers et al., 2015). Finally, the Alzheimer’s Association
report to the World Dementia Council concluded that there
was strong evidence from population-based studies for reg-
ular physical activity and cardiovascular disease risk factors
(diabetes, obesity, smoking and hypertension) influencing
dementia risk (Baumgart et al., 2015).
55.7 DECREASING RATES OF
DEMENTIA
As alluded to above, there is growing evidence for declining
prevalence or incidence of dementia with time (Larson et al.,
2013). The MRC CFAS-II showed a decrease in dementia
prevalence in England from 8.3% to 6.5% over two decades
(Matthews et al., 2013). There is a great deal of interest in
these and similar findings from Europe (Schrijvers et al.,
2012; Qiu et al., 2013) and the United States (Manton et al.,
2005; Langa et al., 2008). Hypothesized mechanisms include
decreased rates of cardiovascular disease (a public health suc-
cess story) and increased levels of educational attainment in
more recent generations – paralleling the mechanisms of vas-
cular risk and cognitive reserve highlighted in the ADI report
above (Prince et al., 2014). However, even with reductions in
dementia prevalence of approximately 20%, the projected
demographic trends of an ageing population worldwide will
dwarf these reductions and result in substantial increases in
the absolute number of people with dementia, particularly in
low-to-middle income countries (Prince et al., 2013).
55.8 CONCLUSIONS
There is evidence that a substantial proportion of cases of
ADis and ADem may be preventable and, indeed, lower levels
 Prevention of Alzheimer’s disease and Alzheimer’s dementia 609
of cardiovascular disease risk factors and greater educational
attainment may already be having an effect to reduce demen-
tia rates, even if absolute numbers are likely to continue to
increase. If total prevention is impossible, even delaying the
onset of dementia would reduce the number of cases and have
substantial public health impact. The question then becomes
one of which risk factors to target and, importantly, at what
point in the life course to intervene. The most important
risk factors seem to be low educational attainment, midlife
hypertension, smoking and diabetes. We have seen that it is
likely that risk and protective factors are probably at work
from birth, if not earlier, and that a comprehensive dementia
prevention strategy would take this into account and send
out the message that it is never too early to start thinking
about reducing one’s risk of developing dementia.
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Trial designs
SERGE GAUTHIER
56.1 INTRODUCTION
Any therapy, whether pharmacological or not, requires
proof of safety and efficacy. This chapter outlines the vari-
ous trial designs that have been used for the treatment of
Alzheimer’s disease (AD). The experience gained so far
has been predominately in the symptomatic treatment
of AD, using parallel group designs over 3–12 months.
A number of randomized clinical trials (RCT) attempt-
ing to modify disease progression have been completed
or are in the process of progression using parallel group
designs over 12–18 months. New adaptive and combina-
tion designs are being proposed to accelerate the approval
of new treatments.
The natural history of AD is described first (see also
Chapter 45), introducing the concepts of disease stages,
disease milestones, symptomatic domains that fluctuate
in intensity as the disease runs its course and biomark-
ers. Lessons from symptomatic studies using cholinester-
ase inhibitors (ChEIs) and memantine are summarized.
Current disease modification study designs are then
outlined.
56.2 NATURAL HISTORY OF AD
The natural history of AD can be broadly considered as a
presymptomatic stage during which a number of pathologi-
cal events take place, an early symptomatic or prodromal
stage with affective and/or cognitive manifestations, symp-
tomatic mild-to-moderate and severe stages. Each of these
stages could be targeted for specific treatments, requiring
different trial designs and outcomes (Table 56.1).
Disease milestones have been defined for AD in
Box 56.1. Some of these milestones can be targets for
56
treatment, with considerable face validity and impact on
care (Galasko et al., 1995). For example, studies in mild
cognitive impairment (MCI) of the amnestic type may
demonstrate that the diagnosis of dementia (predomi-
nately caused by AD) is delayed by 6 months or longer.
Delaying loss of autonomy for self-care and even death
in moderate-to-severe stages of AD using αtocopherol in
only one study of the AD Cooperative Study group (Sano
et al., 1997) has influenced clinical practice to use vita-
min E in all stages of AD, at least in the United States (see
Chapters 54 and 55). Delaying the loss of autonomy for
instrumental activities of daily living (ADLs) or the need
for nursing home care would reduce the need for support-
ive care. Delaying emergence of some of the behavioural
and psychological symptoms of dementia (BPSD) would
reduce caregiver burden and later patient’s need for nurs-
ing home placement.
Symptomatic domains in dementia include cogni-
tion, ADLs and behaviour. One can even add a domain
of changes in motricity, since patents with AD will mani-
fest some features of parkinsonism late in the disease. In
many patients early changes in mood and anxiety precede
the formal diagnosis of AD, sometimes with spontaneous
improvement as insight into the disease is lost. Cognitive
and functional ADL decline are relatively linear over time,
whereas BPSD fluctuations through the course of the dis-
ease resolves spontaneously through the severe stage as
motricity becomes impaired (Gauthier et al., 2001). These
natural fluctuations in the intensity of individual symp-
tomatic domains through the stages of AD have an impact
into trial design and outcomes (Table 56.2). It should be
noted that studies can be of shorter duration and/or of
smaller numbers of subjects in moderate stage compared
to mild stages of AD because of the faster rate of decline
in the former, which may be related to the sensitivity of
measurement scales or to the progression of AD in the
particular patient.
613
614 Dementia

Table 56.1 Examples of trial design and outcomes for each stage of AD

Stage Target population Trial design Primary outcome

Presymptomatic Cognitively normal Survival over 5–7 years Incident dementia
Prodromal Mild cognitive impairment Survival over 3 years Progression to dementia
Mild to moderate AD in the community 6 Months parallel groups Cognition and global
impression of change
Moderate to severe AD in the community or in 6 Months parallel groups ADL and global impression
assisted living of change
Severe AD in institution 6 Months parallel groups Behaviour
Abbreviations: AD, Alzheimer’s disease; ADL, activity of daily living.

BOX 56.1: Clinical milestones in Alzheimer’s disease

●●  mergence of cognitive symptoms

E
●● Progression from amnestic mild cognitive impairment to diagnosable dementia
●● Loss of instrumental activities of daily living (ADLs)
●● Emergence of behavioural and psychological symptoms of dementia
●● Nursing home placement
●● Loss of self-care in ADL
●● Death

Table 56.2 Example of impact of symptoms through stages of AD on trial design and outcomes

Stage Prominent features Types of outcomes Examples

Mild Depression may be present, few BPSD, Cognition, instrumental ADL ADAS-Cog, CDR-SB,
cognitive decline slow but predominant ADCS-ADL, DAD
feature; some instrumental ADL losses
Moderate Cognitive decline more rapid, functional Cognition; instrumental and ADAS-Cog, DAD, ADCS-
decline more rapid; BPSD emerging basic ADL, behaviour ADL, NPI
Severe Cognitive losses harder to measure (floor Cognition, self-care ADL, SIB, ADCS-ADL, NPI, UPDRS
effect); few self-care ADL remaining, behaviour parkinsonism
BPSD abating, parkinsonism emerging
Notes:           BPSD, behavioural and psychological symptoms of dementia; ADAS-Cog, Alzheimer Disease Assessment Scale – Cognitive subscale
(Rosen et al., 1984); CDR-SB, Clinical Dementia Rating Sum of Boxes (Cedarbaum et al., 2013); ADCS-ADL, Alzheimer Disease
Cooperative Study – Activities of Daily Living scale (Galasko et al., 1997); DAD, Disability Assessment for Dementia (Gélinas et al.,
1999); NPI, Neuropsychiatric Inventory (Cummings et al., 1994); SIB, Severe Impairment Battery (Panisset et al., 1994); UPDRS,
Unified Parkinson’s Disease Rating Score (Fahn and Elton, 1987).

of change became the primary outcomes in mild-to-mod-

56.3 SYMPTOMATIC CLINICAL TRIALS
USING CHOLINESTERASE
INHIBITORS AND MEMANTINE
The modern treatment of AD was initiated by the report that
tacrine improved some aspects of cognition and daily life.
The follow-up confirmatory studies used crossover and par-
allel group designs. The US Food and Drug Administration
(FDA) published guidelines (Leber, 1990) greatly influenced
the choice of outcomes for proof of efficacy of drugs improv-
ing symptoms in AD: a cognitive performance-based scale
such as the Alzheimer Disease Assessment Scale – Cognitive
subscale (ADAS-Cog) and an interview-based impression
erate AD, usually defined operationally as scores between
10 and 26 on the Mini-Mental State Examination (MMSE).
Unfortunately, as these FDA guidelines cautioned against the
‘pseudospecificity’ of measurable benefits on neuropsychiat-
ric manifestations in AD, they delayed research in this symp-
tomatic domain. In recent years, discussions and publications
from the FDA and other regulatory agencies have been more
accepting of ADLs and behaviour as important outcomes of
the former. Guidance is also available for developing drugs
for the treatment of early stage disease (US Department of
Health and Human Services, FDA, CDER, 2013).
The following study designs have been used in the proof
of efficacy for ChEIs: parallel groups over 3–12 months and

survival to a predefined clinical end point over 1 year or
longer.
Parallel groups offer the possibility of short-term (mini-
mum 3 months) studies comparing the efficacy of differ-
ent doses of the drug versus placebo. The primary analysis
is done on outcomes at the end of the study using the last
observation carried forward (LOCF) or intent-to-treat (ITT)
analyses, which compensate for missing values in case of
dropouts. Although LOCF/ITT has been favoured by the
FDA, investigators and other regulatory agencies are now
suggesting that for studies of 12 months or longer duration,
the primary analysis should be on observed cases (OCs), i.e.
completers. For practical purpose, both types of analysis will
usually be performed. Although ‘cognitive enhancement’ was
the main hope for ChEIs as a therapeutic class, the reality has
emerged from 6-month studies with open-label extensions
and the 1-year placebo-controlled Nordic study (Winblad et
al., 2001) is that, although there is a small but statistically sig-
nificant improvement in cognition reaching its peak point at
3 months with the ChEIs, the most clinically relevant finding
has been the stabilization of cognitive decline with ‘return
to baseline’ at 9–12 months for the actively treated groups at
the higher therapeutics doses, compared with placebo treated
groups who decline steadily. It should be noted that this natu-
ral decline varies greatly between studies in AD and is even
less evident in AD with cerebrovascular disease or in vascu-
lar dementia (VaD), where control of vascular risk factors
appear to modify p ­ rogression, at least in studies of 6 months’
duration (Schneider, 2003).
Survival studies have primarily looked at loss of ADLs
and have successfully demonstrated a delay in the loss of
autonomy for patients on ChEIs compared with placebo.
Parallel group 6-month studies in patients ranging from
mild-to-moderately severe AD (MMSE 5-26) have also
established that ADLs are more stable during treatment
compared to placebo, but show no reversibility for lost
instrumental ADLs.
The most difficult domain to study, although very signifi-
cant clinically, has been behaviour. Despite the availability of
general BPSD scales such as the Neuropsychiatric Inventory
(NPI), as well as specific scales such as Cohen-Mansfield
Agitation Inventory (Cohen-Mansfield et al., 1989), there is
yet little proof of drug efficacy against BPSD. New methods
of analysis of behaviour have been proposed (Gauthier et al.,
2008; Geda et al., 2013) and will likely be more successful
in defining categories of BPSD symptoms most responsive
to ChEIs (anxiety, hallucinations), to memantine (agitation)
and possibly to other drugs.
Memantine has been found to be effective in a range of
studies using parallel groups, in moderate-to-severe AD.
Scales appropriate for this stage of disease, such as SIB, the
Alzheimer Disease Cooperative Study – Activities of Daily
Living scale (ADCS-ADL) and the NPI have been used and
accepted by the FDA and other regulatory agencies. The
trial design of adding memantine or placebo to a stable
dose of ChEI has been used successfully (Tariot et al., 2004),
Trial designs 615
paving the way for a number of studies, where novel drugs
or placebo are added to ‘standard treatment’.
56.4 DISEASE MODIFICATION
STRATEGIES
Many studies have been made and others are ongoing
with the hope of arresting or slowing significant disease
progression. So far they have used parallel group designs
over 12–18 months in mild-to-moderate AD, with the
new drug or a placebo added to standard treatment with a
ChEI and/or memantine. The primary efficacy outcomes
are usually the ADAS-Cog and the Clinical Dementia
Rating Sum of Boxes (Hugues et al., 1982; Cedarbaum
et al., 2013) and secondary outcomes include volumetric
brain measurement using magnetic resonance imaging at
the beginning and end of the study, looking for a reduced
rate of brain (whole brain or hippocampus) atrophy in the
actively treated group compared to placebo. Although,
this design appears promising, there are uncertainties
and limitations. For instance, the difference in the rate of
brain atrophy may be absent or opposite to expectations,
with accelerated atrophy in the actively treated group.
There may be a discrepancy between a reduced rate of
atrophy but no measurable clinical benefit, as was seen in
some immunotherapy trials. Other biomarkers are being
incorporated in ongoing RCT, some reflecting disease-
specific pathology, such as amyloid-positron emission
tomography (PET) ligands and cerebrospinal fluid (CSF)
aß42 levels, others reflecting neurodegeneration, such as
PET-fluorodeoxyglucose (PET-FDG) and CSF tau levels
(Langbaum et al., 2013). The usefulness of biomarkers for
purpose of enrichment of study populations or as second-
ary efficacy outcomes is periodically reviewed by interna-
tional work groups (Carrillo et al., 2013).
One difficult issue in disease modification strategies is
the decision of the stage of disease, where the proposed
drug is most likely to work. On the ‘proof-of-concept’
Phase II/III efficacy and safety study hinges on the entire
future of the drug. For example, numerous attempts at
treating patients with AD in mild-to-moderate stages
using non-steroidal anti-inflammatory drugs (NSAIDs)
have failed, despite the weight of evidence from epide-
miological research and the biological plausibility of an
inflammatory response to β amyloid deposition. It may
be that treatment in the late presymptomatic or in the
prodromal stages would be the most appropriate time to
initiate treatment. On the other hand, studies in these
stages of AD would require 3–5 years. Alternative subjects
are being studied for ‘proof-of-concept’ using high risk
groups, such as presenilin or amyloid precursor protein
mutation carriers (see Chapter 50), subjects homozygous
with apolipoprotein E ε4 or asymptomatic but amyloid
positive on PET scan (Langbaum et al., 2013).
616 Dementia
56.5 FUTURE STRATEGIES TO DELAY
EMERGENCE OF AD
As hypotheses on the pathophysiology of AD emerges
from epidemiological research in human populations,
post-mortem and biomarker studies in patients and animal
models, we will need to establish whether new therapies
can delay the onset of symptoms in asymptomatic people
at varying degrees of risk of AD. The prototype of trial
designs to establish the safety and efficacy of such thera-
pies is the 5- to 7-year studies comparing Ginkgo biloba
to placebo in elderly subjects with or without memory
complaints but no measurable impairment with incident
dementia as primary end point was noticed (Vellas et al.,
2006; DeKosky et al., 2008). Variations of this design are
possible, by enriching the study population with different
levels of risk, such as a positive family history of AD and/
or selected gene or biological markers, although enrich-
ment of a study population will limit the applicability of
findings to the population as a whole. There are also ethi-
cal considerations in using potentially harmful treatments
on persons who may never progress to dementia in their
lifetime (Peters et al., 2013).
Simultaneous multiple interventions may be required
to obtain benefit in AD: this is being studied using non-
pharmacological intervention such as cognitive training,
physical exercise and diet enrichment (Kivipelto et al., 2013;
Vellas et al., 2014), cognitive training and psychosocial inter-
ventions (Bier et al., 2014). The combination of pathological
factors in AD (amyloid toxicity, tau pathology, inflamma-
tory responses) may require combinations of drugs in a way
similar to cancer chemotherapy. This will need to be care-
fully thought through with participation of clinical trialists,
regulators and patients’ representatives.
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 4
Part    

The Overlap and Interaction

between Alzheimer’s Disease and
Cerebrovascular Disease

57 Vascular factors and Alzheimer’s disease 619

Robert Stewart

Vascular factors and Alzheimer’s disease
ROBERT STEWART
57.1 VASCULAR FACTORS IN
ALZHEIMER’S DISEASE
The increasing acceptance of vascular factors in Alzheimer’s
disease (AD) has challenged traditional dementia sub-­
classification. In particular, the assumption that AD and
vascular dementia are always distinguishable clinical disor-
ders in late-onset dementia has become untenable because
of the large pathological overlap and poor correlations
between diagnosis and pathology. The sub-classification
of dementia according to presumed Alzheimer or vascular
aetiology emerged in the 1960s when dementia was occur-
ring earlier in life, when treatment of vascular risk factors
was limited and when florid cerebrovascular disease was fre-
quently present at post-mortem – i.e. could be assumed to be
a single underlying cause. Dementia cases today, particularly
in high-income nations, are arising much more frequently
in later old age (e.g. ninth and tenth decades) where mixed
pathology is the norm. Developments in neuroimaging have
been a mixed blessing: the ability to detect more minor levels
of vascular disturbance is undoubtedly useful in investigat-
ing causal pathways in a research context; however, detect-
able ‘abnormalities’ are now more likely to be coincidental
than causal, particularly in older age groups, which needs to
be borne in mind in clinical decision making.
‘Vascular dementia’ as a diagnosis implies a single cause
and a discrete outcome. However, this has become hard
to sustain as a useful entity because of evidence that vas-
cular factors frequently influence dementia occurrence in
combination with other pathology (principally AD) – i.e.
because most dementia is ‘mixed’. The fact that people can
be identified with ‘pure’ AD or vascular dementia does not
support separate diagnoses if most cases sit somewhere in
the middle with combinations of underlying pathologies.
Cerebrovascular disease might influence the course of
dementia or its manifestations but would be better described
as a comorbidity (dementia with cerebrovascular disease)
57
rather than an assumed sole underlying cause (vascular
dementia or ‘vascular neurocognitive disorder’). Depressive
disorder after bereavement may have different features from
depression occurring in other circumstances, but this does
not mean that ‘bereavement depression’ is necessarily help-
ful as a diagnosis.
A more fundamental challenge to understanding the
role of vascular factors in AD is the limited interface
between risk factor outcome research and research into
underlying causal pathways. AD can be considered as, in
effect, two disorders – first, a process of nerve cell death
with particular appearances at a cellular level, which can
only be observed at autopsy, and the second, a clinical dis-
order characterized by its symptoms and clinical course.
AD the pathological disorder is likely to be have been
present for a decade or two before AD the clinical disorder
becomes apparent. However, it is important to bear in mind
that sizeable numbers of people have significant Alzheimer
pathology with no clinical evidence of dementia and/or
preserved cognitive function (Neuropathology Group of
the Medical Research Council Cognitive Function and
Ageing Study, 2001; Jack et al., 2014). Furthermore, these
pathological changes more poorly predict dementia in
later old age despite similar associations with cerebral
atrophy (Savva et al., 2009), suggesting that links between
‘traditional’ pathologies and cognitive decline are more
complex than originally envisaged.
57.2 VASCULAR FACTORS AND
CLINICAL AD
There is a substantial body of prospective epidemiological
research supporting a role for vascular risk factors in the
aetiology of AD. Identified risk factors include large vessel
atherosclerosis as estimated by carotid ultrasound or the
ankle:brachial blood pressure index (Hofman et al., 1997),
619
620 Dementia
conventional risk factors for cerebrovascular disease such as
hypertension (Skoog et al., 1996b; Kivipelto et al., 2001), type
2 diabetes (Launer, 2009) and atrial fibrillation (Ott et al.,
1997). ‘Lifestyle’-related risk factors remain a little more con-
tentious, with reasonable evidence for raised cholesterol lev-
els (Notkola et al., 1998; Kivipelto et al., 2001; Anstey et al.,
2008; Solomon et al., 2009) and smoking (Anstey et al., 2007;
Beydoun et al., 2014; Zhong et al., 2015), but more equivocal
evidence for obesity (Gustafson et al., 2003; Hassing et al.,
2009; Albanese et al., 2015; Qizilbash et al., 2015). They also
include risk factors such as homocysteine in some studies
(Clarke et al., 1998; Seshadri et al., 2002; Beydoun et al., 2014),
insulin resistance (Kuusisto et al., 1997) and the metabolic
syndrome (Razay et al., 2007) and protective factors such as
moderate alcohol intake (Ruitenberg et al., 2002), increased
physical activity (Laurin et al., 2001; Scarmeas et al., 2009;
Beydoun et al., 2014; Blondell et al., 2014) and Mediterranean
diet (Scarmeas et al., 2009) where other causal pathways may
be involved, but whose associations with AD may have a vas-
cular component.
57.3 CHANGES IN VASCULAR RISK
FACTORS PRIOR TO DEMENTIA
There is now also substantial evidence that associations
between vascular factors and dementia change over time,
even reversing in some instances. This has been described
in most detail for blood pressure. Raised blood pressure in
midlife is associated with later cognitive impairment and
dementia (Elias et al., 1993; Launer et al., 1995). However,
this has tended to be only apparent in studies with follow-up
periods of 10 years or more. Studies with shorter follow-up
often find no association (Posner et al., 2002), and cross-
sectional studies frequently show associations between
dementia and low rather than high blood pressure (Qiu
et al., 2005). This relative hypotension also seems to become
more marked at more advanced stages of dementia (Guo
et al., 1996). Although a younger age at which blood pres-
sure is measured has been suggested as increasing the likeli-
hood of a positive association with later dementia (Qiu et al.,
2005), an analysis of 15-year follow-up data on people aged
70 at baseline also found that those with AD at the end of
the period had raised systolic blood pressure at the start of
the study but lower blood pressure by the time dementia had
developed (Skoog et al., 1996b). The interval between mea-
surement of blood pressure and ascertainment of demen-
tia therefore seems to be more important. Longitudinal
studies suggest that blood pressure declines over at least
3–6 years prior to the clinical onset of dementia (Qiu et al.,
2004; Stewart et al., 2009), as well as an exaggerated mid-
to late-life increase in blood pressure preceding this decline
(Stewart et al., 2009).
One possible explanation for this late decline in blood
pressure is that early neurodegenerative disease affects
regulating centres (Burke et al., 1994) resulting in relative
hypotension. Of relevance, relative weight loss also occurs
prior to the onset of dementia over a similar period (Stewart
et al., 2005), which may reflect similar underlying processes.
However, it is also possible that late-life hypotension might
be a consequence of earlier sustained hypertension since
dementia-associated decline was modified by antihyperten-
sive treatment in one study (Stewart et al., 2009). This has
been supported by findings from low- and middle-income
countries, where hypertension is substantially less common
and where associations between dementia and low blood
pressure were, if present at all, much weaker than those
reported in higher-income settings (Albanese et al., 2013a),
despite comparable associations with markers of weight loss
(Albanese et al., 2013b).
Associations between dementia and prior cholesterol
levels appear to show a similar pattern to those with blood
pressure – i.e. with relatively high midlife levels but rela-
tively low or normal contemporaneous levels (Notkola
et al., 1998) and declining levels as a predictor of dementia
(Solomon et al., 2007). One study found that this decline
occurred approximately 10–15 years prior to the clinical
onset, and then followed a parallel course (Stewart et al.,
2007), suggesting that a fall in cholesterol levels might be
a marker of another event (e.g. inflammatory or infective)
associated with very early AD pathology, although this find-
ing requires replication and further investigation. Changes
in folate, B12 and homocysteine levels have also been
described around the clinical onset of dementia (Kim et al.,
2008), so the general picture emerges of a range of physi-
cal changes occurring around this time that do need to be
borne in mind in clinical settings when diagnoses are being
assigned and pre-existing risk factors evaluated (because
these earlier risk factors may now no longer be apparent).
From a research perspective there are two key implications:
(1) a need for further investigation of ‘frailty’ and the extent
to which dementia is linked with wider accelerated ageing
processes and (2) caution about inferring causality from
short-term predictive relationships.
57.4 INTERACTIONS WITH APOE
GENOTYPE
The apolipoprotein E (APOE) e4 allele was first recognized
for its associations with cholesterol metabolism and in some
studies has been associated with stroke (Margaglione et al.,
1998; McCarron et al., 1999). However, there has been no
evidence that cholesterol levels or other vascular factors
explain the association between e4 and AD (Slooter et al.,
1999; Prince et al., 2000). The focus instead has shifted to
investigating interactions between vascular factors and e4
as risk factors, although findings have been conflicting.
One community study found that atherosclerosis was more
strongly associated with AD in the presence of APOE e4
(Hofman et al., 1997), but later examinations in the same
study did not support this (Slooter et al., 1999), although

other studies have reported similar interactions for cerebro-
vascular events (Johnston et al., 2000) and atherogenic diet
(Laitinen et al., 2006). On the other hand, insulin resistance
and smoking have been found to be more strongly associ-
ated with AD in people without e4 (Kuusisto et al., 1997; Ott
et al., 1998; Zhong et al., 2015), and because interactions are
frequently not reported when absent, it is difficult to exclude
publication bias.
57.5 POTENTIAL UNDERLYING
MECHANISMS – THE ROLE OF
STROKE AND CEREBROVASCULAR
DISEASE
To what extent are the associations between vascular risk
factors and dementia accounted for by stroke or subclinical
cerebrovascular disease? Most studies of AD as an outcome
have divided these cases into those with and without clini-
cal evidence of co-occurring cerebrovascular disease, and
most have found that associations with vascular risk factors
remain in the less mixed group. An exception may be atrial
fibrillation, which appears to be particularly linked with
stroke-associated dementia (Ott et al., 1997; Kwok et al.,
2011). Furthermore, studies of clinical stroke and cogni-
tive impairment or dementia have tended to support mixed
pathology. Although dementia is unusual following a sin-
gle stroke (Srikanth et al., 2004; Pendlebury and Rothwell,
2009), post-stroke dementia frequently follows an AD-like
clinical course (Kokmen et al., 1996) and post-stroke cogni-
tive decline is more strongly predicted by medial temporal
atrophy than the level of cerebrovascular disease (Firbank
et al., 2012). Furthermore, a history of pre-stroke cognitive
decline is present in many cases of post-stroke dementia
(Hénon et al., 2001); cognitive impairment is a risk factor for
later first onset of stroke (Ferucci et al., 1996). Post-stroke
dementia in turn predicts an increased risk of stroke recur-
rence (Moroney et al., 1997). These findings suggest that
the stroke episode itself, although undoubtedly having an
impact on cognitive function, may frequently occur in the
context of more insidious and gradual decline, suggesting
co-occurring AD in a substantial number of cases. This pic-
ture may change over the period following a stroke, with
early cases of dementia following an AD-like picture and
later cases showing a more typical vascular dementia syn-
drome (Altieri et al., 2004).
There is substantial evidence that vascular and
Alzheimer pathologies frequently co-occur. A ­community-
based neuropathological study found that vascular pathol-
ogy was frequently present in dementia and that ‘pure’ AD
occurred only in approximately 20% of cases (Fernando
et al., 2004). In life, white matter hyperintensities (WMHs)
on magnetic resonance imaging (MRI) are frequently
found in association with AD, although this is by no means
a characteristic feature. Arteriosclerotic changes are often
seen in association with white matter alterations, and
Vascular factors and Alzheimer’s disease 621
ischaemia due to small-vessel occlusion or hypoperfusion
may underlie the demyelination and neuronal loss also
observed. Whatever the pathology, WMHs clearly repre-
sent subclinical cerebrovascular disease in many cases, as
they are associated with other risk factors for cerebrovas-
cular disease such as hypertension (Breteler et al., 1994b;
Liao et al., 1997; Dufouil et al., 2001), smoking (Liao et al.,
1997), hypercholesterolaemia (Breteler et al., 1994b) and
atherosclerosis (Bots et al., 1993). In community samples,
they are associated with worse cognitive function (Breteler
et al., 1994a; Kuller et al., 1998) in people both with and
without dementia (Skoog et al., 1996a). However, although
WMHs on post-mortem imaging were found to improve
the prediction of dementia in life (Fernando et al., 2004),
they are common findings in older populations and may
be present at an apparently severe degree without detect-
able evidence of cognitive impairment (Fein et al., 1990).
WMHs, therefore, appear to be insufficient in isolation to
give rise to dementia and are likely to require interactions
with other pathology.
57.6 POTENTIAL UNDERLYING
MECHANISMS – VASCULAR
PATHOLOGY IN AD
Epidemiological research, as described, supports a role for
conventional vascular risk factors in the aetiology of clin-
ical AD. Parallel neurobiological research has suggested
that vascular processes may be an important feature of
AD at a pathological level. Traditionally, research into the
role of amyloid in AD has focused on its deposition in
parenchymal neuritic plaques. However, other pathology
associated with the disorder has long been recognized.
Cerebral amyloid angiopathy (CAA) describes the depo-
sition of β-amyloid, among other proteins, in the walls
(vascular smooth muscle cell layer) of cortical vessels.
CAA increases with age and is associated with dementia
in population-based studies (Keage et al., 2009). It is also
recognized to be a risk factor for cerebrovascular disorders
such as small and large vessel haemorrhage, leukoenceph-
alopathy and infarction and is a feature of some familial
early-onset dementia syndromes. CAA is therefore a fea-
ture of AD and was also associated with cognitive impair-
ment in a community-based autopsy series (Pfeiffer et al.,
2002). One possible mechanism underlying its role in AD
is that impaired amyloid clearance across the blood–brain
barrier (potentially influenced by APOE genotype) may
give rise to CAA, which in turn compromises vessel wall
integrity and gives rise to cerebrovascular disorders, fur-
ther exacerbating blood–brain barrier function and AD
pathology (Bell and Zlokovic, 2009; Burgmans et al.,
2013). APOE e4 has also been proposed as underlying at
least some of the observed co-occurrence of small vessel
disease and vascular amyloid deposition, in combination
with blood–brain barrier disturbance (Grinberg and Thal,
622 Dementia
2010), and microbleeds have been suggested as a common
consequence (Hommet et al., 2011). Vascular abnormali-
ties in AD are not restricted to arterial and arteriolar amy-
loid deposition, but are also seen in cerebral microvessels
and capillaries. Microangiopathic changes include base-
ment membrane thickening and collagen accumulation
(Farkas et al., 2000), as well as smooth muscle cell irregu-
larities, endothelial degeneration and other abnormalities
(Kalaria and Skoog, 2002). Underlying causal pathways
might include toxic effects of accumulating amyloid
(Smith and Greenberg, 2009) possibly exacerbated by the
microangiopathy itself (de la Torre and Mussivand, 1993;
Preston et al., 2003).
57.7 POTENTIAL UNDERLYING
MECHANISMS – PATHWAYS FOR
VASCULAR ‘INDUCTION’ OF AD
The neuropathological findings summarized above suggest
that vascular abnormalities are a feature of AD pathology
and may be important in its clinical expression. Several
pathways have been proposed, which could potentially
explain an association between vascular risk factors and AD
and which concern direct causal links at the level of patho-
logical processes:
Ischaemic injury and amyloid deposition: β-amyloid
production appears to be a non-specific response to
cerebral trauma but has been described in particular
in the hippocampi of rodents after severe but tran-
sient ischaemia (Kogure and Kato, 1993), providing a
potential link between ischaemia/infarction and AD
pathology (Pluta et al., 2013).
Inflammation: Inflammatory processes are important
in mediating cerebral damage following stroke
(Emsley and Tyrrell, 2002). Inflammation is also
an important feature of AD pathology (Halliday et
al., 2000) and might underlie links between the two
processes.
The blood–brain barrier: Increased permeability of the
blood–brain barrier has been found in association
with transient ischaemia, and this has been suggested
to underlie both perivascular amyloid deposition and
white matter changes (Grinberg and Thal, 2010).
Abnormal protein glycation: Advanced glycation end
products (AGEs) are metabolic oxidation products
associated with diabetes and hyperglycaemia (Vlassara
et al., 1992). Their associations with ­neurofibrillary
tangles and neuritic plaques provide a potential
connection between diabetes and AD (Stewart and
Liolitsa, 1999), although more recent attention has
also focused on the potential role of the AGE ­receptor,
which also transports amyloid-β from the blood to
the brain, and its potential regulation in hypo- and
hyperglycaemic states (Prasad et al., 2014). Peripheral
AGEs have been found to be associated with cognitive
impairment and decline, supporting a relationship
(Yaffe et al., 2011).
57.8 POTENTIAL UNDERLYING
MECHANISMS – EXACERBATION
OF COGNITIVE IMPAIRMENT AND
ACCELERATED AGE OF ONSET
The mechanisms above concern direct influences of
vascular factors on the pathological processes that are
believed to underlie AD. However, clinical AD might still
be ‘caused’ without any direct interaction at a pathologi-
cal level and instead by interaction in clinical manifesta-
tions. Alzheimer pathology develops slowly: possibly over
10–20 years or more. The chance of someone developing
dementia therefore depends a great deal on the extent to
which a given level of pathology affects cognition and
on the extent to which a person can compensate for this.
Alzheimer pathology begins in the hippocampus and
manifests in its early stages as declining memory func-
tion. Mild levels of cerebrovascular disease on the other
hand would be expected to exert most damage on deep
white matter and on fronto-­subcortical connections. The
consequent disruption of executive functions such as
selective attention and mental flexibility may be enough
to ‘unmask’ early AD, which would not otherwise have
become apparent for several years. Vascular factors may
therefore accelerate the age of onset of clinical AD and
precipitate a dementia syndrome at relatively early patho-
logical stages.
57.9 POTENTIAL UNDERLYING
MECHANISMS – EFFECTS ON
‘FUNCTIONAL RESERVE’
The ‘onset’ of dementia is defined, at least in research set-
tings, as the point where declining cognitive function
starts to interfere with daily functioning. This is an unreli-
able definition of ‘incidence’ since it involves considerable
subjective judgement on the part of the participant, their
family and the research worker. It also assumes a process
that can be isolated from all the other factors influencing
daily functioning in older people. A given level of cognitive
impairment may be more likely to be classified as problem-
atic if daily function is already impaired – e.g. because of
motor system impairment due to cerebrovascular disease.
Or, from the opposite perspective, a person in good physical
health may be able to sustain a greater degree of cognitive
decline before this can be said to be problematic. Clearly,
cerebrovascular disease may have an influence on this com-
ponent of ‘reserve’.

57.10 COMMON UNDERLYING
FACTORS
Associations between vascular factors and AD need not
imply direct causal links between the two but might, at
least in part, arise from common underlying processes.
APOE genotype has been considered in this respect,
although, as discussed earlier, it has not been found to
explain substantially the co-occurrence of cerebrovas-
cular disease and AD. Both AD and cerebrovascular
disease are ‘disorders of ageing’ – that is, they become
more common with increased age. However, ‘ageing’ as
a process is not synonymous with increased chronologi-
cal age and there is substantial individual variation in the
physiological changes that occur in the transition from
mid- to late life. ‘Ageing’ is likely to be influenced by a
variety of factors, both genetic and acquired. Many of
these are unknown – e.g. genetic factors common to dis-
eases of ageing – and others may be unquantifiable, such
as lifetime exposure to oxidative stress. Dementia is con-
ventionally emphasized as a disorder that is distinct from
‘normal ageing’. However, it would be surprising if there
were not processes that mediate vulnerability to ageing
processes whether these are experienced in the brain
parenchyma or in the vasculature. Finally, both vascular
disorders and AD can be said to have common origins
in social adversity: increased risk of AD being associated
with lower education and ‘cognitive reserve’; cardiovas-
cular risk factors known to track with social disadvan-
tage across the life course. These processes are difficult to
evaluate directly; however, they do predict that societies
with improving socio-economic status will experience
dementia with a later onset, and lower age-specific preva-
lence, for which there is at least some emerging evidence
(Matthews et al., 2013).
A more specific factor that might link both vascular dis-
ease and AD is insulin resistance, recognized to underlie the
clustering of vascular disorders such as hypertension, type 2
diabetes mellitus and hypercholesterolaemia (Reaven, 1988),
all of which have been found to be associated with AD, as
mentioned. Insulin levels themselves could also have direct
effects on cognitive function, given that insulin receptors
are dense in the hippocampus (Marks et al., 1991), although
the role of insulin in brain function remains to be elucidated
(Gray et al., 2014). Several epidemiological studies have inves-
tigated markers of insulin resistance in association with
dementia/AD risk and findings include associations with
hyperinsulinaemia (Kuusisto et al., 1997; Luchsinger et al.,
2004; Muller et al., 2007), metabolic syndrome (Razay et al.,
2007) and impaired midlife insulin secretion (Rönnemaa et
al., 2008). One potential causal link is in competition between
insulin and amyloid beta for insulin degrading enzyme (Craft
and Watson, 2004; Qiu and Folstein, 2006), but empirical evi-
dence for mediating pathways remains lacking.
Vascular factors and Alzheimer’s disease 623
57.11 DIRECTION OF CAUSE AND
EFFECT
Since vascular risk factors emerge in midlife and a consid-
erable period before AD incidence begins to increase, it is
generally assumed that any causal processes are directed
from the vascular risk factor to AD. However, this does not
exclude additional adverse effects of AD on the vascula-
ture at a later stage. Links between vascular and Alzheimer
pathology have been described above and may be complex
and bidirectional. Vascular factors might, therefore, be
both a cause and a consequence of AD. At a clinical level,
it is likely that worsening cognitive function due to early
AD may have adverse effects on risk for vascular disease,
particularly through difficulties with treatment adherence
because of declining cognitive function, creating a vicious
cycle of decline. This has been suggested for diabetes self-
management (Tran et al., 2014), with some supportive evi-
dence cited below, but remains under-investigated for other
risk factors.
57.12 IMPLICATIONS FOR PREVENTING
DEMENTIA
This chapter has focused on evidence for the involvement of
vascular factors in AD, and on processes that might underlie
these associations. Clearly, there are potentially important
implications for both prevention and treatment of dementia.
A reduction in vascular risk across a population would in the-
ory reduce the risk of later dementia, whether vascular risk
factors were acting on AD pathology or reducing ­cognitive/
functional reserve. However, it is doubtful whether the
effectiveness of this approach can ever be demonstrated in a
standard randomized controlled trial design given the very
long period over which the risk factors may exert their effect.
This is likely to be particularly the case for hypertension and
may well account for the lack of evidence concluded by the
most recent Cochrane review of antihypertensive treatment
to prevent cognitive impairment and dementia for people
without cerebrovascular disease (McGuinness et al., 2009b).
The same challenge could explain similarly negative find-
ings for dementia prevention trials of statins (McGuinness
et al., 2009a). Of preventative interventions for cognitive
decline, increased physical activity currently has the most
support from randomized controlled trials (Kramer et al.,
1999; Lautenschlager et al., 2008).
Prevention of cognitive decline in diabetes is a more read-
ily assessable objective, although evidence is still lacking.
Cognitive impairment has been found to be associated with
earlier age of onset, longer duration, insulin treatment and
presence of complications (Roberts et al., 2008), and higher
HbA1c has been associated with cognitive impairment in
people with diabetes (Cukierman-Yaffe et al., 2009; Yaffe
624 Dementia
et al., 2012). In contrast, potential risks of hypoglycaemia
have been highlighted (Dominquez et al., 2010), and severe
hypoglycaemic episodes have been found to be a risk factor
for dementia incidence (Whitmer et al., 2009). More specifi-
cally, a two-way relationship was found in the Health ABC
Study (Yaffe et al., 2013) with hypoglycaemic episodes both
predicting and being predicted by dementia. In the Action
to Control Cardiovascular Risk in Diabetes–Memory IN
Diabetes (ACCORD-MIND) trial of intensive glycaemic
control in type 2 diabetes mellitus, no difference between
randomization groups was found in the primary cognitive
outcome (Launer et al., 2011), although total brain volume
was higher in the intervention group, and further analysis
indicated intervention-associated deceleration in a particular
(frontal and temporal) distribution of volume loss that was
also associated with longer duration of diabetes, but not with
HbA1c (Erus et al., 2015). Cognitive decline in the full cohort
was predicted by depression (Sullivan et al., 2013) and reti-
nopathy (Hugenschmidt et al., 2014), but baseline cognitive
impairment also predicted worse diabetes outcomes: specifi-
cally, higher risk of severe hypoglycaemia (Punthakee et al.,
2012). The picture in diabetes, therefore, appears to be one
of bidirectional, potentially mutually exacerbating effects of
poor control leading to cognitive impairment leading to fur-
ther worsening of control.
57.13 IMPLICATIONS FOR TREATING
DEMENTIA
Implications for treating AD (i.e. reducing cognitive/­
functional decline after diagnosis) through modifying vas-
cular risk depend on whether there are direct effects on
neurodegenerative processes (i.e. whether vascular risk fac-
tors continue to influence cognitive decline rather than sim-
ply advancing the age of ‘dementia’ onset). The presence of
cerebrovascular disease has been associated with slower pro-
gression of dementia (Bruandet et al., 2009), as has comorbid
diabetes (Mielke et al., 2007; Sanz et al., 2009), which might
indicate that these factors have precipitated the clinical
manifestations of AD at a relatively early stage of pathology.
However, other vascular risk factors such as atrial fibrilla-
tion, hypertension and angina have been found to be associ-
ated with faster dementia progression (Mielke et al., 2007)
and the picture remains unclear and under-­investigated.
Furthermore, a recent review concluded that randomized
controlled trial evidence is currently insufficient, principally
on grounds of methodology, to support treatment of vascular
risk factors as an intervention for slowing dementia progres-
sion (Valenti et al., 2014). However, a commonly neglected
implication concerns the care of people with dementia, who
will commonly have disorders such as hypertension or dia-
betes that require pharmacotherapy and medical review.
Neurodegenerative processes themselves may have effects on
factors such as blood pressure and body composition, alter-
ing susceptibility to drug effects and side effects, and require
close attention. In terms of formal and informal social care,
people with AD will often also have clinically apparent cere-
brovascular disease that may already be affecting non-cog-
nitive areas of functioning, increasing the level of support
required. Vascular factors may have an important impact
on quality of life for people with AD and their caregivers,
regardless of whether relationships with AD reflect cause,
effect or coincidence. This aspect of the interface continues
to receive scant attention but is clearly an important consid-
eration in day-to-day clinical practice.
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 5
Part    

Cerebrovascular Disease and Cognitive

Impairment

58 What is vascular cognitive impairment? 630

Timo Erkinjuntti, Leonardo Pantoni and Susanna Melkas
59 The neuropathology of vascular dementia 643
Raj N. Kalaria
60 Therapeutic strategies for vascular cognitive disorders 660
Gustavo C. Román

What is vascular cognitive impairment?
TIMO ERKINJUNTTI, LEONARDO PANTONI AND SUSANNA MELKAS
58.1 VASCULAR BURDEN OF THE
BRAIN – BACKGROUND
As early as 1896, ‘arteriosclerotic dementia’ (referring to vas-
cular dementia [VaD]) was separated from ‘senile dementia’
(referring to Alzheimer’s disease [AD]). Alois Alzheimer
together with Otto Binswanger recognized the hetero-
geneity of VaD by describing four clinical–­ pathological
­subtypes of VaD (Roman, 2001), as well as vascular lesions
in AD. Nevertheless, until the 1970s cerebral atherosclero-
sis causing chronic decrease of blood supply to the brain
was thought to be the commonest cause of dementia, and
AD was regarded as a rare cause affecting only younger
patients. Tomlinson et al. (1970) reinvented AD as the most
frequent cause of dementia. Hachinski et al. (1974) used the
term multi-infarct dementia (MID) to describe the mecha-
nism by which they considered VaD was produced. As the
pendulum swung in the direction of AD, vascular forms of
dementia became relegated to a position of relative obscu-
rity (Brust, 1988).
During the 1980s and the early 1990s almost all cere-
brovascular disease (CVD) injury leading to dementia was
ascribed to large cortical and subcortical infarcts (so-called
MID) (Erkinjuntti and Hachinski, 1993). The concept of
VaD was introduced to refine further the description of
dementias caused by infarcts of varying sizes, including the
smaller lacunar and microinfarcts, as well as white matter
lesions (WMLs) (Roman et al., 1993). VaD appropriately
defined a group of heterogeneous dementia syndromes of
CVD origin of which the cortical and subcortical vascular
disease were considered as important subtypes (Erkinjuntti
and Hachinski, 1993; Roman et al., 1993, 2002). Although
this was an important step forward, it was not adequate
to fully describe the vascular causes of early cognitive
impairments.
The recognition of AD as the commonest cause of
dementia led to the development of operational criteria for
630
58
the diagnosis of dementia in general. The criteria included
early and prominent memory loss, progressive cognitive
impairment, evidence of irreversibility and presence of
cognitive impairment sufficient to affect normal activities
of daily living (ADLs) (McKhann et al., 1984; Erkinjuntti
et al., 1997). The characteristic episodic memory impair-
ment apparent in AD is attributed to atrophy of the medial
temporal lobe. In contrast, CVD lesions do not have the
same regional predilection. The emphasis of the current
Alzheimer type dementia criteria limited to the episodic
memory impairment underestimates the vascular burden
on cognition. The conventional dementia syndrome con-
cept recognizes the vascular burden of the brain too late,
when often opportunities to prevent and treat are lost.
Accordingly, it was suggested that the ‘Alzheimerized’
dementia concept should be abandoned in the setting of
CVD, and indeed this was one of the motives behind the
development of the broader category of vascular cogni-
tive impairment (VCI) (Hachinski, 1990; Bowler and
Hachinski, 1995; Pasquier and Leys, 1997; O’Brien et al.,
2003; Roman et al., 2004; Moorhouse and Rockwood,
2008), sometimes also referred as vascular cognitive disor-
der (Roman et al., 2004).
58.2 THE MODERN CONCEPT OF VCI
Now VaD has come full circle with the resurgence of inter-
est in the whole spectrum of vascular causes of cognitive
impairment and dementia (Hachinski, 1990; O’Brien et al.,
2003). The new term VCI recognizes the broad spectrum of
cognitive and behavioural changes associated with vascu-
lar pathology (Bowler and Hachinski 1995; O’Brien, et al.,
2003; Moorhouse and Rockwood 2008).
Evidence of complex interactions between vascular aetiolo-
gies, changes in the brain, host factors and cognition prompted
formulation of the new concepts (Chui, 1989; Tatemichi,
1990; Erkinjuntti and Hachinski, 1993; Desmond, 1996;
 What is vascular cognitive impairment? 631

Pasquier and Leys, 1997), as well as underlying the heteroge-
neity of VaDs and recognition of the small vessel ischaemic
subcortical vascular disease and dementia (SIVD) as a con-
cept applicable in clinical studies (Roman, 1985; Erkinjuntti,
1987; Erkinjuntti et al., 2000; Erkinjuntti and Pantoni, 2000;
Roman et al., 2002). The facts that vascular factors relate to
and coexist with AD (Kalaria and Ballard, 1999; Skoog et al.,
1999; Kivipelto et al., 2006) were important too.
Accordingly, the modern concept of VCI aims to cover the
spectrum of cognitive impairments, as well as the spectrum
of the aetiologies of vascular burden of the brain related to
cognitive impairment (O’Brien et al., 2003; Bowler, 2007;
Hachinski, 2008; Moorhouse and Rockwood, 2008). The
modern concept of VCI relates to important shifts in think-
ing (Hachinski, 2008):
1. Shift from arbitrary thresholds, such as the AD
­dementia threshold, to a continuum of cognitive
impairment
2. Shift from the late stages to the early stages of disease
3. Shift from the effects to the causes
The evolution of the new VCI concept is similar to the
more recent evolution in degenerative causes of memory
diseases, i.e. the new research criteria for the amnestic pro-
drome of AD (Dubois et al., 2007).
The cognitive syndrome of VCI encompasses all levels
of cognitive decline, from the earliest deficits to a severe
and broad dementia-like cognitive syndrome (Bowler et al.,
1999; O’Brien et al., 2003). VCI cases that do not meet the
criteria for dementia can also be labelled as VCI with no
dementia or vascular cognitive impairment no demen-
tia (CIND) (Rockwood et al., 2000). These patients have
also been labelled as vascular mild cognitive impairment
(vMCI) in a similar way to that of amnestic mild cognitive
impairment (aMCI) for AD (Petersen et al., 2002). Early
clinical stages of VCI starting from pre-dementia may be
recognized only in a part of patients with VaD, typically in
those with small vessel disease dementia. In other patients,
a single step from the brain-at-risk stage to dementia may
occur (Pantoni et al., 2009) (Figure 58.1).
VCI refers to all aetiologies of CVD including vascular
risk factors that can result in brain damage leading to cog-
nitive impairment. VCI may include cases with cognitive
impairment related to hypertension, diabetes or athero-
sclerosis, transient ischaemic attacks, cortico-subcortical
infarcts, silent infarcts, strategic infarcts, small vessel dis-
ease with WMLs and lacunae, as well as AD pathology with
coexisting CVD. VCI can also encompass those patients
who survive intracerebral and other intracranial haemor-
rhages but are left with residual cognitive impairment.
58.3 VCI PATHOPHYSIOLOGY
The pathophysiology incorporates interactions between vas-
cular aetiologies (CVDs and vascular risk factors), changes
in the brain (infarcts, WMLs, atrophy, AD pathology) and
host factors (age, education) (Chui, 1989; Tatemichi, 1990;
Erkinjuntti and Hachinski, 1993; Desmond, 1996; Pasquier
and Leys, 1997; O’Brien et al., 2003) (Figure 58.2). Aetiologies
of VCI include both CVD and risk factors (Table 58.1).
58.3.1 CEREBROVASCULAR DISEASES
CVDs include small vessel disease, large vessel disease and
strategic infarcts that may be either cortical or subcortical.
CVDs also include haemorrhage, vascular malformations,

Post-stroke dementia Small vessel dementia

VaD

VCI - no dementia

Perisymptomatic
stage

Brain at risk
(vascular risk factors)

Figure 58.1 The pyramid of vascular cognitive impairment (VCI). (From Pantoni et al., Cerebrovascular Disease, 27, 191–
196, 2009.)
632 Dementia

Brain AD Host factors

pathology e.g. age
education
genetics
Vasular
aetiologies Infarcts, Cognitive
Cerebrovascular white impairment
disorders matter
Vascular risk factors lesions Dementia

Brain
atrophy

Figure 58.2 Interactions between vascular causes, brain changes and host factors in vascular cognitive impairment.

Table 58.1 Aetiologies of vascular dementia conditions due to hypoperfusion and hereditary condi-
tions (e.g. cerebral autosomal dominant arteriopathy with
CVDs
subcortical strokes and leukoencephalopathy [CADASIL])
Large vessel disease
(Erkinjuntti, 2007; Pantoni et al., 2009).
  Artery-to-artery embolism
   Occlusion of an extra- or intracranial artery
Cardiac embolic events 58.3.2 RISK FACTORS
Small vessel disease
Risk factors associated with VCI include risks for stroke
  Lacunar infarcts
and ischaemic WMLs (Basile et al., 2006). Clinically
  Ischaemic WMLs
symptomatic infarcts, clinically silent infarcts and
Haemodynamic mechanisms WMLs relate to higher dementia risk (Verdelho et al.,
Specific arteriopathies 2010). Similarly to AD, the risks for VCI may be consid-
Haemorrhages ered under demographic, vascular, genetic and ischaemic
  Intracerebral haemorrhage lesions related ­variables (Skoog, 1994; Gorelick, 1997;
   Subarachnoidal haemorrhage Skoog, 1998; Kivipelto et al., 2006). Hypoxic ischaemic
   Chronic subdural haemorrhage events giving rise to global cerebrovascular insufficiency
  Microbleeds are also important risk factors for incident dementia
Haematological factors in patients with stroke (Sulkava and Erkinjuntti, 1987;
Venous diseases Moroney et al., 1996, 1997a). Furthermore, the tradi-
Hereditary entities tional vascular risk factors and stroke are also indepen-
Risk factors dent factors for the clinical presentation of MCI and AD
Vascular (Snowdon et al., 1997; Skoog et al., 1999). The important
  Arterial hypertension independent midlife risk factors of clinical AD include
  Atrial fibrillation arterial hypertension, high cholesterol, diabetes, obesity
  Myocardial infarction and reduced physical activity among others (Skoog et al.,
   Coronary heart disease 1999; Kivipelto et al., 2006).
  Diabetes
  Generalized atherosclerosis 58.3.3 BRAIN CHANGES
  Lipid abnormalities
  Smoking Brain changes related to VCI include both ischaemic and
Demographic factors non-ischaemic factors (Tatemichi, 1990; Chui et al., 1992;
  High age Brun, 1994; Erkinjuntti et al., 1999b) (Table 58.2). Static
  Low education ischaemic lesions include arterial territorial infarct, distal
Genetic factors field (watershed) infarct, lacunar infarct, ischaemic WMLs
  Family history and incomplete ischaemic injury. Incomplete ischaemic
   Specific genetic factors injury includes focal gliosis and incomplete white mat-
Stroke-related factors ter infarctions in areas of selective vulnerability (Englund
   Type of CVD et al., 1988; Pantoni and Garcia, 1997). Functional isch-
   Site and size of infarcts aemic changes include both focal (around the ischaemic
Abbreviations: CVD, cerebrovascular diseases; WMLs, white matter
lesion) and remote (disconnection, diaschisis) effects (Shim
lesions. et al., 2006). Ischaemia relates also to atrophy without AD

Table 58.2 Brain changes in vascular dementia
Static lesions
Arterial territorial infarct
Distal field (watershed) infarct
Lacunar infarct
Ischaemic WMLs
Incomplete ischaemic injury
Microbleeds
Atrophy
Functional ischaemic changes
Focal (around the ischaemic lesion)
Remote (disconnection, diaschisis)
pathology (Vinters et al., 2000), and brain atrophy accel-
erates cognitive decline in cerebral small vessel disease
(Jokinen et al., 2012).
58.3.4 BRAIN MECHANISMS
Brain mechanisms proposed to be related to VCI include
volume of brain infarcts, number of infarcts (additive,
synergistic), site of infarcts, WMLs, other ischaemic fac-
tors (incomplete ischaemic injury, delayed neuronal death,
functional changes), atrophy and additive effects of other
pathologies (e.g. AD) (Erkinjuntti et al., 1988; Chui, 1989;
Tatemichi, 1990; Desmond, 1996; Erkinjuntti, 1999; O’Brien
et al., 2003; Kalaria et al., 2004). The relationship between
vascular factors and cognition is challenging: do the identi-
fied vascular factors cause, compound or only coexist with
the VCI syndrome? Small vessel disease with subsequent
brain atrophy may well be the cardinal origin of the main
subtypes of VCI (Erkinjuntti, 1987; Roman, 1987; Pantoni
and Garcia, 1995; Roman et al., 2002) (see Chapters 59 and
60). Another important question is whether they contribute
to the risk and clinical picture of AD (Snowdon et al., 1997).
58.3.5 ANATOMICAL BRAIN IMAGING
Computed tomography (CT) and magnetic resonance imag-
ing (MRI) studies on VaD indicate that bilateral ischaemic
lesions are of importance (Erkinjuntti and Hachinski, 1993;
DeCarli and Scheltens 2002). A summary of the interaction
between lesion and cognition in VaD includes (Erkinjuntti,
1999; Erkinjuntti et al., 1999; DeCarli and Scheltens, 2002;
Roman et al., 2002; O’Brien et al., 2003):
●● No single feature, but a combination of infarct features,
extent and type of WMLs, degree and site of atrophy, and
host factors characteristics are correlates of VCI/VaD.
●● Infarct features favouring VaD include bilaterality, mul-
tiplicity (>2), location in the dominant hemisphere and
location in the fronto-subcortical and limbic structures.
●● WML features favouring VaD are extensive WMLs
(extending periventricular WMLs and confluent to
extending WMLs in the deep WM).
What is vascular cognitive impairment? 633
●● It is doubtful that only a single small lesion could sup-
port a diagnosis of VaD. However, rare cases with pure
strategic infarcts may be exceptions.
●● Absence of CVD lesions on CT or MRI is against a
diagnosis of VaD.
Examples of MRI findings in the main subtypes of VADs
are shown in Figure 58.3.
With newer MRI techniques, such as diffusion tension
imaging (DTI), susceptibility weighted imaging (SWI) and
functional MRI, microangiopathic markers of SVD and
white matter tract integrity can be detected and followed
more accurately than before. Diffusion changes in brain
tissue that appears normal in conventional MRI associate
with cognitive decline and gradual loss of independence
(Jokinen et al., 2013).
58.4 VCI – THE SIZE OF THE PROBLEM
The size of the VCI problem can be studied by reviewing
data on (1) VCI and CIND, (2) post-stroke dementia (PSD),
(3) post-stroke cognitive impairment (PSCI), (4) VaD and
(5) AD with CVD.
58.4.1 VCI
Estimates of the population distribution of VCI and its
outcomes are influenced by the variety of definitions used
(Erkinjuntti et al., 1997; Pohjasvaara et al., 1997; Lobo et al.,
2000; Pohjasvaara et al., 2000b). For example, if AD with
CVD or the previously defined VaD with AD pathology is
included, then VCI would most certainly be the most com-
mon cause of chronic progressive cognitive impairment in
elderly people (Rockwood et al., 2000). In a Canadian study,
the prevalence of VCI (including CIND) was estimated at 5%
in people over age 65 years (90). The prevalence of vascular
CIND was 2.4%, that of AD with CVD was 0.9% and of VaD
alone was 1.5%. By comparison, the prevalence of AD with-
out a vascular component, at all ages up to age 85 years, was
5.1% and was less common than VCI (Rockwood et al., 2000).
58.4.2 POST-STROKE DEMENTIA (PSD)
The frequency of PSD varies from 12% to 32% within 3
months to 1 year after stroke (Leys et al. 2005). In the
Helsinki study, the frequency was 25% 3 months after the
incident stroke and the frequency increased with increasing
age: 19% among those aged 55–64 years and 32% in those
aged 75–85 years (Pohjasvaara et al., 1997). The incidence
of PSD increases with a longer follow-up time from 10% at
1 year to 32% after 5 years (Leys et al., 2005). A history of
stroke increases the risk of subsequent dementia by a factor
of 5 (Linden et al., 2004; Leys et al., 2005).
Determinants of PSD include high age, low education,
pre-stroke dependency and cognitive impairment including
634 Dementia
(a) (b)
(c)
(d)
Figure 58.3 Magnetic resonance imaging scans in
patients with (a) cortical vascular dementia, multi-infarct
dementia (bilateral infarcts), (b) subcortical ischaemic vas-
cular dementia (SIVD) with multiple lacunes, (c) SIVD with
confluent white matter lesions and (d) bilateral strategic
thalamic infarcts.
pre-stroke dementia (Leys et al., 2005). Risk factors of inci-
dent PSD include epileptic seizures, sepsis, cardiac arrhyth-
mias and congestive heart failure (Moroney et al., 1996;
Leys et al., 2005). In one large cohort study, the independent
clinical correlates of PSD included dysphasia, major domi-
nant stroke syndrome, history of prior CVD and low educa-
tion (Pohjasvaara et al., 1998). Brain lesion correlates of PSD
include a combination of infarcts features (volume, site),
presence of WMLs (extent, location) as well as brain atro-
phy (Pohjasvaara et al., 2000a; Leys et al., 2005). Important
critical locations include dominant hemisphere and lesions
affecting the prefrontal–subcortical circuit. Lesions mediat-
ing executive dysfunction are critical (Vataja et al., 2003).
58.4.3 POST-STROKE COGNITIVE
IMPAIRMENT (PSCI)
PSCI is a frequent, though neglected, consequence of stroke.
An example of a detailed clinical study is the Helsinki Stroke
Ageing study (Pohjasvaara et al., 1997). Cognitive impair-
ment 3 months after ischaemic stroke was present in one
domain in 62% and in two domains in 35% of patients aged
55–85 years. The cognitive domains affected included short-
term memory (31%), long-term memory (23%), constructive
and visuospatial functions (37%), executive functions (25%)
and aphasia (14%) (Pohjasvaara et al., 1997).
58.4.4 VaD
VaD, defined as the subset of VCI patients who fulfil tradi-
tional AD type dementia criteria, is considered the second
most common cause of dementia accounting for 10%–50%
cases, but this depends on the geographic location, patient
population and the clinical methods used (Lobo et al., 2000).
The prevalence of VaD ranges from 1.2% to 4.2% in persons
aged 65 years and older (Hebert and Brayne, 1995). Using
population-based identification of persons aged 65 years and
older, the European collaborative study reported that the age-
standardized prevalence of dementia was 6.4% (all causes),
4.4% for AD and 1.6% for VaD (Lobo et al., 2000). In this
study, 15.8% of all cases had VaD and 53.7% AD. However,
these studies did not estimate the size of AD with CVD
population in more detail. The incidence of VaD increases
with age, without any substantial difference between men
and women (Fratiglioni et al., 2000). The reported incidence
estimates of VaD range from 6 to 12 cases per year in 1000
persons aged 70 years and older (Hebert and Brayne, 1995).
58.4.5 AD WITH CVD
For too long the focus has been the two ‘pure’ ends of the
dementia spectrum: probable AD (McKhann et al., 1984)
and probable VaD (Roman et al., 1993). One factor has been
the need for homogenous patient populations and high ante-­
mortem diagnostic specificity for randomized clinical trials. At
the same time, combined cases, those with AD and CVD, were
neglected. Alois Alzheimer already recognized the issue of AD
with CVD, which was reinvented by Tomlinson and colleagues
(Tomlinson et al., 1970). In the seminal Newcastle series,
8%–18% of the patients had AD with CVD (Tomlinson et al.,
1970). Accordingly, Roth concluded that ‘There is evidence that
the two types of pathological change augment one another to
a statistically significant degree in the production of dementia’
(Roth, 1971). Today, based on unselected neuropathological
series of patients, we acknowledge that AD with CVD may be
the most frequent single cause leading to cognitive impair-
ment: in the brains of cognitively impaired elderly at least 50%
show combined AD and CVD changes (Roth, 1971; Snowdon
et al., 1997; Neuropathology Group, Medical Research Council
Cognitive Function and Aging Study, 2001). In addition, vas-
cular brain changes relate to a much earlier clinical presenta-
tion of the AD syndrome (Snowdon et al., 1997), and vascular
risk-factors are independent factors related to clinical expres-
sion of the AD syndrome (Kivipelto et al., 2006). Importantly,
AD and CVD can be seen as secret partners in cognitive and
brain health risks; one in every two females aged over 65 years
will have in their coming years of life either CVD, AD or AD
with CVD (Seshadri and Wolf, 2007).
58.5 WML BURDEN
WMLs, frequently detected on neuroimaging, are associ-
ated with cognitive, mood, motor and urinary disorders, all
contributing towards disability (Inzitari et al., 2007, 2009).
In particular, confluent and extensive WMLs relate to cog-
nitive decline, faster progression of disability and death
(Inzitari et al., 2009). In addition, confluent WMLs relate
to other important adverse outcomes including depression,

impaired gait and stability and urinary problems. Further,
extensive WMLs relate to the dysexecutive syndrome
(Jokinen et al., 2005). WMLs are seen as the surrogate of
small vessel disease and they relate to the SIVD syndrome,
the main subtype of progressive VCI (Erkinjuntti et al., 2000;
Roman et al., 2002; Jokinen et al., 2009a). Importantly, the
executive small vessel brain network is the largest human
endothelial organ (Roman, 2008).
58.6 MAIN SUBTYPES OF VCI
VCI encompasses many clinical features, which themselves
reflect a variety of vascular mechanisms and changes in
the brain, with different causes and neurological outcomes
(Figure 58.4). The pathophysiology is attributed to interac-
tions between vascular aetiologies (CVD and vascular risk
factors), changes in the brain (infarcts, WMLs, atrophy) and
host factors (age, education).
The main subtypes of VaD included in current classifica-
tions are small vessel disease, large vessel disease and strate-
gic infarcts that may be either cortical or subcortical (Chui
et al., 1992; Roman et al., 1993; World Health Organisation,
1993b; American Psychiatric Association, 1994; Erkinjuntti
et al., 1997; Chui et al., 2000) (Table 58.3). Hypoperfusion
dementia resulting from global cerebrovascular insuffi-
ciency is also included. Further, subtypes include haemor-
rhagic dementia, hereditary VaD (e.g. CADASIL) and AD
with CVD. The most widely used clinical diagnostic criteria
for VaD are the National Institute of Neurological Disorders
and Stroke–Association Internationale pour la Recherche et
l’Enseignement en Neurosciences (NINDS-AIREN) criteria
Arterial hypertension, diabetes, genetics, high cholesterol, heart disease.
Large vessel disease
Strategic single infarcts
Multiple infarcts
Damage to critical cortical
and subcortical structures
Figure 58.4 VCI: a heterogeneous vascular disorder; SDH, subdural haemorrhage; SAH, subarachnoidal haemorrhage;
ICH, intracerebral haemorrhage; VCI, vascular cognitive impairment.
What is vascular cognitive impairment? 635
(Roman et al., 1993). In addition, research criteria for SIVD
have also been proposed (Erkinjuntti et al., 2000).
58.6.1 LARGE VESSEL DISEASE
Large vessel disease associated VCI (cortical VaD, MID,
post-stroke VaD) relates predominantly to atherosclerotic
disease in large vessels and cardiac embolic events. It is a
syndrome related to strokes, not a disease entity, and rarely
fulfils current criteria modelled on AD type dementia. It
is characterized by predominantly cortical and cortico-
subcortical arterial territorial and distal field (watershed)
infarcts. It is traditionally characterized by a relative abrupt
onset (days to weeks), a stepwise deterioration (some recov-
ery after worsening) and a fluctuating course of cognitive
functions (Erkinjuntti, 1987; Erkinjuntti et al., 1988, 1993;
Chui et al., 1992; Roman et al., 1993). The early cognitive syn-
drome of large vessel ­disease includes some memory impair-
ment, which may be mild, and some heteromodal cortical
symptom(s) such as aphasia, apraxia, agnosia and visuospa-
tial or constructional difficulty. In addition, most patients
have some degree of dysexecutive syndrome (Mahler and
Cummings, 1991). Due to the multiple cortico-subcortical
infarcts, patients with large vessel disease associated VCI
often have additional neurological impairments (visual field
deficits, lower facial weakness, lateralized sensorimotor
changes and/or gait impairment) (Erkinjuntti, 1987).
58.6.2 SMALL VESSEL DISEASE
Small vessel disease associated VCI (SIVD) incorporates
two entities: ‘the lacunar state’ and ‘Binswanger’s disease’
(Erkinjuntti et al., 2000; Chui, 2001; Roman et al., 2002)
(Figure 58.5). Small vessel disease is characterized by lacunar
Vascular risk factors
Damage to cerebral vasculature
Multiple distinct pathologies
Small vessel disease Haemorrhage Hypoperfusion
Multiple Lacunae Chronic SDH Global (e.g. cardiac arrest)
White matter lesions SAH Hypotension
ICH
CADASIL
Final common
pathway
Damage/interruption of
Cholinergic subcortical circuits and
transmission projections
VCI
636 Dementia

Table 58.3 Vascular mechanisms, changes in the brain and clinical heterogeneity in subtypes of traditional VaD (VCI)

Cortical VaD/MID Strategic infarct VaD Subcortical ischaemic VaD/SIVD

Vascular mechanisms
Large vessel disease + + −
Cardiac embolic events + + −
Hypoperfusion + + +
Small vessel disease − + +
Changes in the brain
Arterial territorial infarct + + −
Distal field (watershed) infarct + + −
Lacunar infarct − + +
Focal, diffuse WMLs − + +
Incomplete ischaemic injury − − +
Clinical heterogeneity ++ +++ +
Abbreviations: VaD, vascular dementia; VCI, vascular cognitive impairment; MID, multi-infarct dementia; SIVD, subcortical ischaemic vascular
dementia.

Risk factors and set maintenance, as well as in abstraction (Cummings,

Small vessel change
Critical stenosis
Occlusion Hypoperfusion
Complete infarct Incomplete infarct
Lacunae White matter lesions
‘Lacunar state’ ‘Binswanger syndrome’
Subcortical VCI / SIVD
Figure 58.5 Two main pathways associated with SIVD.
infarcts, focal and diffuse ischaemic WMLs and incom-
plete ischaemic injury (Erkinjuntti, 1987; Erkinjuntti et al.,
2000; Roman et al., 2002; Pantoni, 2010). The MRI corre-
lates of small vessel disease are multiple lacunes, extensive
WMLs, perivascular spaces, microhaemorrhages and atro-
phy (Erkinjuntti et al., 2000; Wardlaw et al., 2013). The onset
is variable: as reported by Babikian and Ropper (1987), 60%
of the patients had a slow onset and only 30% had an acute
onset of cognitive symptoms; the course was gradual without
(40%) and with (40%) acute deficits and fluctuating in only
20%. There is often a clinical history of ‘prolonged transient
ischaemic attacks (TIAs)’ or ‘multiple TIAs’, which mostly
are small strokes without residual symptoms, with only mild
focal findings. Clinically, small vessel dementia is character-
ized by a subcortical cognitive syndrome plus pure motor
hemiparesis, bulbar signs and dysarthria, gait disorder,
variable depressive illness, emotional lability and deficits in
executive functioning (Pohjasvaara et al., 2003; Jokinen et al.,
2006). The early cognitive syndrome of small vessel disease is
characterized by a dysexecutive syndrome with slowed infor-
mation processing, usually mild memory deficit and behav-
ioural symptoms. The dysexecutive syndrome in small vessel
disease includes impairment in goal formulation, initiation,
planning, organizing, sequencing, executing, set shifting
1993, 1994; Jokinen et al., 2006, 2009a, 2009b). The memory
deficit in small vessel disease is usually milder than in AD
and is characterized by impaired recall, relative intact rec-
ognition, less severe forgetting and better benefit from cues.
Behavioural and psychological symptoms include depression,
personality change, emotional lability and incontinence, as
well as inertia, emotional bluntness and psychomotor retar-
dation. Neurological symptoms and signs in the early phases
of small vessel disease may include subtle episodes of mild
upper motor neurone signs (drift, reflex asymmetry, incoor-
dination), gait disorder (apractic–atactic or small stepped),
imbalance and falls, urinary frequency and incontinence,
dysarthria, dysphagia as well as extrapyramidal signs such
as hypokinesia and rigidity (Cummings, 1994; Pohjasvaara
et al., 2003).
Although stroke due to small vessel disease seems to have
a favourable short-term outcome, patients with this condi-
tion seem to have a more malignant long-term outcome
compared with patients with other stroke subtypes (Melkas
et al., 2011). This probably relates on the one hand to the
damage in the fronto-subcortical pathways that are espe-
cially vulnerable in small vessel disease and on the other
hand to the systemic nature of small vessel disease.
58.6.3 STRATEGIC INFARCT DEMENTIA
Depending on the precise location, the time course and clini-
cal features of strategic infarct dementia are highly variable.
Strategic infarct dementia is characterized by focal, often
small, ischaemic lesions involving specific sites critical for
higher cortical functions. The cortical sites include the hip-
pocampal formation, angular gyrus and cingulate gyrus.
The subcortical sites leading to impairment are the thala-
mus, fornix, basal forebrain, caudate, globus pallidus and
the genu or anterior limb of the internal capsule (Tatemichi,
1990; Erkinjuntti and Hachinski, 1993).

58.6.4 AD WITH CVD
Accumulating evidence shows that different vascular fac-
tors, including hypertension and stroke, increase the risk
of AD and frequently CVD coexists with AD (Kalaria and
Ballard, 1999; Skoog et al., 1999; DeCarli, 2004; de la Torre,
2004). This overlap is increasingly important in the oldest
old (>85 years). Clinical recognition of patients with AD
and CVD is problematic as evident from recent neuropatho-
logical series (Snowdon et al., 1997; Neuropathology Group,
Medical Research Council Cognitive Function and Aging
Study, 2001; Schneider et al., 2007). These patients exhibit
a history of vascular risk and signs of CVD, providing a
clinical picture that is close to VaD. However, fluctuating
course and history of strokes were the only items differenti-
ating AD from AD with CVD (Moroney et al., 1997b). AD
with CVD patients may present clinically either as AD with
evidence of CVD lesions on brain imaging or with features
of both AD and VCI (Rockwood et al., 1999). It remains a
major clinical undertaking to distinguish dementia due to
AD from that arising from CVD in view of the considerable
overlap (Langa et al., 2004). Both result in cognitive, func-
tional and behavioural impairments. There are also shared
pathophysiological mechanisms (e.g. WMLs, delayed neu-
ronal death and apoptosis) (Pantoni and Garcia, 1995;
Snowdon et al., 1997; Skoog et al., 1999), associated risk fac-
tors (e.g. age, education, arterial hypertension) (Skoog et al.,
1999; DeCarli, 2004) and neurochemical deficits, includ-
ing cholinergic neuronal dysfunction (Wallin et al., 2002;
Roman and Kalaria, 2006). Based on the findings from the
Nun Study, it has been further suggested that CVD may play
an important role in determining the presence and severity
of clinical symptoms of AD (Snowdon et al., 1997). A better
solution to recognizing patients with AD plus CVD would
be to discover reliable biological markers of clinical AD.
Potential markers include early prominent episodic mem-
ory impairment, early and significant medial temporal lobe
atrophy on MRI, bilateral parietal hypoperfusion on single
photon emission CT or positron emission tomography,
findings in brain amyloid imaging or low concentrations
of cerebral spinal fluid amyloid-β42 (CSF Aβ42) peptide
(Dubois et al., 2007).
58.7 CLINICAL CRITERIA FOR VCI
Since the 1970s, several general clinical criteria for VaD
have been used (Pohjasvaara et al., 1997). Widely used cri-
teria for VaD include the Diagnostic and Statistical Manual
of Mental Disorders, 4th Edition (DSM-IV) (World Health
Organisation, 1993a; American Psychiatric Association,
1994), International Statistical Classification of Diseases,
10th Revision (ICD-10) (World Health Organisation,
1993b), the Alzheimer’s Disease Diagnostic and Treatment
Center (ADDTC) criteria (Chui et al., 1992) and the NINDS-
AIREN criteria (Roman et al., 1993).
What is vascular cognitive impairment? 637
DSM-5 was launched in 2013, introducing the concepts
of mild and severe neurocognitive disorders, the latter cor-
responding to dementia (American Psychiatric Association,
2013). One of the subtypes of neurocognitive disorder is vas-
cular neurocognitive disorder; among other subtypes there
are AD and frontotemporal disorder. The International
Society for Vascular Behavioral and Cognitive Disorders
(VASCOG) has launched its own definition of vascular
cognitive disorder based on DSM-5 criteria (Sachdev et al.,
2014), but a compact definition with capacity to standardize
research and clinical practice still remains to be formulated.
The two cardinal elements implemented in the clinical
criteria for VaD are the definition of the cognitive syndrome
of dementia (Erkinjuntti et al., 1997) and the definition of
the vascular cause of the dementia (Wetterling et al., 1996;
Pohjasvaara et al., 2000b). Variation in defining these two
critical elements has caused different definitions in use to
give different point prevalence estimates, identify different
groups of subjects and consequently also identify different
types and distribution of brain lesions. Further, this hetero-
geneity may have been a factor in negative results in prior
clinical trials on VaD (Inzitari et al., 2000). All the clini-
cal criteria used are consensus criteria, which are neither
derived from prospective community-based studies on vas-
cular factors affecting the cognition nor based on detailed
natural histories. All the cited criteria are mainly based on
the ischaemic infarct concept and designed to have high
specificity, although they have been poorly implemented
and validated.
The general NINDS-AIREN criteria include (1) empha-
size heterogeneity of VaD syndromes and pathologic sub-
types including not only ischaemic stroke but also other
causes of CVD including cerebral hypoxic–ischaemic
events, WMLs and haemorrhagic strokes; (2) recognize
the variability in clinical course, which may be static,
remitting or progressive; (3) highlight the question of the
location of ischaemic lesions and the need to establish a
causal relations between vascular brain lesions and cogni-
tion; (4) recognize the need to establish a temporal rela-
tionship between stroke and dementia onset; (5) include
specific findings early in the course that support a vascular
rather than a degenerative cause; (6) emphasize the impor-
tance of brain imaging to support clinical findings and
(7) give value of neuropsychological testing to document
impairments in multiple cognitive domains. The NINDS-
AIREN criteria handle VaD as a syndrome with different
aetiologies and different clinical manifestations and not
as a single entity and list possible subtypes to be used in
research studies. The focus is on consequences of CVD
but the criteria also take into account different aetiolo-
gies. These criteria incorporate different levels of certainty
of the clinical diagnosis (probable, possible and definite).
However, in randomized clinical trials using the NINDS-
AIREN criteria, all potential subtypes have been lumped
together as ‘general VaD’. The SIVD criteria of Erkinjuntti
et al. (2000) represent an attempt to define a more homog-
enous subtype.
638 Dementia
In a neuropathological series, the sensitivity of the
NINDS-AIREN criteria for probable and possible VaD was
58% and specificity was 80% (Gold et al., 1997). The crite-
ria successfully excluded AD in 91% of cases; the propor-
tion of combined cases misclassified as probable VaD was
29%. Compared to the other modern criteria (the ADDTC
criteria), the NINDS-AIREN criteria were more specific
and better at excluding combined cases (54% vs. 29%). In
another series, the sensitivity of the NINDS-AIREN criteria
for probable VaD was 20% and specificity 93%; the corre-
sponding figures for probable ADDTC were 25% and 91%
(Gold et al., 2002). The inter-rater reliability of the NINDS-
AIREN criteria is moderate to substantial (κ 0.46–0.72)
(Lopez et al., 1994).
58.8 CLINICAL CRITERIA FOR VCI
The concept and definition of VCI or vascular CIND are
still evolving but it seems clear that the diagnosis should
not be confined to a single aetiology comparable to the tra-
ditional ‘pure AD’ concept. The three main factors to be
defined in VCI are the severity of cognitive impairment,
the pattern of affected cognitive domains and the assumed
aetiologies and brain changes. It is important to avoid new
arbitrary threshold criteria, recognize a continuum of cog-
nitive impairment, focus on causes instead of consequences
and acknowledge complex interactions of coexisting differ-
ent aetiologies and brain changes. General VCI criteria are
probably not needed. It is better to avoid arbitrary clinical
threshold criteria such as the old AD type dementia crite-
ria. General common VCI criteria may hamper discovery of
interactive processes related to the continuum of individual
cognitive changes. Separate criteria, designed according to
the target group, the assumed biological surrogate and the
assumed clinical outcomes would be better.
The target groups may be
1. CVD patients at risk of cognitive impairment
2. VCI patients at risk of further cognitive and functional
decline
3. Non-demented, non-disabled patients with extensive
WMLs at risk of functional decline
4. AD patients with WMLs at risk of cognitive and func-
tional decline
5. Elderly with gait instability
6. Depressed elderly with dysexecutive syndrome
Potential surrogates include white matter burden, lacu-
nar infarct burden as well as frontal cortical atrophy. The
clinical outcomes may relate to cognitive functions, behav-
ioural symptoms, ADLs or gait and stability.
The vascular cognitive impairment harmonization stan-
dards (Hachinski et al., 2006) are an important step to
guide and harmonize VCI studies wordwide. They include
a recommendation on minimum, common, clinical and
research standards for the description and study of VCI.
58.9 CONCLUSIONS
VCI is the modern term related to vascular burden of the
brain, reflecting all the encompassing effects of CVD on cog-
nition. VCI includes all levels of cognitive decline from mild
deficits in one or more cognitive domain to a broad dementia-
like syndrome. VCI incorporates the complex interactions
between vascular risk factors, CVD aetiologies and cellular
changes within the brain and cognition. Vascular risk factors
towards VCI include arterial hypertension, high cholesterol
and diabetes. VCI includes the common PSD and VaD. The
main subtype of VCI is caused by cerebral small vessel disease
and other subtypes are caused by large vessel disease, strategic
infarcts or a combination of AD and CVD. Traditional vas-
cular risk factors and stroke are also independent factors for
the clinical presentation of AD. In addition to these vascular
factors, CVD/strokes, infarcts and WMLs may trigger and
modify the progression of AD. While CVD is preventable and
treatable it clearly is a major factor in the prevalence of cog-
nitive impairment worldwide. The new VCI harmonization
standards are an important step towards international coop-
eration and the new imaging methods that enable assessment
of small vessels pave way for innovative intervention studies.
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The neuropathology of vascular dementia
RAJ N. KALARIA
59.1 INTRODUCTION
Cerebrovascular disease (CVD) is the second most common
cause of age-related dementia. Alzheimer and Kraeplin
(Berrios and Freeman, 1991) both entertained the notion
that gradual strangulation of the brain causes cognitive and
behavioural deficits. They reasoned that progressive hard-
ening of the arteries led to arteriosclerotic dementia. Until
the late 1960s, arteriosclerotic dementia was commonly
described in hospital records and attributed to cerebral soft-
ening with loss of relatively large volume, at least 50 mL,
and preferably 100 mL of brain tissue (Tomlinson et al.,
1970). It was often clinically overdiagnosed in comparison
to Alzheimer’s disease (AD). The current concepts of vascu-
lar dementia (VaD), including pathology, have evolved over
a long period, often biased by AD diagnosis.
VaD is now recognized as a cognitive disorder explained
by vascular causes in the absence of other pathologies. The
first clear recognition of subclasses of VaD, probably, should
be credited to Otto Binswanger, who described subcortical
arteriosclerotic encephalopathy or a type of small vessel dis-
ease (SVD) related to dementia upon pathological verifica-
tion of cerebral white matter (WM) disorder in patients with
hypertensive disease (Berrios and Freeman, 1991). In the more
recent times, based on extensive experience, C. Miller Fisher
proposed that cerebrovascular dementia is a matter of both
large and small strokes and provided lucid accounts of lacunar
syndromes (Fisher, 1982). Multiple small infarcts in associa-
tion with hypertension (état lacunaire) are one of the com-
monest pathological changes linked to VaD. It is characterized
by abrupt episodes, which lead to weakness, slowness, dysar-
thria, dysphagia, small-stepped gait, brisk reflexes and exten-
sor plantar responses. All these signs are usually present by
the time mental deterioration occurs (Hachinski et al., 1974).
The recognition of subtypes of clinical VaD was an impor-
tant step towards current pathological classifications based
on vascular aetiology. Multi-infarct dementia predominantly
59
results from cortical infarcts attributed to large vessel disease,
whereas subcortical ischaemic or Binswanger type of VaD
involving subcortical structures and the WM results from
intracranial small vessel changes (Table 59.1).
59.2 FROM ARTERIOSCLEROTIC
DEMENTIA TO VASCULAR
COGNITIVE IMPAIRMENT
Several terms are commonly used to relate the clinical and
pathological descriptions of vascular disease to cognitive
impairment and dementia. Cerebrovascular dementia or
more commonly VaD implies a clinically diagnosed demen-
tia syndrome comprising subtypes with both ischemic and
haemorrhagic aetiologies (Román, 2004). Vascular cognitive
impairment (VCI) (Bowler and Hachinski, 1995) was devised
to incorporate conditions in any cognitive domain that have
a vascular origin or impaired brain perfusion (O’Brien et al.,
2003). However, it has been challenging to establish the
degree of pathological burden that relates to impaired cogni-
tion (O’Brien et al., 2003; Gorelick et al., 2011).
Like VCI, VCD (Sachdev, 1999) is a continuum described
by cognitive disorders of vascular aetiology with diverse
pathologies and clinical manifestations. The Diagnostic and
Statistical Manual of Mental Disorders, Fifth Edition (DSM-5)
criteria and guidelines propose that the categories of mild
and major vascular cognitive disorders can be recognized
(American Psychiatric Association, 2013). Vascular cognitive
disorder has also been suggested to indicate the global diag-
nostic category, restricting the term ‘VCI’ to patients whose
cognitive impairment falls short of dementia (Román, 2004).
The major neurocognitive disorder classification, as a sub-
stitute for VaD, appears to fit better with patients and more
adapted to neurodegenerative cognitive disorders for which
memory impairment is not predominant but would com-
prise substantial frontal lobe pathology (Sachdev et al., 2014).
643
644 Dementia
Table 59.1 VaD subtypes defined by blood vessel size
and pathological process
Large vessel dementia (multiple infarcts or MID)
Small vessel dementia (microinfarction)
Strategic infarct dementia (infarcts in strategic locations
e.g. thalamus)
Hypoperfusive dementia
Dementia related to angiopathies (hypertension, amyloid)
Haemorrhagic dementia
Other causes of VaD (vasculitis)
Familial VaD (CADASIL, CARASIL, RVCL)
Source: Natte, R. et al., Annals of Neurology, 50, 765–772, 2001.
Notes: Familial or hereditary forms of cerebral amyloid angiopa-
thy involving ischaemic strokes and intracerebral haem-
orrhages may also lead to cognitive impairment and
stroke.
Abbreviations: VaD, vascular dementia; MID, multi-infarct demen-
tia; CADASIL, cerebral autosomal dominant arteriopathy
with subcortical infarcts and leukoencephalopathy
(Kalimo and Kalaria, 2005); CARASIL, cerebral autosomal
recessive arteriopathy with subcortical infarcts and leuko-
encephalopahty (Hara et al., 2009); RVCL, autosomal
dominant retinal vasculopathy with cerebral leukodystro-
phy (Kavanagh et al., 2008).
Cognitive impairment or dementia is relatively common
following stroke (Leys et al., 2005; Pendlebury and Rothwell,
2009). Incident dementia or post-stroke dementia (PSD)
may develop within 3 months or after a stabilization period
of 1 year or longer after stroke injury (Pohjasvaara et al.,
1997; Bejot et al., 2011; Allan et al., 2012). PSD can have a
complex aetiology with varying combinations of large SVD
as well as non-vascular pathology. Stroke injury or CVD
may unmask other pre-existing disease processes, such as
AD although it has been demonstrated that at least 75% of
PSD cases are pathologically confirmed as post-stroke VaD
with little or no AD pathology (Allan et al., 2012).
Recent advances in neuroimaging and systematic neuro-
pathological examination have enabled better definitions of
clinically diagnosed cerebrovascular disorders, which cause
cognitive impairment (Hachinski et al., 2006). The patho-
logical diagnosis of VaD or VCI, however, requires system-
atic evaluation of potentially relevant clinical or phenotypic
features with particular attention to timing of events
(Ferrer, 2010). It is difficult to define which neuropathologi-
cal changes and to what degree these changes contribute
to dementia because of the heterogeneous localization of
lesions and the coexistence of other pathologies including
neurodegenerative changes such as those in AD. More than
one factor may contribute to the overall impairment and the
VaD phenotype (Table 59.2). These include origin and type
of vascular occlusion, presence of haemorrhage, distribution
of arterial territories and the size of vessels involved. Thus,
many brain regions including the territories of the anterior,
posterior and middle cerebral arteries; the angular gyrus,
caudate and medial thalamus in the dominant hemisphere;
the amygdala and hippocampus as well as the hippocampus
Table 59.2 Key variables to define pathology of VaD
Identify as ischaemic or haemorrhagic infarct(s)
Presence of lacunes and lacunar infarcts: état lacunaire
(grey matter) and état crible (WM)
Location of infarcts: cortex, WM, basal ganglia,
brainstem (pontine), cerebellum
Circulation involved: arterial territories-anterior, middle
or posterior
Laterality: right or left anterior and posterior
Sizes and number of infarcts = dimension: 0–4 mm,
5–15 mm, 16–30 mm, 31–50 mm and >50 mm, if size
<5 mm determine as small or microinfarcts
Presence and location of SVD: lipohyalinosis, fibroid
necrosis, CAA
Presence of WM disease: rarefaction or incomplete
infarction
Degree of microgliosis and astocytosis: mild, moderate
or severe
Presence of Alzheimer pathology (including NFT and
neuritic plaque staging). If degree > stage III, the case
is mixed AD and VaD
Presence of hippocampal sclerosis
Source: Hachinski, V. et al., Stroke, 37, 2220–2241, 2006.
Notes: 
For reporting purposes, each of above features can be
scored numerically to provide a summary. For example, 0 is
absent and 1 means present. Less frequent lesions ­including
watershed infarcts and laminar necrosis. Increasing numeri-
cal value may also be assigned to the infarcts.
Abbreviations: WM, white matter; SVD, small vessel disease; CAA,
cerebral ­amyloid angiopathy; NFT, neurofibrillary tangles;
AD, Alzheimer’s disease.
have been implicated in VaD (Markesbery, 1998). Factors
that define pathology in subtypes of VaD include multiplic-
ity, size, anatomical location, laterality and age of the lesions
besides genetic influences and previous existence of sys-
temic vascular disease. Subcortical ischaemic VaD is likely
to be the most significant subtype of VaD (Román, 2002),
and it seems that smaller subcortical lesions are key players
(Table 59.2).
59.3 PREVALANCE OF PATHOLOGICALLY
DIAGNOSED VAD
As with AD, confirmation of VaD diagnosis is definitive at
autopsy derived from appropriate sampling of both cerebral
hemispheres and minimal neuropathological examination
(Hachinski et al., 2006) to rule out significant pathological
changes associated with other dementias. The prevalence
of early-onset dementia VaD (<65-years old) ranges from
3.1% to 44% in various clinical and population-based stud-
ies across the world (Vieira et al., 2013). These values may
not reflect true prevalence and incidence rates of VaD due
to inconsistencies in diagnostic criteria, sampling methods,
subject or country demographics and variation in morbidity

Pure Other
VaD types
10% 2%
AD
40%
Mixed
(SVD)
40%
Mixed
Mixe
(LV)
(LV
8%
Figure 59.1 Pathological outcomes of clinically diagnosed
vascular dementia (VaD). Mixed type 1 revealed large
infracts, whereas mixed type 2 predominantly exhibited
small vessel disease (SVD) with microinfarction. Other
included Lewy body disease, dementia, mild Parkinson
disease and depression. AD, Alzheimer’s disease; LV, large
vessel.
and mortality trends (Figure 59.1). When a range of clini-
cal criteria have been applied to sample sizes of 59 to 1929,
autopsy studies demonstrate pathologically diagnosed VaD
ranges from as low as 0.03% to as high as 58% with an over-
all mean estimate of 17% (Markesbery, 1998; Jellinger, 2008).
In western countries, the estimated rates of pathologically
diagnosed VaD as defined by various criteria lie between
8% and 15%. In studies where diagnosis was restricted to
the current National Institute of Neurological Disorders
and Stroke–Association Internationale pour la Recherché
et l’Enseignement en Neurosciences (NINDS-AIREN) crite-
ria (Román et al., 1993), the frequencies were reported to be
~7%. Taking all these estimates into account, the worldwide
frequency of VaD in autopsy verified cases is determined to
be 10%–15%, being marginally less than when clinical criteria
alone are used (Barker et al., 2002; Knopman et al., 2003). In
Japan, the incidence of autopsy verified VaD was previously
reported to be 35% (Seno et al., 1999) and later 22% (Akatsu
et al., 2002). Population-based cohorts should provide the
best estimates for pathology verified VaD, but there are only
few such studies and all existing ones show that microvas-
cular lesions occur more frequently than neurodegenerative
lesions in elderly c­ ommunity-dwelling subjects with demen-
tia (Neuropathology Group of the Medical Research Council
Cognitive Function and Ageing Study [MRC CFAS], 2001;
White et al., 2005; Schneider et al., 2007; Sonnen et al., 2007).
59.4 PATHOLOGICAL DIAGNOSIS
OF VAD
Diagnostic criteria for the neuropathological validation
of VaD are generally lacking. However, neuroimaging and
clinicopathological studies suggest that VaD is related to the
extent of cerebral damage caused to a patient. A combination
of factors including origin, volume, location and number of
lesions, contribute to the development of dementia. Blessed
The neuropathology of vascular dementia 645
and colleagues observed that the total volume of infarcts
in demented stroke patients was usually over 50 mL and in
some cases was greater than 100 mL, exceeding that in non-
demented stroke patients (Blessed et al., 1968; Tomlinson
et al., 1970). Subsequent clinicopathological studies reported
that only 5 out of 23 patients with a pathological diagnosis of
VaD had more than 50 mL of infarcted tissue and 7 had less
than 10 mL (Erkinjuntti et al., 1988). It is now apparent that
widespread small ischaemic lesions or multiple microinfarcts
(White, 2009; Westover et al., 2013) distributed throughout
the CNS, correlate with dementia and are key predictors of
cognitive impairment (Kalaria, 2012). Location of lesions
may also be more critical than total volume (Desmond et al.,
2000; Erkinjuntti et al., 2000). For example, infarction in
the left hemisphere disproportionately increases the risk of
dementia (Gorelick et al., 1992; Liu et al., 1992; Censori et al.,
1996; Pohjasvaara et al., 1998; Desmond et al., 2000). Bilateral
infarcts with more involvement of the dominant hemisphere
also increase the risk of dementia after stroke (Erkinjuntti
et al., 1988; del Ser et al., 1990; Liu et al., 1992).
Relatively few prospective studies have validated criteria
for VaD. Previous criteria for Binswanger’s disease or cerebral
SVD (Bennett et al., 1990) proposed that the clinical diagnosis
of dementia accompanied by neuromaging evidence (comput-
erized axial tomography [CT] or magnetic resonance imag-
ing [MRI]) of bilateral abnormalities and at least two of three
findings included evidence of (1) a vascular risk factor or sys-
temic vascular disease, (2) focal cerebrovascular disease and
(3) ‘subcortical’ cerebral dysfunction described by gait disor-
der, parkinsonism or incontinence. These criteria were vali-
dated in a prospective series of 184 patients with AD and only
1.6% of the patients were diagnostically misclassified when all
the three clinical criteria were met (Bennett et al., 1990).
The Oxford Project to Investigate Memory and Ageing
(OPTIMA) study has developed a simple, novel, image-match-
ing scoring system (Smallwood et al., 2012) to relate the extent
of SVD with cognitive function in a study of 70 cases with
insufficient pathology to the meet criteria involved in diagno-
sis of AD. Severity of SVD pathology was inversely related to
cognitive scores and 43% of the cases with high SVD scores
were designated to be demented. To better define clinico-
pathological correlation in subtypes of VaD, including SVD,
a staging system related to the natural history of cerebrovas-
cular pathology and an algorithm for the neuropathological
quantification of the CVD burden in dementia have been pro-
posed (Deramecourt et al., 2012). The staging system (I–VI)
needs further evaluation against cognitive function scores to
determine whether this system would be useful in large-scale
studies to understand clinicopathological correlations.
Neuropathological diagnosis of VaD should be based
on the absence of a primary neurodegenerative disease
known to cause dementia and the presence of cerebrovas-
cular pathology that defines one or more VaD subtypes
(Table 59.1). These would also include dementia among
post-stroke survivors who fulfil the NINDS-AIREN cri-
teria (Román et al., 1993) for probable VaD. Stroke sur-
vivors with mild cognitive impairment or VCI (O’Brien
646 Dementia

et al., 2003) may also have sufficient pathology for neu-
ropathological diagnosis of VaD. An approach to neuro-
pathological diagnostic evaluation of VaD was previously
proposed by the Newcastle group (Figure 59.2). According
to these criteria, there are two neuropathological diag-
nostic groups: probable VaD is based on the exclusion
of a primary neurodegenerative disease known to cause
dementia plus the presence of cerebrovascular pathology
that defines one or more of the VaD subtypes. Possible VaD
is designated to a patient when the brain contains vascu-
lar pathology that does not fulfil the criteria for one of the
subtypes, but where no other explanation for dementia is
found. Post-stroke cases are usually included in subtypes
I–III. Cases with extensive WM disease in the absence of
other significant features are included under SVD. Subtype
I may result from large vessel occlusion (atherothrombo-
embolism), artery-to-artery embolism or cardioembolism.
Subtype II usually involves arteriolosclerosis, lipohyalino-
sis and hypertensive, arteriosclerotic, amyloid or collagen
angiopathy. Subtypes I, II and V may result from aneu-
rysms, arterial dissections, arteriovenous malformations
and various forms of arteritis (vasculitis).
Assessing the neuropathological substrates of VaD involves
systematic assessment of parenchymal lesions, including
microinfarcts and haemorrhages and the vascular abnor-
malities that may have caused them to relate to progression
of impairment (Mirra, 1997; Kalaria et al., 2004; Strozyk et al.,
2010; Deramecourt et al., 2012; Smallwood et al., 2012). In
addition to this, systemic factors (e.g. hypotension, hypogly-
cemia) may cause brain or neuronal lesions in the absence of
severe vascular disease and should be taken in account when
attributing causes to VaD. As discussed earlier, parenchymal
abnormalities of neurodegenerative type may be present that
are not obviously associated with either vascular disease or
systemic factors, i.e. Alzheimer type or hippocampal lesions.
59.5 DIFFERENT CEREBROVASCULAR
PATHOLOGIES LEAD TO
DEMENTIA
Atherothromboembolism is the main cause of infarctions
associated with major arterial territories, which
may be admixed in cortical and subcortical regions.
Thromboembolic events may be responsible for up to 50%
of all ischaemic strokes, whereas intracranial SVD causes
25% of the infarcts. Small vessel alternations involve
arteriolosclerosis and hyalionsis and associated with lacu-
nar infarcts and lacunes predominantly occurring in the
subcortical structures. WM disease or subcortical leukoen-
cephalopathy with incomplete infarction and SVD are com-
mon pathological changes in CVD associated with dementia
(Deramecourt et al., 2012). Other features include border
zone (watershed) infarctions, laminar necrosis and amyloid
angiopathy. Complicated angiopathies such as fibromuscu-
lar dysplasia, arterial dissections, granulomatous angiitis,
collagen vascular disease and giant-cell arteritis are rarer
causes of cerebrovascular disease and VaD (Table 59.1).
Previous studies have recorded ischaemic, o ­edematous
and haemorrhagic lesions induced by pathological changes
in the brain circulation or perfusion to be associated with

Newcastle categorization of the major CV lesions

associated with cognitive impairment
I II III IV V VI

Large infarct or Multiple small or Strategic Cerebral Cerebral CV lesions

several infarcts microinfarcts infarcts hypoperfusion haemorrhage with AD pathology

Multi-infarct White matter Thalamus Hippocampal Lobar Mixed

dementia lesions hippocampus sclerosis ICH dementia
basal forebrain SAH

Figure 59.2 (See colour insert.) Schematic diagram of different cerebrovascular pathologies associated with dementia.
The proposed Newcastle categorization includes six subtypes (Kalaria et al., 2004). In all of the subtypes, the age of the
vascular lesion(s) should correspond with the time when disease began. The post-stroke cases are usually included in
subtypes I–III. While these may not be different from other published subtypes (Jellinger, 2008), they are practical and
simple to use. Cases with extensive white matter (WM) disease in the absence of significant other features are included
under SVD. Subtype I may result from large vessel occlusion (atherothromboembolism), artery-to-artery embolism or
cardioembolism. Subtype II usually involves descriptions of arteriosclerosis, lipohyalinosis, hypertensive, arterioscle-
rotic, amyloid or collagen angiopathy. Subtypes I–II and V may result from aneurysms, arterial dissections, arteriove-
nous malformations and various forms of arteritis (vasculitis). CAA, cerebral amyloid angiopathy; ICH, intracerebral
haemorrhage; SAH, subarachnoid haemorrhage. (Original diagram courtesy of Dr K. Nagata, Akita, Japan.)
 The neuropathology of vascular dementia 647

Types of vascular and hippocampal lesions in VaD and smaller vessels, beyond the circle of Willis involving
80
proximal segments of the middle and anterior cerebral arter-
60
ies, is generally rare but may be found in very old subjects
40 (Kalaria et al., 2012). The presence of dolichoectasia and fusi-
20 form aneurysms has also been noted in some cases. In severe
0 cases, medium-sized arteries in the leptomeninges and prox-
% Cases imal perforating arteries are involved. The damage could be
ns

s
ct
io

s
worse depending upon the presence of hypertension.

ts
ct
ar
ct

A
rc
ar
nf
ar

H
CA
fa
nf

IC
Arterial territorial infarctions involve four principal
nf

ri

is
in
oi
na
ei

s
ro
ic
icr
et

cu

areas, particularly, those supplied by the major arteries:

st

cle
l/m
pl

Cy
La

ls
m

al

anterior, middle cerebral artery, posterior artery and the

pa
Co

Sm

am
territory between the anterior and middle cerebral artery.

oc
pp
Hi
Figure 59.3 Types of vascular and hippocampal lesions
reported in VaD. Data compiled from 214 cases reported
in previous studies (Kalaria et al., 2004; Kalaria et al.,
unpublished data). Percentage of cases is averaged from
two or more reported studies. Cystic infarcts (possibly
also lacunar) with typically ragged edges were admixed in
both cortical and subcortical structures. Lacunar infarcts
were mostly in the basal ganglia and white matter.
The intensity of gliosis, both astrocytic and microgliosis, is
an important consideration in judging the degree and age
of infarction. However, there is no clear evidence to suggest
that these are related to cognitive impairment. Degrees of
gliosis or glial scars may be noted in VaD brains subjected
to global ischaemia i.e. after transient cardiac arrest where
responses may be observed in vulnerable neuronal groups
within the hippocampus or neocortical laminae.

VaD (Table 59.2). In 10 different studies where VaD was diag-

nosed, 78% of cases revealed cortical and subcortical infarcts
suggesting that other v­ ascular pathologies involving incom-
plete infarction or border zone infarcts could be important
factors (Figure 59.3). Among other lesions, 25% of cases
had cystic infarcts whereas 50% showed lacunar infarcts
or microinfarcts. Lacunar infarcts, however, appear to be
a common category of infarcts and currently recognized as
the most frequent cause of stroke. Severe amyloid angiopathy
was present in 10% of the cases. Hippocampal sclerosis and
cell atrophy, which may be caused by remote ischaemic
injury, was apparent in 55% of cases in a study based on clini-
cal diagnosis of ischaemic VaD (Vinters et al., 2000).
59.6 L ARGE VESSEL DISEASE
Large infarction or macroinfarction is defined as that vis-
ible upon gross examination of the brain at autopsy. Stenosis
arising from atherosclerosis within large vessels is consid-
ered to be the main cause of large infarction, which may
sometimes extend beyond the arterial territories. The stages
of atherosclerosis may vary from accumulation of foam cells
causing fatty streaks to complicated atheromas involving
extracellular matrix components and even viral or bacterial
infections. Approximately 15% of VaD assumes occlusion of
the extracranial arteries such as, the internal carotid artery
and the main intracranial arteries of the circle of Willis
including the middle cerebral artery lead to multiple infarcts
and dementia (Brun, 1994). The differences between the
anterior versus posterior portions of the circle of Willis and
left versus right sides may be variable and stenosis of major
arteries could be up to 75% in very severe cases. Typical ath-
erosclerosis or microatheromatous disease in the meningeal
59.7 CEREBRAL SVD
SVD per se involves hyalinization of vessels, expansion of the
perivascular space and pallor of adjacent perivascular myelin,
with associated astrocytic gliosis (Figure 59.4). The smaller
vessels of the brain including intracerebral end arteries and
arterioles undergo progressive age-related changes (Lammie,
2000), which alter perfusion and cause lacunar infarcts (cystic
lesions generally < 1 cm) and microinfarcts. The arteriolar
changes range from wall thickening by hyalinosis, reduction
or increment of the intima to severe arteriolosclerosis and
fibroid necrosis. Arteriolosclerotic changes likely promote loss
of elasticity to dilate and constrict in response to variations
of systemic blood pressure or auto-regulation, which in turn
causes fluctuations in blood flow response and changes in tis-
sue perfusion. The deep cerebral structures and WM would be
rendered most vulnerable because the vessels are end arteries,
almost devoid of anastomoses. Small vessel pathology could
also lead to oedema and damage of the blood–brain barrier
(BBB) with chronic leakage of fluid and macromolecules in the
WM (Ho and Garcia, 2000; Wardlaw, 2010; Giwa et al., 2012).
Microvascular disease may also be associated with degrees
of inflammation including the presence of lymphocytes or
macrophages localized on blood vessels (and not necessarily
a function of brain ischaemia). In the oldest SVD cases, there
may also often be evidence of remote haemorrhage in the
form of perivascular haemosiderin (Deramecourt et al., 2012).
59.8 LACUNAR INFARCTS
Lacunar infarcts, about 1 cm or less in diameter, may occur as
complete or cavitating lesions frequently in both subcortical
648 Dementia
(a) (b)
(c) (d)
(e) (f )
Figure 59.4 (See colour insert.) Pathological features
associated with SVD in VaD. Panels show examples of
lacunes, small infarcts and microinfarcts: (a) typical cavi-
tated lacunar lesions (arrow) in the putamen of a 65-year-
old man. (b) Multiple infarcts in the basal ganglias of an
80-year-old man with vascular and neurofibrillary pathol-
ogy. (c)–(e) Cerebral microvessels with variable hyalinosis,
perivascular rarefaction, microinfarcts and perivascular
spaces in three different cases. Moderate gliosis in the
surrounding region is also evident in case in (c); (f) small
cortical infarct in a VaD case with severe CAA. A penetrat-
ing arteriole with CAA is seen in the middle of the infarct
(arrow). Magnification bar: (a) = 1 cm, (b), (f) = 500 μm; (c),
(d) = 100 μm, (e) = 200 μm.
grey matter and WM in VaD. They represent small foci of
ischaemic necrosis resulting from narrowing or occlusion of
penetrating arteries branching directly from larger cerebral
arteries (Fisher, 1982). Lacunar infarcts are frequently multi-
ple and bilateral and often coexist with other vascular lesions
(e.g. large infarcts or diffuse WM damage). Whether single or
multiple, they may be asymptomatic, depending on their loca-
tion and the volume of normal brain tissue lost. Lacunes may
also represent small haemorrhages or dilated perivascular
spaces without infarction or haemorrhage. A few lacunes may
represent healed or reabsorbed as minute or petechial haem-
orrhages. Microlacunes have also been described that are
essentially should be thought of as large cystic microinfarcts.
Aside from critical lesions occurring often in the internal
capsule or caudate nucleus, recent meta-analyses suggested
there were no pathological differences between symptom-
atic and asymptomatic patients. Perivascular oedema and
thickening, inflammation and disintegration of the arterio-
lar wall were common, whereas vessel occlusion was rare
(Bailey et al., 2012). In neuropathological studies of elderly
patients with vascular disease, but without evidence of AD or
other neurodegenerative pathologies, dementia was associ-
ated with severe cribriform change and associated with sub-
cortical WM damage and microinfarcts (Esiri et al., 1997).
In the Highly Accelerated Stress Screen (HAAS) analysis
(White, 2009), microvascular infarcts (lacunar and micro-
infarcts) were identified as the sole or dominant lesion in
34% of the definitely impaired decedents (Figure 59.4). Cases
of VaD without significant AD pathology show more severe
cribriform change and deep WM and grey matter lacunar
or microinfarcts than do stroke subjects with macroscopic
infarcts and elderly subjects without dementia (Smallwood
et al., 2012). Similarly, lacunar infarcts and microinfarcts
were the most common neuropathological features in more
than 50% of elderly patients with ischaemic VaD (Vinters et
al., 2000) and also strong determinants of dementia in the
Geneva brain ageing study (Giannakopoulos et al., 2007).
However, all these findings were also often accompanied by
moderate-to-severe atherosclerosis.
59.9 WM DISEASE
WM hyperintensities on T2-weighted MRI or leukaraiosis
as a decreased signal on CT is a neuroimaging construct
to describe diffuse and focal WM changes. Leukoariaosis
predominantly refers to vascular disease and not only
incorporates WM rarefaction, incomplete infarction,
lacunar strokes, perivascular spacing and demyelination
but sometimes also axonal and Wallerian degeneration
(Figure 59.5). Both in areas of leukoaraiosis and zones
outside the lesions, decreased vascular density is noticed
indicating that leukoaraiosis appears as a generalized fea-
ture of CVD rather than limited to deep WM (Brown et al.,
2007). This is consistent with finding of an association with
unstable carotid plaques and the number of WM lesions,
suggesting a thromboembolic role in some patients with
leukoaraiosis (Altaf et al., 2006).
Neuroimaging and pathological studies demonstrate
WM hyperintensisties and represent degeneration of the
WM, mostly explained by SVD (Pantoni and Garcia, 1997;
Pantoni, 2010). Diffuse and focal WM lesions are a hall-
mark of VaD (Ihara et al., 2010), but also occur mostly
in ~30% of AD and in dementia with Lewy bodies (DLB)
cases (Englund, 1998). There is some controversy whether
deep or periventricular lesions are of more importance, but
this depends on the definition of boundaries between the
periventricular and deep WM if the coursing of the fibres is
used as markers (Kovari et al., 2007). Lacunar infarcts are
produced when the ischaemic damage is focal and of suf-
ficient severity to result in a small area of necrosis, whereas

(a) (b)
(c) (d)
Figure 59.5 (See colour insert.) WM lesions visualized by
conventional histopathological staining in an 85-year-old
man diagnosed with vascular encephalopathy. (a) >75%
stenosis in the internal carotid artery 8 mm above the
bifurcation. The narrowed lumen (arrow) is seen. (b) WM
rarefaction and myelin loss in the medial temporal lobe
but sparing of U fibres; (c), post-mortem T2W magnetic
resonance image of a formalin-fixed block from the parietal
lobe. Area of hypersignal can be seen in the WM (*);
(d), H&E stained section from the block in (c) showing
severe deep WM ­pallor in the area of hypertensity (*).
A small cortical infract is also seen (arrow). Magnification
bar: (a) = 500 mm, (b) = 400 μm, (c) = 1 cm, (d) = 500 μm.
diffuse WM change is considered a form of rarefaction or
incomplete infarction where there may be selective damage
to some cellular components. Although, the U-fibres are
frequently spared, WM disease may comprise several pat-
terns of alterations including pallor or swelling of myelin,
loss of oligodendrocytes, axons and myelin fibres, cavita-
tions with or without presence of macrophages and areas
of reactive astrogliosis (Simpson et al., 2007), where the
astrocytic cytoplasm and cell processes may be visible with
standard stains.
Lesions in the WM also include spongiosis i.e. vacuoliza-
tion of the WM structures and widening of the perivascu-
lar spaces (Yamamoto et al., 2009). Affected regions do not
have sharp boundaries, in contrast to the plaques of multi-
ple sclerosis. These changes may be associated with chronic
pro-thrombotic endothelial dysfunction in cerebral SVD
(Hassan et al., 2003) also involving the WM (Brown and
Thore, 2011). However, there may be a cerebral response to
the SVD by increasing endothelial thrombomodulin (Giwa
The neuropathology of vascular dementia 649
et al., 2012). The projected misery perfusion due to capil-
lary loss or abnormalities occurring prior to leukoaraiosis
corroborates the finding of a chronic hypoxic state in the
deep WM (Fernando et al., 2006), which also releases sev-
eral growth promoting factors (Simpson et al., 2009). Some
of the WM damage in demented patients may simply reflect
Wallerian changes secondary to cortical loss of n ­ eurones.
However, this is unlikely since histological changes char-
acteristic of Wallerian degeneration are not evident as in
WM pallor. Conversely, in AD patients with severe loss of
cortical neurones, similar WM lesions are not apparent
(Englund, 1998).
While WM changes focus on the arterial system, nar-
rowing, in many cases, occlusion of veins and venules by
collagenous thickening of the vessel walls also occur. The
thickening of the walls of periventricular veins and venules
by collagen (collagenosis) increases with age and perivenous
collagenosis is increased further in brains with leukoara-
iosis (Brown et al., 2002b). The presence of apoptotic cells
in WM adjacent to areas of leukoaraiosis suggests that such
lesions are dynamic, with progressive cell loss and expan-
sion (Brown et al., 2002b). Vascular stenosis caused by col-
lagenosis may induce chronic ischaemia or oedema in the
deep WM leading to capillary loss and widespread effects
on the brain (Brown et al., 2007; Brown et al., 2009).
59.10 CEREBRAL MICROINFARCTS
The accumulation of small, even miniscule ischaemic lesions
as an important substrate of VaD has been emphasized in
recent years (Kalaria, 2012). Microinfarcts are widely accepted
to be small lesions visible only upon microscopy (Figure 59.4;
Table 59.2). These lesions of up to 5-mm diameter may or
may not involve a small vessel at their centre but are foci with
pallor, neuronal loss, axonal damage (WM) and gliosis. These
are estimated to occur in thousands. Sometimes, these may
include regions of incomplete infarction or rarefied (subacute)
change. Microinfarcts have been described as attenuated
lesions of indistinct nature occurring in both cortical and
subcortical regions. Such lesions or combinations are reported
when there are multiple or at least greater than three present
in any region (Table 59.2). Microvascular infarcts (lacunar
infarcts and microinfarcts) appear central to the most
common cause of VaD (Figure 59.4) and predict poor outcome
in the elderly (Ballard et al., 2000; Vinters et al., 2000; Brown
et al., 2002a). In autopsied older Japanese-American men, the
importance of microvascular lesions as a likely explanation
for dementia was nearly equal to that of Alzheimer lesions
(White et al., 2002; White, 2009). Microinfarction in the
subcortical structures has been emphasized as a substrate of
cognitive impairment (Arvanitakis et al., 2011a; Kalaria, 2012)
and correlated with increased Alzheimer type pathology, but
cortical microinfarcts also appear to contribute to the progres-
sion of cognitive deficits in brain ageing (Kovari et al., 2004).
650 Dementia
In addition to microinfarction in the subcortical structures,
it appears increasingly important that multiple cortical areas
of microinfarction are associated with subcortical VaD
or SVD (Figure 59.4). Thus, these lesions should be taken
into account when defining the neuropathological criteria.
Cortical microinfarcts increase in the presence of cerebral
amyloid angiopathy (CAA) (Okamoto et al., 2012). In a recent
study, cortical microinfarcts were frequently detected in AD
and associated with CAA, but rarely observed in subcortical
VaD linked to SVD (Suter et al., 2002; Okamoto et al.,
2009). Microinfarcts in the cerebral cortex associated with
severe CAA may be the primary pathological substrate in a
significant proportion to VaD cases (Haglund et al., 2006).
Cortical microinfarcts and to lesser extent periventricular
demyelination were significantly associated with cognitive
decline in individuals at high risk of dementia (Gold et al.,
2007). It is proposed that the changes in hemodynamics, e.g.
hypotension and atherosclerosis may play a role in the genesis
of cortical watershed microinfarcts.
59.11 CEREBRAL MICROBLEEDS
Cerebral microbleeds (CMB) detected by MRI are small,
dot-like hypotense abnormalities and have been associated
with extravasated haemosiderin derived from erythrocytes,
lipohyalinosis and CAA (Fazekas et al., 1999). They are likely
to be a surrogate marker of SVD evident on MRI along with
lacunes and WM changes (Van der Flier and Cordonnier,
2012). The prevalence of radiological microbleeds in
VaD ranges 35%–85%. Microbleeds mainly result from
hypertensive vasculopathy, but the frequent co-occurrence of
lobar microbleeds suggests that neurodegenerative pathology
or CAA is also of importance (Werring et al., 2011). The rel-
evance of this radiological construct is increasingly being
recognized due to their relation to clinical outcome and
occurrence in anti-amyloid vaccination trials (Greenberg
et al., 2009). However, the presence of multiple microbleeds
in the context of VaD is related to worse performance on
cognitive tests, mainly in psychomotor speed and executive
functioning. Since microbleeds are common in cogni-
tively normal older individuals, attribution of these to VaD
should follow a careful exclusion of other causes of cognitive
impairment and only if numerous such lesions are present.
Both radiological cerebral microbleeds and foci of
haemosiderin containing single crystalloids or larger
perivascular aggregates are found in brains of older
subjects including those diagnosed with VaD and AD, but
the radiological and pathological relationship between
these findings has not been entirely clear. Recent evidence
suggests that cerebral microbleeds detected by MRI are
a surrogate for ischaemic SVD rather than exclusively
haemorrhagic diathesis (Janaway et al., 2013). Greater
putamen haemosiderin was significantly associated with
indices of small vessel ischaemia including microinfarcts,
arteriolosclerosis and perivascular spacing and with
lacunes in any brain region, but not large vessel disease
or whole brain measures of neurodegenerative pathology.
Higher levels of putamen haemosiderin were correlated
with more microbleeds upon MRI, but it is possible that
brain iron homeostasis and small vessel ischaemic change
are responsible for these rather than only as a marker for
minor episodes of cerebrovascular extravasation.
59.12 HIPPOCAMPAL ATROPHY AND
SCLEROSIS
Neuroimaging studies show that medial temporal lobe and
hippocampal atrophy are associated with VaD (Bastos-Leite
et al., 2007; Firbank et al., 2011) and SVD (O’Sullivan et al.,
2009; van de Pol et al., 2011) albeit, not to the same extent
as in AD (Burton et al., 2009). Pathological evidence shows
that ischaemic VaD and SVD are also associated with hip-
pocampal changes and atrophy remote to ischaemic injury
(Zarow et al., 2005; Matthews et al., 2009). Hippocampal
neurones in the Sommer’s sector are highly vulnerable to
disturbances in the cerebral circulation or hypoxia caused
by systemic vascular disease. The focal loss of CA1 neurones
in ischemic VaD has been related to lower hippocampal vol-
ume and memory score (Zarow et al., 2005), but the degree
of loss appears to be less in VaD (Kril et al., 2002) than in
AD. However, selective hippocampal neuronal shrinkage is
also an important substrate for VaD. This is also evident in
delayed dementia after stroke in the absence of any neuro-
degenerative pathology (Gemmell et al., 2012). Thus, there
is a clear vascular basis for hippocampal neurodegeneration
and concurs with the neuroimaging observations of hip-
pocampal atrophy even in population-based incident VaD
(Scher et al., 2011). The simplest mechanistic explanation for
the atrophy is that the neuronal or dendritic arbour results
in subsequent loss in connectivity, which contributes to
brain’s structural and functional changes. This is consistent
with the finding that soluble synaptophysin was decreased
in VaD as well as AD.
Hippocampal sclerosis is likely a major contributing
factor in the hippocampal atrophy and occurs in approx-
imately 10% of individuals over the age of 85 and slightly
higher in VaD. It is characterized by severe cell loss with
the CA fields in the presence or absence of microinfarc-
tion and gliosis that is not explained by AD. TAR DNA
protein 43 immunohistochemistry can be used to dem-
onstrate that hippocampal sclerosis, regardless of accom-
panying pathologies (e.g. AD or VaD), is consistent with
an underlying neurodegenerative pathogenetic mecha-
nism (Zarow et al., 2012). Any focal loss or patterns of
hippocampal sclerosis can be graded (Rauramaa et al.,
2013) and recorded together with any microinfarctions.
Sometimes, the patchy neurone loss and gliosis in some
brains with AD pathology may be difficult or impossible

to distinguish from anoxic-ischaemic change. The aeti-
ology of hippocampal sclerosis is defined in association
with neurodegenerative process, a pathologic condition
presumed to arise from hypoxic/ischaemic mechanisms
(Rauramaa et al., 2013). Hippocampal sclerosis pathol-
ogy can be associated with different underlying causes
but a large study (Nelson et al., 2011) found no evidence
for associations between hippocampal sclerosis and lacu-
nar infarcts, large infarcts, circle of Willis atherosclerosis
or CAA. However, there was a correlation between
hippocampal sclerosis and arteriolosclerosis in multiple
brain regions outside of the ­h ippocampus including the
frontal cortex (Brodmann area 9) (Nelson et al., 2011).
This is ascribed to a pathogenetic change in aged human
brain arterioles that affects multiple brain areas and
contributes to hippocampal sclerosis of ageing (Neltner
et al., 2014).
59.13 BORDER ZONE (WATERSHED)
INFARCTS
The border zone or watershed infarctions mostly occur
from haemodynamic events, usually in patients with
severe internal carotid artery stenosis. They could occur
bilaterally or unilaterally and are disposed to regions
between two main arterial territories, deep and superficial
vessel systems. Typical border zone infarctions may be 5
mm or wider as wedge-shaped regions of pallor and rar-
efaction extending into the WM. Larger areas of incom-
plete infarction may extend into the WM (Ihara et al.,
2010). These are characterized by mild-to-moderate loss of
oligodendrocytes, myelin and axons in areas where there
may be hylainzed vessels (Brun, 1994). This may be accom-
panied by astrogliosis, some microgliosis and macrophage
infiltration. The morphology of incomplete or subinfarc-
tive changes, though, suspected to be associated with
cognitive function, is not consistently described in VaD.
It may variably manifest as tissue rarefaction assessed by
conventional stains and revealed as injury response, such
as microgliosis and astrocytosis, or the presence of other
‘reactive’ cells or surrogate markers of dendritic, synaptic
or axonal damage.
59.14 LAMINAR NECROSIS
Laminar necrosis is characterized by neuronal ischaemic
changes leading to neuronal loss and gliosis in the cortical
ribbon. This is particularly apparent in cases where global
ischaemia or hypoperfusion has occurred as in the case of
cardiac arrest. Typical topographic distribution of spongi-
form change can be readily apparent with standard stains.
They appear more commonly at the arterial border zones
The neuropathology of vascular dementia 651
(Brun, 1994; Ferrer et al., 2008) that may fall into the sub-
type IV of VaD pathology.
59.15 SPORADIC CEREBRAL AMYLOID
ANGIOPATHY IN VAD
CAA is most common in AD but it often occurs in CVD
in the general absence of Alzheimer pathology (Cohen
et al., 1997). In sporadic cases, CAA alone is considered
a substrate for cognitive impairment (Pfeifer et al., 2002;
Greenberg et al., 2004; Arvanitakis et al., 2011b). Tissue
microstructural damage caused by CAA prior to pre-
intracerebral haemorrhage is independently associated
with cognitive impairment (Viswanathan et al., 2008). The
prevalence of CAA in VaD is not known, but it is a major
cause of intracerebral and lobar haemorrhages leading to
profound ischaemic damage (Reijmer et al., 2015). Several
familial forms of CAA involving ischaemic and haemor-
rhagic infarcts (see below) and cerebral hypoperfusion
demonstrate the link between CAA and VaD. In a study of
surgical biopsies exhibiting cerebral and cerebellar infarc-
tion, CAA was significantly more common in samples
showing infarction than in age-matched controls with
non-vascular lesions (Cadavid et al., 2000). There is also
an association between severe CAA and cerebrovascular
lesions coexisting with AD, including lacunar infarcts,
microinfarcts and haemorrhages (Olichney et al., 1995;
Ellis et al., 1996; Olichney et al., 1997, 2000a; Okamoto et
al., 2012). This association apparently is not attributable to
apolipoprotein E (APOE) ε4 allele, as the vascular lesions
correlated best with severity of CAA, regardless of geno-
type (Olichney et al., 2000b). There is some evidence to
suggest CAA is related to WM changes but not exclusively
in the oldest (Tanskanen et al., 2013). It appears that the
first stroke-like episode triggers multiple cerebral bleeds,
which is preceded by diffuse WM changes that, in turn,
lead to rapid decline of cognitive functions.
59.16 NEUROCHEMICAL PATHOLOGY
OF VAD
The neurochemical basis of cognitive decline in CVD is
poorly understood. There are few concerted studies on the
protein and lipid chemistry of VaD. Various cellular sig-
nalling and regulatory mechanisms including apoptosis,
autophagy, oxidative stress and inflammation are associ-
ated with VaD by virtue of their involvement in cerebral
ischaemia or oligaemia. VaD subjects also mount to a selec-
tively attenuated neuroinflammatory response (Mulugeta
et al., 2008). It was reported that the monocyte chemoat-
tractant protein-1 and interleukin-6 concentrations were
significantly reduced in the frontal lobe of VaD and mixed
652 Dementia
dementia subjects suggesting that these changes had a vas-
cular basis rather than due to Alzheimer pathology.
The perivascular nerve plexus (Hamel, 2006) is highly
vulnerable, yet only few transmitter specific changes
reflecting neurovascular pathology have been described
in subtypes of VaD. Selective transmitter-specific changes
have been described in some cases of VaD (Kalaria and
Ballard, 1999).Two different groups had previously shown
that compared to AD patients, choline acetyltransferase
activity was also reduced albeit to a lesser degree in the
­temporal cortex and hippocampus in patients diagnosed
with multi-infarct dementia or VaD (Perry et al., 1977;
Gottfries et al., 1994). Furthermore, choline acetyltrans-
ferase activities were significantly reduced by 60%–
70% in frontal and temporal cortices of subjects with
Cerebral Autosomal Dominant Arteriopathy with Sub-
cortical Infarcts and Leukoencephalopathy (CADASIL),
which models SVD (Keverne et al., 2007). Choline
acetyltransferase and p75 (neurotrophin receptor) immu-
noreactivities were also affected within the cholinergic
cell bodies of the basal forebrain in CADASIL, but these
were not so pronounced. This may depend on severity of
the WM degeneration (Mann et al., 1986; Keverne et al.,
2007). However, loss of cholinergic function is consis-
tently greater in VaD patients with concurrent Alzheimer
pathology (Román and Kalaria, 2006). Conversely, a novel
increase in cholinergic activity in the frontal cortex was
revealed in infarct dementia (Sharp et al., 2009).
Other studies have reported deficits in monoamines
including dopamine and 5-hydroxytryptamine (5HT) in
the basal ganglia and neocortex in VaD (Gottfries et al.,
1994). To compensate for the loss (Elliott et al., 2009),
5-HT(1A) and 5-HT(2A) receptors are likely to be increased
in the temporal cortex in multi-infarct but not subcortical
VaD. Such findings, albeit fragmentary, reveal distinctions
between the neurochemical pathology of VaD subtypes and
suggest possibilities of pharmacological manipulation with
novel therapies in VaD. There was also loss of glutamater-
gic synapses, assessed by vesicular glutamate transporter 1
concentrations, in the temporal cortex of VaD (Kirvell et al.,
2011), but preservation of these in the frontal lobe suggests a
role in sustaining cognition and protecting against demen-
tia following a stroke. Identification of the morphological
equivalents of these changes in types of pyramidal cells in
the frontal lobe would be relevant.
59.17 INTERACTION BETWEEN
VASCULAR AND ALZHEIMER-
TYPE PATHOLOGIES
Concurrent cerebrovascular disease is a common neuro-
pathological finding in aged subjects with dementia and
more common in AD than in other neurodegenerative dis-
orders, especially in younger subjects and lowers the thresh-
old for dementia due to AD and alpha-synucleinopathies
(Toledo et al., 2013). The burden of mixed pathology is
even greater in elderly people within the community at
large (Neuropathology Group of the Medical Research
Council Cognitive Function and Ageing Study [MRC
CFAS], 2001; Riekse et al., 2004; Sonnen et al., 2007). In
one community-based sample, 38% of dementia cases had
mixed pathology, with both Alzheimer-type changes and
vascular lesions but ‘pure AD’ represented only 21%–24% of
cases (Schneider et al., 2007). WM lesions indicating isch-
aemic or oligaemic aetiology are also high in community-
dwelling subjects by as much as 94% and this change is
an independent substrate for dementia (Fernando et al.,
2004). In addition, atherosclerosis in cerebral arteries and
the circle of Willis (Roher et al., 2005; Yarchoan et al., 2012)
is frequently present in AD. The commonest overlapping
pathologies involve smaller cerebrovascular lesions rather
than large infarcts (Deramecourt et al., 2012) (Figure
59.1). These include most features of SVD such as corti-
cal infarcts, lacunes, diffuse and periventricular myelin
loss, WM microvacuolation, microinfarcts, microhaem-
orrhages, arteriolosclerosis and focal and diffuse gliosis
(Esiri et al., 1997; Ballard et al., 2000; Vinters et al., 2000).
AD pathology was three times greater in VaD cases with
small (<15 mL) compared to large infarcts (Ballard et al.,
2000). These findings also corroborate the importance of
microvascular disease rather than large vessel disease as
the critical substrate in VaD and in AD.
Clinicopathological studies also suggest that vascular
disease influences the burden of the neurodegenerative
lesion (Zekry et al., 2002; Riekse et al., 2004). The den-
sity of neocortical plaques was lower in AD cases with
coexistent vascular lesions interpreted as contributing to
the dementia (Nagy et al., 1997) as well. In the Religious
Order study involving elderly nuns who exhibited coexis-
tent AD and brain infarcts at autopsy had poorer cogni-
tive function and a higher prevalence of dementia than
did those without vascular change (Snowdon et al., 1997).
Compared to pure AD, lower burden of Alzheimer-type
pathology particularly fewer neurofibrillary tangles was
required to reach the threshold for dementia when there
were concomitant lacunar infarcts in subcortical struc-
tures including the basal ganglia, thalamus or deep WM.
Similarly, in another religious order study, after account-
ing for AD lesion burden, the presence of other pathol-
ogies or infarcts increased the odds of dementia over
fivefold (Schneider et al., 2007) and caused earlier onset of
dementia (Esiri et al., 1999).
59.18 PATHOLOGICAL FEATURES OF
FAMILIAL CAA AND SVDS AS
MODELS OF VAD
There are more than 10 different hereditary cerebral amy-
loid angiopathies caused by mutations in different genes
(Yamamoto et al., 2011). All these angiopathies lead to

some degree of cognitive impairment or dementia. They are
characterized by multiple haemorrhages and haemorrhagic
or ischaemic infarcts in addition to severe amyloid deposi-
tion within walls of the meningeal and intracerebral ves-
sels. In hereditary cerebral haemorrhage with amyloidosis
of the Dutch type, dementia occurs in most patients sur-
viving their initial stroke (Haan et al., 1990) and may occa-
sionally be the presenting feature (Wattendorff et al., 1982;
Haan et al., 1989). The extensive CAA alone is sufficient to
cause dementia and this has implications for CAA related
cognitive dysfunction in sporadic CAA and AD (Natte
et al., 2001). In the Icelandic type of hereditary cerebral
haemorrhage with amyloidosis (HCHWA-I), which is
associated with a point mutation in the gene encoding the
cysteine protease inhibitor Cystatin C (Levy et al., 1989),
dementia, occurring in some patients, has been attributed
to the multiple vascular lesions. Individuals with gelsolin-
related amyloidosis manifest facial palsy, mild peripheral
neuropathy and corneal lattice dystrophy; atrophic bulbar
palsy, gait ataxia and mild cognitive impairment (Kiuru
et al., 1999). Familial British dementia with severe amy-
loid angiopathy (Vidal et al., 1999) is characterized by
dementia, progressive spastic tetraparesis and cerebellar
ataxia, the onset is usually in the sixth decade (Mead et al.,
2000). Neuropathological features also include Alzheimer-
type neurofibrillary tangles and neuropil threads in
the anteromedial temporal lobe that may contribute to
dementia (Plant et al., 1990; Revesz et al., 2009). Familial
Danish dementia (FDD), also known as heredopathia
ophthalmooto-encephalica (HOOE), is another condition
with severe and widespread CAA (Vidal et al., 2000). FDD
is clinically characterized by cataracts, deafness, progres-
sive ataxia and dementia.
Several familial stroke disorders also appear to cause
cognitive impairment or dementia. A common feature in
these is subcortical SVD often characterized by severe arte-
riolosclerosis in the perforating vessels (Yamamoto et al.,
2011). CADASIL is the most common form of hereditary
SVDs (Chabriat et al., 2009). Motor deficits, an ataxic hemi-
paresis, hemianopsia and dysarthria may be present as key
neurological features akin to SVD. Vascular changes includ-
ing apoptotic loss of brain vascular smooth muscle cells
(Gray et al., 2007) and vessel wall thickening (Craggs et al.,
2013) are likely to reduce blood flow and affect the vasodila-
tory response to cause lacunar infarcts and microinfarcts in
grey matter and WM (Yamamoto et al., 2011). The exten-
sive demyelination and axonal damage in the underlying
WM contributes to cortical atrophy (Craggs et al., 2013) and
impacts on frontal lobe cognitive functions that is consis-
tent with the disconnection of the fronto-striatal circuits in
CADASIL. Neuronal apoptosis, predominantly in neocorti-
cal layers III and V, is also likely to contribute to dementia
in CADASIL (Gray et al., 2007).
The Maeda syndrome or cerebral autosomal recessive
arteriopathy with subcortical infarcts and leukoencepha-
lopathy (CARASIL) is an autosomal recessive disorder
similar to CADASIL (Hara et al., 2009). The normotensive
The neuropathology of vascular dementia 653
affected subjects exhibit not only severe arteriolosclerosis,
leukoencephalopathy and lacunar infarcts but also spi-
nal anomalies and alopecia. Strokes lead to stepwise dete-
rioration with most subjects becoming demented in older
age. Familial cerebral SVDs, involving progressive visual
impairment (Kalimo and Kalaria, 2005), cause deteriora-
tion in cognitive function. Hereditary endotheliopathy with
retinopathy, nephropathy and stroke (HERNS), cerebro-
retinal vasculopathy (CRV) and hereditary vascular reti-
nopathy (HVR) were reported independently, but represent
different phenotypes in the same disease spectrum (Jen
et al., 1997; Terwindt et al., 1998; Ophoff et al., 2001). These,
now described as autosomal dominant retinal vasculopathy
with cerebral leukodystrophy lead to early death and cause
dementia. Retinal microvessels undergo severe distortions
and become tortuous predictive of the SVD type of pathol-
ogy with multilaminated vascular basement membranes in
the brain (Jen et al., 1997).
Some rarer and less characterized hereditary SVDs also
exist that are associated with clinical SVD features and dif-
ferent degrees of cognitive impairment but the pathologies
in these have not been described. They include conditions
with abnormalities in the skin and eye and multiple lacunar
infarcts in deep WM and pons (Pavlovic et al., 2005), reti-
nal arteriolar tortuosity and leukoencephalopathy (Vahedi
et al., 2003; Gould et al., 2006) and profound WM changes
upon MRI (Verreault et al., 2006).
59.19 CONCLUSIONS
Defining the neuropathological substrates of VaD relies on
uniformity in sampling and pathological examination. VaD
resulting from severe VCI or vascular cognitive disorder or
from delayed impairment after stroke appears to result from
the accumulation of several lesions including cerebral atro-
phy. While robust neuropathological criteria for VaD are
still being developed, multiple microinfarcts, small infarcts
or lacunes in the subcortical structures, rather than mac-
roinfarction or large vessel disease appear robustly related
to cognitive impairment. Diffuse WM changes involving
periventricular and deeper regions are frequent in VaD.
Concomitant hippocampal pathology including sclerosis
and Alzheimer pathology compound disease progression.
Further definitions of the ­­neuropathological correlates of
VaD and investigation of genetic models would be ­valuable
for exploring the pathogenesis as well as management of
VaD through preventative and treatment strategies in
the future.
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Zekry, D., Duyckaerts, C., Moulias, R. et al. (2002).
Degenerative and vascular lesions of the brain have
synergistic effects in dementia of the elderly. Acta
Neuropathologica, 103 (5): 481–487.

Therapeutic strategies for vascular cognitive
disorders
GUSTAVO C. ROMÁN
60.1 INTRODUCTION
The therapeutic management of vascular cognitive dis-
orders (VCDs) including vascular dementia (VaD) is par-
ticularly challenging because of the multiple types of
cerebrovascular injuries and circulatory events that may
lead to cognitive decline and eventual dementia. The mul-
tiplicity of pathogenetic mechanisms results in a variety
of clinical presentations that have hampered the formula-
tion of diagnostic criteria and the ascertainment of cases
for controlled clinical trials. The International Society for
Vascular Behavioural and Cognitive Disorders (VASCOG)
recently proposed a unified set of criteria for VCD (Sachdev
et al., 2014) that addressed most of those problems. The
VASCOG criteria recognized the continuum of vascular
cognitive impairment (VCI) ranging from mild VCD at one
end to VaD or major VCD at the other end, and addressed
the important role of brain imaging in clinical trials of VaD
(Black, 2007; Román et al., 2010).
A recent development is the recognition of the impor-
tance of vascular lesions in the pathogenesis and clinical
presentation of most cases of late-onset Alzheimer’s dis-
ease (AD) (Roman, 2002a), supporting the concept that
vigorous treatment of vascular risk factors in patients
with early cognitive decline could delay the onset or pre-
vent dementia (Román et al., 2012; Willis and Hakim,
2013; Román and Boller, 2014). It has been estimated that
one-third of AD cases worldwide might be attributable to
potentially modifiable vascular risk factors (Norton et al.,
2014). According to Barnes and Yaffe (2011) ‘A 10%–25%
reduction in all seven risk factors (diabetes, midlife hyper-
tension, midlife obesity, smoking, depression, cognitive
inactivity or low educational attainment and physical
inactivity) could potentially prevent as many as 1.1–3.0
million AD cases worldwide’. A recent, population-based
660
60
double-blind randomized controlled trial (RCT) in
Finland (Ngandu et al., 2015), on 1260 subjects ages 60–77
years, demonstrated that after 2 years of a multidomain
intervention (diet, exercise, cognitive training, vascular
risk monitoring), cognition improved or remained bet-
ter in the intervention group compared with the control
group that received only general health advice.
Lastly, VaD is often complicated by neuropsychiatric
symptoms, in particular depression, apathy, aggressiveness
and other behavioural changes requiring careful manage-
ment (Román, 2014). With exception of the dextromethor­
phan plus ultra low-dose quinidine trial showing reduction
of pseudobulbar effect and some of the above manifesta-
tions (Pioro et al., 2010), few clinical trials have addressed
these issues.
60.2 DEFINITIONS
60.2.1 VASCULAR COGNITIVE DISORDERS
(VCDs)
Sachdev (1999) first indicated the need for a categorical
entity – a disorder – to include the large numbers of patients
with dementia and cognitive decline of vascular aetiol-
ogy and proposed the name ‘vascular cognitive disorder’.
VASCOG formally proposed VCD as a diagnostic category
(Sachdev et al., 2014). VCD recognizes the need for a cat-
egorical diagnosis that encompasses mild impairment, pre-
dementia and dementia syndromes. VASCOG included
the recommendations of expert groups from the National
Institute of Neurological Disorders and Stroke (NINDS)–
Canadian Stroke Network (Hachinski et al., 2006) and the
statement from the American Heart Association/American
 Therapeutic strategies for vascular cognitive disorders 661

Stroke Association (Gorelick et al., 2011). VCD is defined
as a diagnostic category that embraces many syndromes
and diseases, and acknowledges the common occurrence of
non-cognitive syndromes such as depression, anxiety and
psychosis. It includes all forms of cognitive decline result-
ing from cerebrovascular disease (CVD) ranging from
mild cognitive deficits (mild VCD) to VaD (Román et al.,
2004). VCD excludes isolated cognitive dysfunctions result-
ing from stroke (e.g. aphasia, apraxia or agnosia). VCD
includes all the syndromes and diseases characterized by
cognitive impairment resulting from cerebrovascular aeti-
ologies including post-stroke VaD, Cerebral Autosomal
Dominant Arteriopathy with Subcortical Infarcts and
Leukoencephalopathy (CADASIL), Binswanger’s disease
(BD) and mixed dementia (AD+CVD). Regarding specific
aetiologies of VCD (Table 60.1), Mendez and Cummings
(2003) collected more than 100 potential vascular causes
of cognitive impairment and dementia. This concep-
tual clarification should facilitate epidemiological and
pharmacological research in this domain of major public
health importance.
The VASCOG statement (Sachdev et al., 2014) unified
seven sets of criteria for VaD, including Hachinski Ischaemic
Score (HIS) (Hachinski et al., 1975), National Institute of
Neurological Disorders and Stroke–Association Internationale
pour la Recherche et l’Enseignement en Neurosciences
(NINDS-AIREN) (Román et al., 1993), Alzheimer’s Disease
Diagnostic and Treatment Center (ADDTC) (Chui et al.,
1992), Diagnostic and Statistical Manual of Mental Disorders,
4th Edition (DSM-IV) (American Psychiatric Association,
1994), International Statistical Classification of Diseases, 10th
Revision (ICD-10) (World Health Organization, 2008), the
subcortical VaD criteria (Erkinjuntti et al., 2000) and the vas-
cular cognitive impairment without dementia (VCI-ND) crite-
ria (Rockwood et al., 2000; Ingles et al., 2002). Although all of
them are useful in selecting VaD patients with varying sensitiv-
ity and specificity, they are not interchangeable (Verhey et al.,
1996; Wetterling et al., 1996; Chui et al., 2000; Pohjasvaara

Table 60.1 Pathological basis for vascular cognitive disorders according to VASCOG criteria
Parenchymal lesions of vascular aetiology
(1) Large vessel or atherothromboembolic disease
(a) Multiple infarcts
(b) Single strategically placed infarct
(2) Small vessel disease
(a) Multiple lacunar infarcts in white matter and deep grey matter nuclei
(b) Ischemic white matter change
(c) Dilatation of perivascular spaces
(d) Cortical/subcortical microinfarcts and microhemorrhages
(3) Haemorrhage
(a) Intracerebral haemorrhage
(b) Multiple cortical and subcortical microbleeds
(c) Subarachnoid haemorrhage
(4) Hypoperfusion
(a) Hippocampal sclerosis
(b) Laminar cortical sclerosis
Types of vascular lesions
(1) Atherosclerosis
(2) Cardiac, atherosclerotic and systemic emboli
(3) Arteriolosclerosis
(4) Lipohyalinosis
(5) Amyloid angiopathy
(6) Vasculitis – infectious and non-infectious
(7) Venous collagenosis
(8) Arteriovenous fistulae – dural or parenchymal
(9) Hereditary angiopathies – cerebral autosomal dominant arteriopathy with subcortical infarcts and
leukoencephalopathy (CADASIL), cerebral autosomal recessive arteriopathy with subcortical autosomal recessive
leukoencephalopathy (CARASIL), etc.
(10) Giant cell arteritis
(11) Berry aneurysms
(12) Miscellaneous vasculopathies – fibromuscular dysplasia, Moya-Moya
(13) Systemic microangiopathies without vascular inflammatory cell infiltrates
(14) Cerebral venous thrombosis
Source: Sachdev, P. et al., Alzheimer Disease and Associated Disorders, 28, 206–218, 2014.
Abbreviation: VASCOG, International Society for Vascular Behavioural and Cognitive Disorders.
662 Dementia

et al., 2000; Wiederkehr et al., 2008a, 2008b). The VASCOG
criteria provide a scientific and coherent approach to the study
of this group of disorders unifying the terminology under the
name VCD. Also, VASCOG provides diagnostic thresholds
and proposes clinical and neuroimaging criteria for establish-
ing a vascular aetiology, describes subtypes and emphasizes the
frequent co-occurrence of AD and vascular pathology.
60.2.2 MILD VCD – MILD VCI
In 2004, an International Working Group on Mild Cognitive
Impairment (VCI) proposed a set of recommendations for
the diagnosis of VCI (Winblad et al., 2004). According to
VASCOG (Sachdev et al., 2014), the term ‘impairment’ in this
context should be discouraged because of two major limita-
tions: (1) impairment is used in medicine to indicate a reduc-
tion or loss of function applied either as a statistical construct
based on normative data or as a demonstration of disability
and (2) VCI has sometimes been used to denote mild cogni-
tive impairment (MCI) due to vascular factors, insufficiently
severe to be diagnosed as dementia (Román et al., 2004) by
analogy to MCI and considered as the earliest manifestation
of AD (Petersen et al., 1999). Also, VCI is sometimes equated
with dysexecutive MCI (Winblad et al., 2004) and with
VCI without dementia or VCI-ND (Rockwood et al., 2000;
Ingles et al., 2002). Instead of VCI and to harmonize with
Diagnostic and Statistical Manual of Mental Disorders, 5th
Edition (DSM-5) (American Psychiatric Association, 2013),
VASCOG recommended using the categories mild VCD, at
one end of severity, and VaD or major VCD, at the other end.
Table 60.2 summarizes the VASCOG criteria for mild VCD.
60.2.3 VASCULAR DEMENTIA
Román (2002b, 2003a) defined VaD as an aetiological
category of dementia characterized by acquired intellec-
tual impairment, severe enough to interfere with social
and personal independence, resulting from ischaemic or
haemorrhagic stroke, as well as from ischaemic hypoper-
fusive brain injuries, affecting brain regions important for
memory, cognition and behaviour.
Table 60.1 lists the most common neuropathological
lesions capable of producing VaD including brain haemor-
rhages and hypoperfusive and ischaemic (occlusive) vas-
cular brain injuries (Brun, 1994; Parnetti, 1999; Mikol and
Vallat-Decouvelaere, 2000; Vinters et al., 2000; Jefferson
et al., 2015a, 2015b).
The VASCOG criteria for VaD (Sachdev et al., 2014)
require that in addition to the criteria of mild cognitive
disorder listed above, the objective deficits in neurocogni-
tive tests typically should fall ≥2 standard deviations (SDs)
below the mean (or below the third percentile) of people of
similar age, sex, education and sociocultural background,
or an equivalent level as judged by the clinician; also, the
cognitive deficits are sufficient to interfere with the subject’s
independence.
60.2.3.1 The NINDS-AIREN VaD criteria
The criteria developed by the NINDS-AIREN (Román
et al., 1993) were developed specifically for research stud-
ies in VaD, including most vascular aetiologies and clini-
cal manifestations (Table 60.3). These criteria have the
highest specificity (0.84–0.94) (Gold et al., 1997, 2002) and
have been used in most RCTs of VaD (Rosen et al., 1980;
López-Pousa et al., 1997; Kittner, 1999; Erkinjuntti et al.,
2002a; Orgogozo et al., 2002; Wilcock et al., 2002; Black et al.,
2003; Wilkinson et al., 2003; Black, 2007). These criteria rec-
ognize patients with multiple forms of stroke and CVD, but
establish strict requirements to classify patients appropri-
ately. Two cardinal elements of the clinical syndrome of VaD
must be identified: the cognitive syndrome of dementia and
the definition of the vascular cause of the dementia. CVD is
defined by the presence of focal neurological signs and brain
imaging showing evidence of stroke or ischaemic changes in
the brain. A defining element of the criteria is the need for a

Table 60.2 VASCOG diagnostic criteria for mild cognitive disorder

A. Acquired decline from a documented or inferred previous level of performance in ≥1 of the following cognitive
domains: (1) attention and processing speed, (2) frontal executive function, (3) learning and memory, (4) language,
(5) visuoconstructional–perceptual ability, (6) praxis-gnosis-body schema, (7) social cognition, as evidenced by the
following:
(a) Concerns of a patient, knowledgeable informant or a clinician of mild levels of decline from a previous level of
cognitive functioning. Typically, the reports will involve greater difficulty in performing the tasks or the use of
compensatory strategies.
(b) Evidence of modest deficits on objective cognitive assessment based on a validated measure of neurocognitive
function (either formal neuropsychological testing or an equivalent clinical evaluation) in ≥1 cognitive domains listed
above. The test performance is typically in the range between 1 and 2 standard deviations below appropriate norms
(or between the 3rd and 16th percentiles) when a formal neuropsychological assessment is available or an equivalent
level as judged by the clinician.
B. The cognitive deficits are not sufficient to interfere with independence (i.e. instrumental activities of daily living are
preserved), but greater effort, compensatory strategies or accommodation may be required to maintain
independence.
Source: Sachdev, P. et al., Alzheimer Disease and Associated Disorders, 28, 206–218, 2014.
 Therapeutic strategies for vascular cognitive disorders 663

Table 60.3 NINDS-AIREN diagnostic criteria for vascular dementia (VaD)

I. The criteria for the diagnosis of probable VaD include all of the following:
(a) DEMENTIA: Impairment of memory and two or more cognitive domains (including executive function), interfering with
ADLs and not due to physical effects of stroke alone. Exclusion criteria: Alterations of consciousness, delirium,
psychoses, severe aphasia or deficits precluding testing, systemic disorders, Alzheimer’s disease or other forms of
dementia.
(b) CEREBROVASCULAR DISEASE (CVD): Focal signs on neurological examination (hemiparesis, lower facial weakness, Babinski
sign, sensory deficit, hemianopsia, dysarthria) consistent with stroke (with or without history of stroke) and evidence
of relevant CVD by brain CT or MRI including multiple large vessel infarcts or a single strategically placed infarct
(angular gyrus, thalamus, basal forebrain, or PCA or ACA territories), as well as multiple basal ganglia and white
matter lacunes or extensive periventricular white matter lesions, or combinations thereof. Exclusion criteria:
Absence of cerebrovascular lesions on CT or MRI.
(c) A RELATIONSHIP BETWEEN THE ABOVE TWO DISORDERS: Manifested or inferred by the presence of one or more of the following:
(i) Onset of dementia within 3 months following a recognized stroke.
(ii) Abrupt deterioration in cognitive functions or fluctuating, stepwise progression of cognitive deficits.
  II. Clinical features consistent with the diagnosis of probable VaD include the following:
(a) Early presence of gait disturbances (small step gait or marche à petits pas, or magnetic, apraxic–ataxic or
parkinsonian gait).
(b) History of unsteadiness and frequent, unprovoked falls.
(c) Early urinary frequency, urgency and other urinary symptoms not explained by urologic disease.
(d) Pseudobulbar palsy.
(e) Personality and mood changes, abulia, depression, emotional incontinence, or other deficits including psychomotor
retardation and abnormal executive function.
III. Features that make the diagnosis of VaD uncertain or unlikely include:
(a) Early onset of memory deficit and progressive worsening of memory and other cognitive functions such as language
(transcortical sensory aphasia), motor skills (apraxia) and perception (agnosia), in the absence of corresponding
focal lesions on brain imaging.
(b) Absence of focal neurological signs, other than cognitive disturbances.
(c) Absence of CVD on CT or MRI.
Source: Román, G.C. et al., Neurology, 43, 250–260, 1993.
Abbreviations: INDS-AIREN, National Institute of Neurological Disorders and Stroke–Association Internationale pour la Recherche et
l’Enseignement en Neurosciences; ADLs, activities of daily living; CT, computerized tomography; MRI, magnetic resonance imaging;
PCA, posterior cerebral artery; ACA, anterior cerebral artery.

temporal relationship between dementia and CVD whereby
dementia onset should occur within 3 months following a
recognized stroke. The temporal relationship proved to be
difficult to fulfil due to silent strokes and subcortical VaD.
The accuracy of the NINDS-AIREN criteria increases by
excluding subjects with pre-existing diagnosis of AD, those
with isolated memory impairment (MCI), as well as those
with history of obvious progressive cognitive decline prior
to a stroke or pre-stroke dementia (Hénon et al., 1997, 2001).
VaD dementia typically occurs in patients with stroke and
multiple vascular risk factors. The HIS quantifies this profile
with high interrater reliability (kappa = 0.61). A score >4
in the HIS usually excludes AD. Using the NINDS-AIREN
criteria (Román et al., 1993), three international trials of
donepezil in VaD (Black et al., 2003; Wilkinson et al., 2003;
Román et al., 2010) recruited 2193 patients with relatively
pure or unmixed VaD enrolled at 111 investigational sites
in the United States, Europe, Canada and Australia (Román
et al., 2005). The VaD population selected was older and
had a male preponderance, in agreement with popula-
tion-based epidemiological data on VaD (Román, 2008b).
Furthermore, the 6-month progression of the placebo
groups selected in the donepezil VaD studies was different
from placebo groups in AD (Román and Rogers, 2004) as
well as in mixed AD plus CVD trials (Erkinjuntti et al.,
2002a, 2002b), further indicating the separate identity of the
VaD cases selected (Pratt, 2002). The latest donepezil trial in
VaD recruited 974 patients (mean age 73.0 years) with prob-
able or possible VaD who were randomized 2:1 to receive
donepezil 5 mg/day or placebo (Román et al., 2010). Thus,
almost 2200 patients with unmixed VaD identified with the
NINDS-AIREN criteria have been studied in clinical trials
using a cholinesterase inhibitor (ChEI).
60.2.4 VaD WITH AD
Specific brain pathological lesions define the two most com-
mon forms of senile dementia, AD and VaD. Stroke and
CVD are the hallmarks of VaD, while senile plaques and
neurofibrillary tangles typify AD. When these two patholo-
gies are combined, the neuropathological diagnoses of
AD+CVD, VaD with AD, or ‘mixed dementia’ are invoked
(Zekry et al., 2002a). However, the term ‘mixed dementia’ is
ambiguous and is not recommended by VASCOG.
In the experience of the Consortium to Establish a
Registry for AD (CERAD), vascular pathology also coexists
664 Dementia
with Lewy body disease in isolation or in combination with
AD pathology (Mirra, 1997). Coexistent lesions occur in
up to one-third of unselected elderly demented patients
(Kalaria and Ballard, 1999; Zekry et al., 2002a, 2002b,
2002c) or in 10%–15% of cases of post-stroke dementia
(PSD) (Hénon et al., 1997, 2001; Barba et al., 2000, 2001),
but mixed lesions also occur in patients without dementia
(Román and Royall, 2004).
A solid body of clinical, imaging, epidemiological and
neuropathological evidence has accumulated over the past
two decades confirming the critical role of CVD in AD
and other dementias of the aged subjects (Chui et al., 2006;
Schneider et al., 2007; Fotuhi et al., 2009; Gorelick et al.,
2011; Wharton et al., 2011; De Carli, 2012; Yarchoan et al.,
2012; Bennett et al., 2013; Yates et al., 2014). Data from the
National Alzheimer’s Coordinating Center (Toledo et al.,
2013) showed the presence of vascular pathology in 80%
of 4629 brains from patients with neuropathologically
confirmed AD. Lesions included large vessel disease with
atherosclerosis in the arteries of the circle of Willis and its
branches resulting in large territorial infarcts, small vessel
disease with arteriolosclerosis and small infarcts includ-
ing lacunes and multiple microinfarcts, Binswanger’s type
ischaemic periventricular leukoencephalopathy and brain
haemorrhages. Notably, cerebral amyloid angiopathy (CAA)
was present in less than half of the brains (41%). Population-
based autopsy studies find pure AD and pure cases of VaD
to be uncommon in older demented subjects. In this age
group, the neuropathology rule is the presence at autopsy of
mixed dementia with a predominant vascular component
(Zekry et al., 2002a). According to Matthews et al. (2009),
the main attributable risks at death for dementia are age
(18%), small brain (12%), neocortical neuritic plaques (8%)
and neurofibrillary tangles (11%), small vessel disease (12%),
multiple vascular pathologies (9%), hippocampal atrophy
(10%), CAA (7%) and Lewy bodies (3%). The confirmation
of the role of vascular lesions in AD explains some of the
difficulties with consensus criteria for VaD (Black, 2007)
and offers hope for the treatment and prevention of late-
life dementia (Brookmeyer et al., 2007; Polidori et al., 2012;
Anstey et al., 2013).
60.3 METHODOLOGICAL ASPECTS OF
CLINICAL TRIALS IN VaD
The methodological requirements for RCTs in patients with
dementia were reviewed by the International Working Group
on Harmonization of Dementia Drug Guidelines at the
Sixth International Congress on AD and Related Disorders
in Amsterdam (Whitehouse et al., 1998), and at the 1998
Osaka Conference on VaD (Erkinjuntti and Sawada, 1999;
Erkinjuntti et al., 1999); for more recent reviews, see Mills
and Chow (2003), Mani (2004), Erkinjuntti et al. (2004),
Hachinski et al. (2006) and Sachdev et al. (2014).
The first and foremost requirement for a valid trial in
dementia, and VaD in particular, is the use of appropriate
inclusion and exclusion criteria. This requirement is crucial
for the selection of a homogeneous population that would
allow the generalized application of the trial results. Given the
clinical variety of VaD, some authors have suggested limiting
the trials to patients with subcortical VaD using various sets
of criteria (Pantoni et al., 1996, 2000; Erkinjuntti et al., 2000;
Moretti et al., 2001, 2002, 2004) or to cases of mixed demen-
tia, including AD+CVD (Erkinjuntti et al., 2002a, 2002b,
2003a) or AD plus arterial hypertension (Kumar et al., 2000).
However, as discussed above, the criteria proposed by Román
et al. (1993) are appropriate for VaD trials. Several instru-
ments such as the Mini-Mental State Examination (MMSE)
(Folstein et al., 1975), the Cambridge Cognitive Examination
(CAMCOG) (Roth et al., 1986; Huppert et al., 1995), the
Alzheimer’s Disease Assessment Scale-cognitive subscale
(ADAS-cog) (Rosen et al., 1984), the Clinical Dementia Rating
(CDR) (Berg, 1988) and the Montreal Cognitive Assessment
(MoCA) (Nasreddine et al., 2005) are used to ensure that
dementia severity is comparable across the trial.
The next requirement is an appropriate number of par-
ticipants (sample size). The sample size is a function not
only of the drug’s effectiveness but also of the degree of
responsiveness – or lack thereof – of the measuring instru-
ments, as well as of the accuracy of the end points selected
for the trial. Instruments that are relatively insensitive to
change require larger sample sizes in order to demonstrate
a statistically significant difference from the placebo group.
Other requirements include randomization with appro-
priate group allocation concealment, placebo-controlled,
double-blinded design with parallel group, and specific
outcome measures, adequate instruments and well-defined
end points. Potential targets for the symptomatic treatment
of VaD include: (1) symptomatic improvement of the core
symptoms (cognition, function and behaviour), (2) slow-
ing of progression and (3) treatment of neuropsychiatric
symptoms.
All the current VaD trials have used the same primary
outcome measures used in AD trials, as recommended
by the US Food and Drug Administration (FDA). These
instruments include the ADAS-cog (Rosen et al., 1984),
the Clinician’s Interview-Based Impression of Change plus
caregiver input (CIBIC-plus) (Schneider et al., 1997) or the
Clinical Global Impression of Change (CGIC) (Berg, 1988).
The European Medicines Agency (EMEA) Committee
for Medicinal Products for Human Use (CHMP) also
requires positive impact on activities of daily living (ADLs)
using scales such as the Alzheimer’s Disease Functional
Assessment and Change Scale (ADFACS), which pro-
vides a measure of instrumental ADLs (IADLs) and basic
ADLs (Mohs et al., 2001), or the Disability Assessment for
Dementia (DAD) scale (Gélinas et al., 1999). The CHMP
also requires a responder analysis. To the extent that ADAS-
cog and CIBIC-plus assess the multiple cognitive domains
affected in all forms of dementia, it is not unreasonable to
use the same measures in both AD and VaD populations.

However, Quinn et al. (2000) showed difficulties with
CIBIC-plus ratings in instances of clinical improvement;
often physicians failed to recognize successful disease treat-
ment beyond reversal of progression.
More importantly, current tests are relatively insensitive
to frontal/subcortical executive dysfunction, a key cognitive
domain in VaD (Román and Royall, 1999; Pohjasvaara et al.,
2002). To address this issue, at least two VaD clinical trials,
one of donepezil in CADASIL – a genetic, predominantly
subcortical form of VaD (Dichgans et al., 2008; Chabriat
et al., 2009), and in VaD (Román et al., 2010), incorpo-
rated tests such as the vascular equivalent of the ADAS-cog
called the Vascular-Alzheimer’s Disease Assessment Scale-
cognitive subscale (V-ADAS-cog) (Ferris and Gauthier,
2002), as well as other tests that include formal measurement
of executive function. These include CLOX, an executive
clock drawing task (Royall et al., 1998) and the EXIT25, an
executive interview (Royall et al., 1992). ADLs are consid-
ered a proxy evaluation of executive function. Pohjasvaara
et al. (2002) confirmed that executive dysfunction was the
main determinant of abnormalities in both basic and IADLs
in patients with post-stroke VaD.
Recent clinical trials in dementia have relied on brain
imaging end points such as quantification of cortical atrophy
over time (de Jager et al., 2012). In comparison with neuropsy-
chological end points, brain imaging methods in dementia
trials are much more sensitive to change and allow a decrease
in the sample size for RCTs (Román and Pascual, 2012).
For instance, Douaud et al. (2013) in the Oxford Project to
Investigate Memory and Ageing (OPTIMA) trial used mag-
netic resonance imaging (MRI) scans with optimized voxel-
based morphometry in 80 subjects with MCI (Petersen et al.,
1999; Petersen, 2004) compared with 76 subjects on placebo.
After 24 months of treatment, B-group vitamins (the active
arm) resulted in significant decrease of the rate of grey matter
atrophy resulting from neurodegeneration. Compared with
the usual trials in dementia, the sample size reduction in
this trial was one order of magnitude. Thus, the use of brain
imaging end points could decrease substantially the cost of
controlled clinical trials in VaD and other forms of VCD.
60.4 CLINICAL FORMS OF VaD
Despite the anatomical and pathophysiological complexity
of VaD, Román (1999a, 2002b) has simplified the diverse
clinical forms into two main groups, acute and subacute,
according to the temporal profile of presentation.
60.4.1 ACUTE FORMS OF VaD
Acute VaD is defined by new onset of dementia after a
demonstrated stroke, either from a single ‘strategic stroke’
resulting from occlusion (or rupture) of a large-sized ves-
sel, following a symptomatic lacunar stroke caused by
ischaemic small vessel disease, or from recurrent strokes
Therapeutic strategies for vascular cognitive disorders 665
(multi-infarct dementia or MID). VaD can result from a
single stroke located in one of the following three possible
areas (Delay and Brion, 1962):
1. Posterior cerebral artery (PCA) territory, involving
ventral-medial temporal lobe, hippocampus, occipital
structures and thalamus.
2. Anterior cerebral artery (ACA) territory and medial
frontal lobe lesions, often from an anterior communi-
cating artery aneurysm rupture.
3. Basal ganglia and thalamus, usually from small vessel
disease; this is the so-called ‘thalamic dementia of
vascular origin’ caused by butterfly-shaped bilateral
paramedian thalamic artery polar infarcts. Some cases
of caudate stroke may also result in VaD.
Numerous reports have confirmed the occurrence of
true ‘lacunar dementia,’ i.e. acute VaD resulting from a
single lacunar stroke involving the inferior genu of the
internal capsule and causing ipsilateral blood flow reduc-
tion to the inferomedial frontal cortex by a mechanism of
diaschisis (Tatemichi et al., 1992, 1995; Chukwudelunzu
et al., 2001). This thalamo-cortical disconnection syndrome
is manifested by sudden change in cognitive function, often
associated with fluctuating attention, memory loss, confu-
sion, abulia, striking psychomotor retardation, inattention
and other features of frontal lobe dysfunction but with mild
focal findings such as hemiparesis or dysarthria.
60.4.2 SUBACUTE–SUBCORTICAL FORMS
OF VaD
Subcortical ischaemic vascular dementia (SIVD) (Román
et al., 2002) is the prototype of subacute VaD. This frequent
clinical form is defined clinically by insidious onset of sub-
cortical dementia with frontal lobe deficits, depressive mood
changes – the so-called ‘vascular depression’ (Alexopoulos
et al., 2002), along with psychomotor slowing, parkinsonian
features, urinary disturbances and pseudobulbar palsy, usu-
ally resulting from small vessel disease (Román et al., 2002).
Symptoms are due to interruption by ischaemic lesions
of prefrontal–subcortical circuits for executive control of
working memory, organization, language, mood, regulation
of attention, constructional skills, motivation and socially
responsive behaviours (Cummings, 1993). Prefrontal–
subcortical loops may be severed by lacunes in the striatum,
by globus pallidus or thalamus or by white matter lesions
that disconnect the prefrontal or the anterior cingulate cor-
tex from their basal ganglia or thalamo-cortical connections
(Swartz et al., 2003; Vataja et al., 2003).
Loss of executive function is a major component of VaD
(Román and Royall, 1999) leading to cognitive disability
and clinically significant loss of planning capacity, working
memory, attention, concentration, discrimination, abstrac-
tion, conceptual flexibility and self-control (Román and
Royall, 1999; Vataja et al., 2003). Some patients are unable
to initiate the required behaviour, others fail to inhibit
666 Dementia
irrelevant behaviours and most can perform individual
steps of a complex problem but cannot provide a correct
strategy to solve it. These symptoms often lead to post-
stroke depression and functional disability (Pohjasvaara
et al., 1998, 2002).
The main clinical forms of subacute VaD are BD (état
lacunaire), CADASIL and rare instances of CAA, including
those that present with leukoencephalopathy (Gray et al.,
1985; Sarazin et al., 2002). The temporal profile of presenta-
tion of these conditions is typically subacute, with a chronic
course marked by fluctuations and progressive worsening.
60.4.2.1 Binswanger disease
In 1894, Otto Binswanger described a disease characterized
by the presence of ischaemic periventricular leukoencepha-
lopathy typically sparing the arcuate subcortical U-fibres
(Binswanger, 1894; Román, 1987). Brain imaging (com-
puted tomography [CT] and MRI) usually correlates well
with the pathological features that include diffuse myelin
pallor and ventricular dilatation. Microscopically there is
loss of myelin and axons resulting in rarefaction, spongio-
sis and vacuolization without definite necrosis (incomplete
white matter infarction); there is loss of oligodendrocytes
and astrocytic gliosis with clasmatodendrosis (Sahlas et al.,
2002), axonal thinning, demyelination, gliosis at the dorso-
lateral angles of the frontal horns, along with loss of epen-
dymal lining (ependymitis granularis) allowing leakage of
ventricular cerebrospinal fluid (CSF) (Black et al., 2009).
Moody et al. (1995) found that a non-inflammatory, peri-
ventricular venulopathy with concentric collagen deposi-
tion causing intramural thickening, stenosis and ultimately
venous luminal occlusion could be relevant in the patho-
genesis. This periventricular occlusive venous collagenosis
increases markedly with age (65% after age 65 years and
older) and correlates with the severity of the periventricular
leukoencephalopathy. In addition, small vessel disease with
arteriolosclerosis and other hypertensive lesions (Lammie,
2002), and état criblé or widening of perivascular spaces are
present. Advanced white matter lesions include focal necro-
sis and cavitations (lacunes); there are also lacunar infarcts
in the basal ganglia and the pons. Román (1985a) suggested
the identity of BD and a remarkably similar clinical condi-
tion, état lacunaire (Marie, 1901), characterized by multiple
lacunes, ventricular dilatation and lesions of the white mat-
ter with a moth-eaten appearance. The syndrome included
mild residual hemiparesis, a peculiar gait with short steps
(marche à petits pas), dysarthria, pseudobulbar palsy and
extrapyramidal features such as inexpressive facies, slow-
ness of movement, axial rigidity, loss of postural reflexes
and frequent falls.
Dementia is not a salient feature of état lacunaire (Marie,
1901), but some intellectual deficit is constantly present.
However, Fisher (1965) remarked that lacunar strokes typi-
cally do not cause disturbances in higher cerebral func-
tions, and when present ‘always exclude a lacunar diagnosis’.
Among 114 patients with lacunes he examined at necropsy,
dementia was uncommon or mild. Population-based stud-
ies of elderly subjects indicate that in the vast majority of
cases lacunes are silent (Longstreth et al., 1998); however,
silent lacunes particularly in the thalamus cause more than
double the risk of dementia (hazard ratio [HR] 2.26, 95%
confidence interval [CI] 1.09–4.70) (Vermeer et al., 2003).
Hospital-based series of lacunar infarctions show that
about 30% of these patients develop dementia (Babikian
et al., 1990; Tatemichi et al., 1993). In a clinicopathological
review of 100 consecutive autopsies of patients with lacu-
nar strokes at the Hôpital de la Salpêtrière (Román, 1985b),
72 cases with multiple lacunes were found, but only 36%
were clinically demented (état lacunaire). In six cases AD
and lacunes coexisted and an additional six patients had BD
(Mikol, 1968). In the demented patients, dilatation of the
lateral ventricles was the only morphological feature that
separated état lacunaire patients from cases with multiple
lacunes but without dementia, suggesting that either white
matter disease or normal pressure hydrocephalus could
have contributed to dementia (Román, 1991).
The Secondary Prevention of Small Subcortical Strokes
(SPS3) trial was a large multicentre international study con-
ducted in relatively young patients (mean age 63 ± 11 years)
with acute lacunar stroke causing no major functional defi-
cit or cognitive loss (Benavente et al., 2011, 2014). Of the 2916
participants recruited, 56% were English-speaking from the
United States or Canada, 40% were Spanish-speaking from
Latin America, Spain and the United States and 4% were
French-speaking Canadians (White et al., 2013). Cognitive
function was determined by the Cognitive Abilities
Screening Instrument (CASI) (Teng et al., 1994; McCurry
et al., 1999); participants were tested annually for up
to 5 years. The SPS3 trial showed that a treatment that
reduces systolic blood pressure (BP) (<130 mm Hg) lowers
the risk of recurrent stroke compared with a higher target
(130–149 mm Hg) (The SPS3 Study Group, 2013; Pearce
et al., 2014); the addition of clopidogrel to aspirin (ASA)
increased bleeding risk and was not beneficial compared
with ASA alone (The SPS3 Investigators, 2012). MCI was
found in 46% of participants at study entry (Jacova et al.,
2012, 2015); of the remaining, 27% developed MCI in the
absence of a stroke during the study: 6% amnestic, 19%
non-amnestic and 1% multidomain (Pearce et al., 2014).
Cognitive decline beyond age-expected changes over a
median follow-up of 3 years was not observed in the entire
group and cognition was not affected by short-term dual
antiplatelet treatment or BP reduction (Pearce et al., 2014).
Neuropathological studies show that as many as 60% of
patients with AD have Binswanger-type white matter lesions
(Brun and Englund, 1988; Englund et al., 1988). These
lesions have been postulated as being caused by cerebral
hypoperfusion resulting from cardiac disease or orthostatic
hypotension; this form could be called AD with Binswanger-
type lesions (AD+BD). Moreover, Snowdon et al. (1997)
in the Nun Study reported that in very old subjects lacu-
nes are an important factor in the clinical expression of
AD. This was confirmed in the Religious Orders Study

(Schneider et al., 2009), the Honolulu-Asian Aging Study
(Petrovitch et al., 2005) and the Medical Research Council
Cognitive Function and Ageing Study (MRC-CFAS)
(Matthews et al., 2009). Likewise, according to Jellinger and
Mitter-Ferstl (2003), the presence of cerebrovascular pathol-
ogy in patients with AD is significantly higher at autopsy
than in controls (48% versus 7.4%). On post-mortem exami-
nation, Zekry et al. (2002b, 2002c) demonstrated the syner-
gistic effect of vascular lesions in patients with AD dementia.
Presence of vascular lesions had a direct correlation with
dementia severity. Furthermore, the density of AD lesions
(neuritic plaques, focal amyloid β deposits and neurofibril-
lary tangles) was significantly lower when vascular lesions
were present.
60.4.2.2 CADASIL
CADASIL was described in France in the early 1990s
(Bousser and Tournier-Lasserve, 1994). This condition was
originally called ‘familial Binswanger’ (van Bogaert, 1955)
and ‘hereditary MID’ (Sourander and Walinder, 1977;
Sonninen and Savontaus, 1987). CADASIL appears to be
the most common genetic form of VaD (Dichgans, 2002;
Kalimo et al., 2002; Chabriat and Bousser, 2003; Chabriat
et al., 2009). This autosomal dominant disorder of cere-
bral small vessels maps to chromosome 19 and is caused by
Notch3 gene mutations. The underlying vascular lesion is a
unique non-amyloid non-atherosclerotic microangiopathy
involving arterioles (100–400 μm in diameter) and capil-
laries, primarily in the brain but also in other organs. The
diagnosis may be established by skin biopsy (Ruchoux et al.,
1995) with confirmation by immunostaining using a Notch3
monoclonal antibody.
CADASIL offers a natural model for the study of
subcortical–subacute forms of VaD, in particular BD.
Numerous pedigrees have been described in Europe and
North America. Clinical manifestations include transient
ischaemic attacks (TIAs) and strokes (80%); cognitive defi-
cits, apathy and VaD (50%); migraine with focal deficits
(40%); mood disorders (30%) and epilepsy (10%). Onset
is usually in early adulthood (mean age: 46 years) in the
absence of risk factors for vascular disease, culminating in
dementia and death usually about 20 years after symptom
onset. The dementia is slow in onset, subcortical, frontal in
type, accompanied by gait and urinary disturbances and
pseudobulbar palsy clinically identical to that of sporadic
BD. MRI reveals a combination of small lacunar lesions and
diffuse white matter abnormalities, including typical lesions
of the corpus callosum and tip of the temporal lobes; MRI
lesions are often present in asymptomatic relatives. Also,
cerebral blood flow (CBF) reactivity to inhaled carbon diox-
ide (CO2) is impaired. Widespread smooth muscle cell loss
results in decreased regional cerebral blood volume (CBV);
these values correlate inversely with cognitive performance.
The disease is caused by highly stereotyped mutations in the
Notch3 gene that encodes a phyllogenetically old transmem-
brane cell surface receptor that regulates cell fate during
Therapeutic strategies for vascular cognitive disorders 667
embryonic development. The large extracellular domain of
Notch3 contains 34 tandem epidermal growth factor (EGF)-
like repeats where the mutations result in gain or loss of a
cysteine residue.
Other rare genetic forms of VCD include: cerebral
autosomal recessive arteriopathy with subcortical autoso-
mal recessive leukoencephalopathy (CARASIL); heredi-
tary endotheliopathy retinopathy, nephropathy and stroke
(HERNS); pontine autosomal dominant microangiopathy
and leukoencephalopathy (PADMAL); retinal vasculopathy
with cerebral leukodystrophy (RVCL) and, collagen type IV,
α1 (COL4A1)-related disorders (Leblanc et al., 2006).
60.4.2.3 Cerebral amyloid angiopathy
CAA is a heterogeneous group of disorders characterized
by amyloid deposition in the walls of leptomeningeal and
cerebral cortical blood vessels, manifested clinically by
recurrent lobar haemorrhages, cognitive deterioration and
ischaemic strokes. Cerebral MRI displays diffuse white
matter abnormalities along with ischemic or haemorrhagic
focal brain lesions. On histology, the vessels show amyloid
deposition, microaneurysms and fibrinoid necrosis.
There are several autosomal dominant forms of CAA
with differences in their clinical, genetic, biochemical and
pathologic findings. A-β, the major amyloid component in
the Dutch-, Flemish- and Iowa-type of familial CAA, is also
the major amyloid component in sporadic CAA and in AD.
Familial British dementia with amyloid angiopathy (FBD)
is an autosomal dominant condition characterized by VaD,
progressive spastic paraparesis and cerebellar ataxia with
onset in the sixth decade (Mead et al., 2000). A point muta-
tion in the BRI gene is the genetic abnormality. On brain
MRI, Binswanger-type deep white matter hyperintensities
and lacunar infarcts are seen, but without intracerebral
haemorrhages. The corpus callosum is severely affected and
atrophic. Plaques and tangles are present but the amyloid
subunit (ABri) found in FBD brains is entirely different
and unrelated to other amyloid proteins. FBD combines
neurodegeneration and dementia with systemic amyloid
deposition.
60.5 RISK FACTORS FOR VaD
A number of case–control studies of PSD have provided
quantification of risk factors for VaD (Tatemichi et al., 1990;
Pohjasvaara et al., 1997; Barba et al., 2001; Leys et al., 2005;
Brainin et al., 2015). In the Framingham study, the occur-
rence of stroke doubled the risk of dementia (Ivan et al.,
2004); the prevalence of PSD in stroke survivors is about
30% and the incidence of new-onset dementia after stroke
increases from 7% after 1 year to 48% after 25 years (Leys
et al., 2005). In patients with ischaemic stroke, the most
important risk factors for the development of PSD are older
age, lower educational level and loss of independence or
668 Dementia
cognitive decline prior to stroke, as well as recurrent stroke,
presence of dysphagia, gait limitations and urinary impair-
ment. The left-sided predominance of lesions in demented
patients with large vessel stroke in the territories of the
anterior and posterior cerebral arteries is well established
(Leys and Pasquier, 2000). Also important are silent cere-
bral infarcts, and global and medial temporal lobe atrophy.
Less often considered are obstructive sleep apnoea, hyper-
homocysteinaemia and mutations of the methylenetetrahy-
drofolate reductase (MTHFR) gene (Román, 2015).
Other risk factors include diabetes mellitus (Pasquier
et al., 2006; Umegaki, 2010), atrial fibrillation (Lefebvre
et al., 2006), as well as conditions resulting in cerebral hypo-
perfusion (Román, 2004) (e.g. myocardial infarction, car-
diac arrhythmias and congestive heart failure) (Jefferson
et al., 2015a, 2015b). Johnston et al. (2004) observed progres-
sive decline in cognitive function among Cardiovascular
Health Study participants with stenosis of the left internal
carotid artery (ICA), but not in those with stenosis of the
right ICA, in the absence of stroke. Possible explanations
include the fact that the left hemisphere has larger choliner-
gic innervation than the right one and that most cognitive
tests rely heavily on language functions.
Other risk factors for PSD include current smoking,
lower BP, orthostatic hypotension and larger periventricu-
lar white matter ischaemic lesions by brain CT or MRI (Liu
et al., 1991; Gorelick et al., 1992). Orthostatic hypotension
is an important factor in VaD (Román, 2004) and a strong
predictor of periventricular white matter ischaemic lesions
(Longstreth et al., 1996). Hypoxic and ischaemic complica-
tions of acute stroke (e.g. cardiac arrhythmias, aspiration
pneumonia, sepsis, etc.) are strong and independent risk
factors for PSD (Moroney et al., 1996); these complications
increase more than fourfold the risk of developing PSD
(odds ratio [OR] 4.3, 95% CI 1.9–9.6, after adjustment for
demographic factors, recurrent stroke and baseline cogni-
tive function). Seizures following stroke (Cordonnier et al.,
2007) are independent predictors of new-onset dementia
within 3 years after stroke (HR 3.81, 95% CI 1.13–12.82).
Pendlebury and Rothwell (2009) reviewed 21 hospital-based
and 8 population-based cohorts (7511 patients) described in
73 articles and concluded that PSD is associated with mul-
tiple strokes rather than with underlying vascular risk fac-
tors. However, as noted by Hennerici (2009), most studies
were from the 1970s and 1980s, emphasizing the concept
of MID and stroke recurrences rather than distinct mecha-
nisms of stroke causation.
PSD is a strong predictor of poor outcome (Desmond et al.,
1998; Barba et al., 2001; Linden et al., 2004; Leys et al., 2005). In
Rochester, Minnessota, 10% of 482 incident cases of dementia
had onset or worsening of the dementia within 3 months of a
stroke (Knopman et al., 2003). Overall, patients with VaD had
worse mortality than matched subjects (relative risk [RR] 2.7),
particularly among cases of PSD (RR 4.5).
The main correctable population-attributable risk (PAR)
factors (Nyenhuis and Gorelick, 2007) include hyperten-
sion (PAR = 65%), hypercholesterolemia (PAR = 36.5%),
smoking (PAR = 16.7%), diabetes mellitus (PAR = 7.7%),
excessive alcohol drinking (PAR = 5.4%) and atrial fibril-
lation (PAR = 2%). The seven potentially modifiable vas-
cular risk factors include diabetes, midlife hypertension,
midlife obesity, smoking, depression, cognitive inactivity or
low educational attainment and physical inactivity (Barnes
and Yaffe, 2011; Norton et al., 2014). As noted, at least one
population-based controlled trial in Finland (Ngandu et al.,
2015) demonstrated positive cognitive effects after 2 years
of a multidomain intervention that included diet, exercise,
cognitive training and vascular risk monitoring.
A brief review of the main results of antihypertensive tri-
als and dementia now follows.
60.5.1 HYPERTENSION AND
PREHYPERTENSION
Several prospective studies have shown that hypertension
increases dementia risk (Tzourio et al., 1999; Birkenhäger
and Staessen, 2006; Nagai et al., 2010, 2012). Also, disrup-
tion of diurnal BP variation is closely associated with cogni-
tive impairment (Sakakura et al., 2007; Nagai et al., 2008).
Therefore, there is heightened interest in the diagnosis and
treatment of the large population with prehypertension,
defined as BP in the range of >120–139 mm Hg systolic or
>80–89 mm Hg diastolic (Schunkert, 2006). In the Trial of
Preventing Hypertension (TROPHY), Julius et al. (2006)
studied the use of the angiotensin receptor blocker cande-
sartan or placebo for 2 years in persons with prehyperten-
sion (first phase). Then, all participants received placebo
for another 2 years (second phase). TROPHY showed that
after 2 years of active treatment, candesartan may interfere
with development of hypertension and prevent target organ
damage with a RR reduction of 15.6% for the development
of hypertension after 4 years. Schunkert (2006) noted that
most people with prehypertension have additional risk fac-
tors including obesity, and most of the complications asso-
ciated with prehypertension result from these cofactors
including diabetes mellitus and chronic kidney disease. The
JNC7 guidelines recommended antihypertensive treatment
of such patients if a trial of lifestyle modification failed to
reduce BP below 130/80 mm Hg (Chobanian et al., 2003).
More recent experience indicates that there is insufficient
information to recommend drug therapy for prehyperten-
sion (Marta et al., 2014).
Shah et al. (2009) reviewed the role of antihypertensive
drugs on dementia incidence and progression. These authors
analysed 536 publications from 1999 to 2008 that included
calcium channel blockers (CCBs), diuretics and angiotensin-
converting enzyme inhibitors (ACE-I). All three drug types
appeared to be beneficial in dementia, but only ACE-I plus
diuretics showed a significant reduction of dementia risk and
progression. A meta-analysis of the Systolic Hypertension
in the Elderly Program (SHEP), Systolic Hypertension in
Europe (Syst-Eur) and Study on Cognition and Prognosis in
the Elderly (SCOPE) trials (McGuinness et al., 2009) showed
that antihypertensive therapy resulted in non-statistically

significant reduction of the risk of dementia by 11% (OR
0.89, 95%CI 0.69–1.16). Statistically significant reduction
of the risk of dementia (HR 0.87, 95%CI 0.76–1.00) with
BP control was found in a meta-analysis of the SHEP, Syst-
Eur, Perindopril Protection Against Recurrent Stroke Study
(PROGRESS) and Hypertension in the Very Elderly Trial
(HYVET) trials (Peters et al., 2008). As mentioned, in SPS3,
strict control of BP post-lacunar stroke produced no change
in cognitive decline beyond age-expected changes over a
median follow-up of 3 years; dual antiplatelet treatment did
not improve the prognosis (Pearce et al., 2014).
60.5.1.1 Diuretics
Although diuretics remain the mainstay of hypertension treat-
ment (Prince, 1997; Chobanian et al., 2003), there were no
differences in cognition in those treated with diuretics alone
versus controls in the Medical Research Council’s (MRC)
study (Prince et al., 1996), in the SHEP cohort (Applegate
et al., 1994) nor in Hypertension in the Very Elderly Trial
Cognitive Function Assessment (HYVET-cog) trial (Peters
et al., 2008). However, at population level, in the Cache County
Study (Kachaturian et al., 2006) potassium-sparing diuretics
reduced (HR 0.26, 95% CI 0.08–0.64) the incidence of AD.
60.5.1.2 Calcium channel blockers
In the Syst-Eur trial (Forette et al., 1998), treatment with the
CCB nitrendipine decreased 42% the primary end point of fatal
and non-fatal stroke. Of 2418 participants in the dementia
sub-study, 60% of the treatment group received nitrendipine
alone; the rest also had enalapril and/or a hydrochlorothiazide
(HCTZ). Compared with the controls, antihypertensive ther-
apy reduced the risk of dementia by 55% (Forette et al., 2002).
60.5.1.3 Angiotensin-converting enzyme
inhibitors
In PROGRESS trial (Tzourio et al., 1999, 2003), perindopril
plus a diuretic (indapamide) – but not ACE-I alone – caused
a RR reduction of dementia of 23% (95% CI 0–41%). In the
Heart Outcomes Prevention Evaluation (HOPE) study,
ramipril compared with placebo significantly reduced (RR
0.59, 95%CI 0.37–0.94) the rate of cognitive decline (Bosch
et al., 2002).
60.5.1.4 Angiotensin II receptor blockers
(ARBs)
In SCOPE trial of candesartan versus placebo (Lithell et al.,
2003) and in Prevention Regimen for Effectively Avoiding
Second Strokes (PRoFESS), a trial of telmisartan versus pla-
cebo with over 20,332 subjects (Diener et al., 2008), there
were no significant differences in the rate of cognitive decline
or dementia with either one of the two ARBs compared
with placebo. Hanon et al. (2008) reported in Observational
Therapeutic strategies for vascular cognitive disorders 669
Study on Cognitive function And systolic blood pressure
(SBP) Reduction (OSCAR) that lowering of SBP by the ARB
eprosartan slowed cognitive decline (OR 0.77, 95% CI 0.73–
0.82). According to Fogari et al. (2006), antihypertensive
therapy with an ARB (telmisartan) plus HCTZ showed sig-
nificant improvement in cognitive function compared with
ACE-I plus diuretic (lisinopril and HCTZ). ARBs have been
shown to reduce stroke risk, in part independently of their
BP-lowering effect (Diener, 2009).
60.5.2 VASCULAR CARE AND STROKE
PREVENTION IN PATIENTS WITH
DEMENTIA
Richard et al. (2010) in the Evaluation of Vascular Care in
AD (EVA) study demonstrated that improved vascular care
in patients with AD+CVD slows the progression of white
matter lesions on MRI. There was no difference in the num-
ber of new lacunes or change in global cortical atrophy or
medial temporal lobe atrophy between the standard care
and the improved vascular care group.
Savva and Stephan (2010) have emphasized the need for
stroke prevention given that a history of stroke doubles the
risk of incident dementia in older populations. This increase
is not explained by demographic or cardiovascular risk fac-
tors or by pre-stroke cognitive decline. The excess risk of
incident dementia diminishes with time after stroke and
may be higher in those without an apolipoprotein E ε4
(APOEε4) allele. There is no excess risk of incident dementia
in those aged ≥85 years with a history of stroke. The effect
of stroke on dementia incidence in the population is not
explained by common risk factors.
Staekenborg et al. (2009) showed that patients with MCI
who converted to VaD were older and had lower baseline
MMSE than non-converters, and on baseline MRI showed
more severe white matter hyperintensities, higher preva-
lence of lacunes in the basal ganglia and microbleeds. Deep
white matter lesions (HR = 5.7, 95%CI 1.2–26.7), periven-
tricular hyperintensities (HR = 6.5, 95%CI 1.4–29.8) and
microbleeds (HR = 2.6, 95% CI 0.9–7.5) increased risk of
progression to VaD. Medial temporal lobe atrophy and
markers of CVD predict the development of different types
of dementia in MCI. It is important to control all vascular
risk factors in patients with vascular MCI, particularly when
MRI brain imaging shows white matter hyperintensities,
lacunes in the basal ganglia and microbleeds. Homocysteine
may play a role in the conversion from MCI to AD.
60.6 PHARMACOLOGICAL THERAPY
OF VaD
A review of the history of VaD (Román, 2002c, 2002d) sug-
gests that the prevailing concepts of pathogenesis at a given
time influence not only the elaboration of clinical criteria but
670 Dementia
also the approach to therapy. Until the 1970s, it was believed
that the cause of VaD was a progressive strangulation of blood
flow to the brain resulting in chronic cerebral hypoperfusion.
Therefore, beginning with nicotinic acid, a number of vaso-
dilating agents were recommended for the treatment of non-
specific senile symptoms, cognitive decline and dementia.
Following the same logic, some authors (Walsh, 1968; Walsh
et al., 1978) claimed significant improvement of symptoms
of presenile and senile dementia with a combination of war-
farin anticoagulation and psychotherapy. A vascular patho-
genesis mediated by recurrent multiple strokes (multi-infarct
dementia) also underlay the use of antithrombotic agents,
ergot alkaloids, nootropics, thyrotropin-releasing hormone
(TRH) analogue, Ginkgo biloba extract, plasma viscosity
drugs, hyperbaric oxygen, antioxidants, serotonin and his-
tamine receptor antagonists, vasoactive agents, xanthine
derivates and calcium antagonists (Román, 2000). With
increasing recognition of AD and new knowledge of neu-
rotransmitters, neuronal metabolism and biochemical tissue
reactions to ischaemia-hypoxia and oxidative stress, more
specific medications were developed leading to neuroprotec-
tion (Mondadori, 1993) and neurorepair; including agents
that may have effects similar to those of stem cells, such as
citicoline (Álvarez-Sabín and Román, 2013). The most recent
advance in the treatment of VaD has been the development
of medications to enhance specific neurotransmitters, such
as acetylcholine (ACh). Furthermore, these products have
been studied by strict controlled clinical trials. The ChEIs
will be discussed first, followed by memantine, CCBs, noo-
tropic agents, xanthines, ergot derivatives, vasodilators and
then other treatments for VaD.
With the demonstration of reduced regional CBF in late-
life dementias (Román, 2008a), the pendulum has returned
to the concept of brain hypoperfusion as a critical element in
dementia pathogenesis. This has led to a proposal to treat VaD
using sphenopalatine ganglion (SPG) stimulation to augment
CBF (Henninger and Fisher, 2007; Khurana et al., 2009).
60.6.1 CHOLINERGIC DYSFUNCTION IN
VaD
Cholinergic dysfunction is well documented in VaD,
independently of any concomitant AD pathology; these
deficits consist of decreased levels of ACh in the CSF and
reduced cholinergic markers such as choline acetyltrans-
ferase (ChAT) in the brain (Szilagyi et al., 1987; Wallin
et al., 1989; Wallin and Gottfries, 1990; Gottfries et al., 1994;
Tohgi et al., 1996; Wang et al., 2009). Hippocampal ChAT
deficits of up to 60% were reported in the brains of both AD
and VaD patients (Perry et al., 1977; Sakurada et al., 1990;
Kalaria et al., 2001). The cholinergic basal forebrain nuclei
are irrigated by penetrating arterioles and are therefore sus-
ceptible to the effects of arterial hypertension (Román and
Kalaria, 2006). Moreover, ischaemic lesions in the white
matter and the basal ganglia can interrupt the cholinergic
projections (Swartz et al., 2003; Bocti et al., 2005; Behl et al.,
2007). Selden et al. (1998) described in the human brain two
highly organized and discrete bundles of cholinergic fibres
extending from the nucleus basalis of Meynert (nbM) to the
cerebral cortex and amygdala. Mesulam et al. (2003) dem-
onstrated cholinergic denervation from ischaemic pathway
lesions in CADASIL, a pure genetic form of VaD, entirely
unmixed with AD lesions.
Cholinergic mechanisms play a role in the modula-
tion of regional CBF (Sato et al., 2001). Stimulation of the
nbM results in increased blood flow in the cerebral cortex
(Biesold et al., 1989). This cholinergic vasodilatory system
relies upon activation of both muscarinic and nicotinic
cholinergic receptors and the response declines with age
(Lacombe et al., 1997; Uchida et al., 2000). Therefore, there
is loss of cholinergic function in patients with VaD and this
is associated with reductions in CBF (Court et al., 2002).
These observations provide reasonable arguments to jus-
tify the use of ChEIs in patients with VaD, both unmixed
with AD, as well as in patients with AD+CVD (Zekry and
Gold, 2010). Three of the ChEIs approved for use in AD –
donepezil, galantamine and rivastigmine – have been stud-
ied also in VaD.
60.6.1.1 Donepezil
Donepezil hydrochloride is a reversible, non-competitive
ChEI with highly selective central action, approved for the
treatment of mild, moderate and advanced AD (see Chapter
52). Donepezil is unrelated to other ChEIs and has greater
selectivity for cerebral acetylcholinesterase (AChE) than for
butirylcholinesterase (BuChE).
The safety and efficacy of donepezil have been studied
in three of the largest (N = 2193) clinical trials of pure VaD
(Goldsmith and Scott, 2003; Román et al., 2005; Román et al.,
2010). A total of 1219 subjects were recruited for a 24-week,
randomized, placebo-controlled, multicentre, multinational
study, which is divided into two identical trials comprising
307 (Black et al., 2003) and 308 (Wilkinson et al., 2003). The
patients were randomized to one of three groups: placebo,
donepezil at a dosage of 5 mg/day or donepezil, 10 mg/day.
The group receiving 10 mg/day initially received 5 mg/day for
4 weeks; the dosage was then titrated up to 10 mg/day. Most
patients (73%) fulfilled diagnosis of probable VaD accord-
ing to the NINDS-AIREN criteria (Román et al., 1993). All
had brain imaging prior to enrolment (CT or MRI) with
demonstration of cerebrovascular lesions. Patients with
pre-existing AD and those with ‘mixed dementia’ (AD plus
CVD) were excluded. Exclusion criteria also included other
neurodegenerative or psychiatric disorders (e.g. schizo-
phrenia, major depression), an MMSE (Folstein et al., 1975)
score >26 or <10, the occurrence of new strokes within the
28 days prior to baseline or myocardial infarction within 3
months of enrolment. These two VaD studies enrolled more
men than women (58% versus 38%) and their mean age
was older than in AD (74.5 ± 0.2 versus 72 ± 0.2 years). The
more severe vascular pathology of VaD was reflected in the

high HIS score (6.6 ± 0.2 versus <4 in AD); most subjects
had hypertension, hypercholesterolemia, cardiovascular dis-
ease, diabetes, smoking, previous stroke and TIAs. The third
study (319 trial) recruited 974 subjects (mean age 73.0 years)
with probable or possible VaD that were randomized 2:1 to
receive donepezil 5 mg/day or placebo. Coprimary outcome
measures were the V-ADAS-cog (Ferris and Gauthier, 2002)
and the CIBIC-Plus (Schneider et al., 1997).
There were three main end points: (1) cognition, mea-
sured with the ADAS-cog (Rosen et al., 1984) and the
MMSE; (2) global function, evaluated with the CIBIC-plus
and with the sum of boxes of the Clinical Dementia Rating
(CDR-SB) (Berg, 1988) and (3) ADLs, measured with the
ADFACS (Mohs et al., 2001).
In study 307 (Black et al., 2003), both donepezil treatment
groups showed statistically significant cognitive improve-
ment measured with the MMSE and the ADAS-cog; the mean
changes from baseline ADAS-cog scores were the following:
donepezil 5 mg/day −1.90 (p = 0.001); donepezil 10 mg/day
−2.33 (p < 0.001). The donepezil 5 mg/day group showed sig-
nificant improvement in global function on the CIBIC-plus but
did not reach significance in the 10 mg/day group (p = 0.27). The
CDR-SB showed non-significant benefit in the 5 mg/day group
and statistical significance in the 10 mg/day group (p = 0.022).
Compared with placebo, there was significant benefit in ADLs
(p < 0.05) in both donepezil groups using the ADFACS.
Similar results were observed in study 308 (Wilkinson et al.,
2003); donepezil treatment resulted in significant improvement
in cognition measured with the MMSE and the ADAS-cog. For
the latter, the mean changes from baseline score were the fol-
lowing: donepezil 5 mg/day −1.65 (p = 0.003); donepezil 10
mg/day −2.09 (p = 0.0002). Global function on the CIBIC-plus
was significantly better in the 5 mg/day group (p = 0.004) and
was barely below significance in 10 mg/day group (p = 0.047).
The CDR-SB showed benefits with 5 mg/day (non-significant),
and it reached significance with 10 mg/day (p = 0.03). ADLs
improved in patients treated with donepezil when compared
with placebo using the ADFACS, but did not reach significance
at the end of the study. Comparison of cortical versus subcorti-
cal forms of VaD showed no differences in the overall results
(Salloway et al., 2003).
In trial 319 (Román et al., 2010), donepezil-treated
patients showed significant improvement from baseline
to end point on the V-ADAS-cog (least squares [LS] mean
difference −1.156; 95% CI −1.98 to −0.33, p < 0.01) but not
on the CIBIC-Plus. Donepezil-treated patients with hip-
pocampal atrophy demonstrated stable cognition versus
decline in the placebo-treated group; in those without
atrophy, cognition improved with donepezil versus relative
stability with placebo. Results on secondary efficacy mea-
sures were inconsistent. The incidence of adverse events
(AEs) was similar across groups. Eleven deaths occurred
in the donepezil group (1.7%) – similar to rates previously
reported for donepezil trials in VaD – whereas no deaths
occurred in the placebo group. Donepezil 5 mg/day showed
significant improvement in cognitive, but not global, func-
tion, with differential treatment response of VaD patients by
Therapeutic strategies for vascular cognitive disorders 671
hippocampal size. Donepezil was relatively well tolerated;
AEs were consistent with current labelling. Mortality in the
placebo group was unexpectedly low (Román et al., 2010).
In comparison with AD patients, cognitive decline in
untreated VaD patients during 24 weeks of study in these
trials was less severe, using similar instruments. These dif-
ferences were also noted for global effects, measured by
the CIBIC-plus. Substantial decline of IADLs was noted in
untreated VaD patients. A combined analysis of the total
population confirmed the effects on cognition and global
function. Donepezil-treated patients demonstrated statis-
tically significant improvements in IADLs compared with
decline in the placebo group (LS mean change from base-
line at end point: placebo 0.60; 5 mg/day −0.09, p < 0.05;
10 mg/day −0.18, p < 0.01). These results suggest that donepe-
zil treatment may improve or maintain the patients’ abilities
to perform ADLs. Executive dysfunction is a major compo-
nent of disability in patients with VaD and the beneficial
effect of donepezil on IADLs may be related to improvement
or stabilization of executive function.
Donepezil was generally well tolerated, although more
adverse effects were reported in the 10 mg/day group than
in the 5 mg/day or placebo groups. The adverse effects were
assessed as mild to moderate and transient, and were typi-
cally diarrhoea, nausea, arthralgia, leg cramps, anorexia
and headache. The incidence of bradycardia and syncope
was not significantly different from the placebo group. The
discontinuation rates were 15% for placebo, 18% for 5 mg
and 28% for the 10 mg group. There was no significant inter-
action with cardiovascular medications or antithrombotic
agents. These three large trials offer evidence that donepezil
is effective and well tolerated in VaD patients.
Dichgans et al. (2008) conducted a trial of donepezil
in patients with CADASIL that randomized 168 patients
(mean age 54.8 years) to 10 mg donepezil per day (n = 86) or
placebo (n = 82). Inclusion criteria included an MMSE score
of 10–27 or a Trail Making Test (TMT) B time score at least
1.5 SD below the mean, after adjustment for age and edu-
cation. The primary end point was the V-ADAS-cog at 18
weeks. Secondary end points included ADAS-cog, MMSE,
TMT A and B times, Stroop test, EXIT25, CLOX, DAD and
CDR sum of boxes. Donepezil (5–10 mg/day) had no effect
on V-ADAS-cog but had significant effect on two measures
of executive function: EXIT25 and TMT-B. These subjects
were younger than most VaD patients and most (75%) had
no clinically significant memory dysfunction. The positive
effect of donepezil on executive function, however, indicates
some cholinergic deficit in executive dysfunction.
60.6.1.2 Galantamine
Galantamine is approved for the treatment of mild-
to-moderate AD. It is a reversible specific inhibitor of AChE,
and in addition it modulates central nicotinic receptors to
increase cholinergic neurotransmission. The safety and
efficacy of galantamine in AD have been studied in trials
recruiting over 2600 patients (see Chapter 52).
672 Dementia
Birks et al. (2013) conducted a Cochrane review of galan-
tamine in VCD. Among others (Craig and Birks, 2006),
galantamine has been studied in VaD in the GAL-INT-6
study, a large Phase III, randomized, multicentre, double-
blind, placebo-controlled RCT in patients with probable VaD
or with AD combined with CVD (Erkinjuntti et al., 2002a).
Patients received galantamine 24 mg/day (n = 396) or placebo
(n = 196) for 6 months; the age of the patients ranged from 40
to 90 years. Eligible subjects met either the clinical criteria of
probable VaD by NINDS-AIREN criteria (Román et al., 1993)
or of possible AD according to the NINCDS-ADRDA crite-
ria (McKhann et al., 1984). Radiological evidence of CVD on
brain CT or MR was required (i.e. AD plus CVD), including
multiple large vessel infarcts or a single, strategically placed
infarct (angular gyrus, thalamus, basal forebrain, territory of
the PCA or ACA) or at least two basal ganglia and white mat-
ter lacunes or white matter changes involving at least 25%
of the total white matter. Mild-to-moderate dementia was
defined by scores of ≥12 in the ADAS-cog/11 (Rosen et al.,
1984) and 10–25 on the MMSE.
Primary end points were cognition, as measured using
the ADAS-cog/11 and global functioning as measured
using the CIBIC-plus (Schneider et al., 1997). Secondary
end points included assessments of ADLs, using the DAD
(Gélinas et al., 1999), and behavioural symptoms using the
Neuropsychiatric Inventory (NPI) (Cummings et al., 1994).
Galantamine demonstrated greater efficacy than placebo on
all outcome measures in analyses of both groups of patients
as a whole (Corey-Bloom, 2013): ADAS-cog (2.7 points,
p ≤ 0.001) on the CIBIC-plus (74% versus 59% of patients
remained stable or improved, p ≤ 0.001). ADLs and behav-
ioural symptoms in the NPI were also significantly improved
compared with placebo (both p < 0.05). Galantamine was
safe and well tolerated; however, nausea was six times com-
moner in patients on galantamine than those on placebo.
In comparison, nausea was twice as common in patients
with AD treated with galantamine compared with placebo-
treated patients (Erkinjuntti et al., 2002a), suggesting lesser
tolerability in VaD patients.
In an open-label extension (Erkinjuntti et al., 2003a), the
original galantamine group of patients with probable VaD
or AD+CVD showed similar sustained benefits in terms
of maintenance of or improvement in cognition (ADS-
cog), functional ability (DAD), and behaviour (NPI) after
12 months. Although not designed to detect differences
between subgroups, the subgroup of patients with AD+CVD
on galantamine (N = 188, 48%) showed greater efficacy than
placebo (N = 97, 50%) at 6 months on the ADAS-cog (p ≤
0.001) and the CIBIC-plus (p = 0.019) (Erkinjuntti et al.,
2002a). In the open-label extension, patients with AD+CVD
on galantamine maintained cognition at baseline for 12
months (Erkinjuntti et al., 2003a).
In the subgroup of patients with VaD treated with
galantamine for 6 months, the ADAS-cog scores improved
significantly (mean change from baseline 2.4 points,
p < 0.0001), compared with no response in placebo group
(mean change from baseline 0.4, treatment difference versus
galantamine 1.9, p = 0.06) (Erkinjuntti et al., 2003a). More
patients treated with galantamine than with placebo main-
tained or improved global function (CIBIC-plus, 31% versus
23%, not statistically significant). In these patients, the cog-
nitive benefits of galantamine were maintained at least up
to 12 months, demonstrating a mean change of −2.1 in the
ADAS-cog score compared to baseline, and the active group
was still close to baseline at 24 months (Erkinjuntti et al.,
2003a). During the 12-month trial, the most frequently
reported AEs were depression (13%), agitation (12%) and
insomnia (11%).
Erkinjuntti et al. (2008) performed responder analyses
for cognitive, behavioural and functional outcome mea-
sures in GAL-INT-6. Galantamine treatment resulted in sig-
nificant cognitive and functional improvements compared
with placebo at 6 months. Significantly higher percentage
of treatment responders were found for the ADAS-cog/11
(60.5% for galantamine versus 46.0% for placebo, p = 0.013);
the CIBIC-plus (75% versus 53.6% with placebo, p = 0.0006);
behaviour (64.9% versus 56.6%, p = 0.024), and numerically
favourable responder rates were seen with galantamine for
ADLs, indicating a broad range of cognitive, functional and
behavioural benefits with galantamine across the spectrum
of AD and AD+CVD.
In another trial of galantamine in VaD, the GAL-INT-26
study (Auchus et al., 2007), 788 patients with probable VaD
and strict centrally read MRI criteria were randomized to
galantamine or placebo. Efficacy was evaluated using mea-
sures of cognition, daily function, and behaviour using the
NPI (Cummings et al., 1994); EXIT-25 was used for the
assessment of executive functioning. Safety and tolerability
were also monitored. Galantamine showed improvement in
ADAS-cog/11 after 26 weeks compared with placebo (−1.8
versus −0.3; p < 0.001), but there was no difference on the
ADCS-ADL score (0.7 versus 1.3; p = 0.783). Improvement
in global functioning by the CIBIC-plus approached sig-
nificance (p = 0.069). In patients with VaD, galantamine
significantly improved cognition, including executive func-
tion, but ADLs were similar to the placebo group (Auchus
et al., 2007).
In Thai patients, Thavichachart et al. (2006) reported
the results of a 6-month trial of galantamine in AD with
or without CVD and VaD. Galantamine showed favourable
effects on ADLs; behavioural symptoms and sleep quality
were also significantly improved (p < 0.05). Galantamine
was well tolerated.
In the Cochrane review of galantamine for VaD, Birks
et al. (2013) concluded that there is positive evidence of
improved cognition and executive functioning in VCDs;
however, galantamine produced higher rates of gastrointes-
tinal side effects.
60.6.1.3 Rivastigmine
Rivastigmine is a slowly reversible AChE inhibitor and
BuChE inhibitor approved for use in mild-to-moderate AD
(see Chapter 52). Rivastigmine is metabolized at the synapse

rather than by hepatic cytochrome enzymes; hence, there
are no drug–drug interactions (Polinsky, 1998). The role of
BuChE inhibition in glial cells in AD remains unclear. After
treatment of AD with rivastigmine for 12 months, CSF and
plasma AChE activity decreased by 46% and BuChE by 65%
from baseline (Darreh-Shori et al., 2002). There was a sig-
nificant correlation between plasma ChE inhibition and
cognition, particularly in relation to attention (Almkvist
et al., 2004).
Rivastigmine was used in small open-label studies of
patients with subcortical VaD followed for 12 months
(Moretti et al., 2001) and 22 months (Moretti et al., 2002);
rivastigmine resulted in the stabilization of cognition and
ADLs, with slight improvement of executive function and
planning, less caregiver stress and improved behaviour.
More recently, Moretti et al. (2008) observed significant
improvement in behavioural symptoms in two forms of
VaD, MID and subcortical VaD, except delusions, suggest-
ing that rivastigmine helps reduce concomitant neuroleptic
and benzodiazepine use.
Rivastigmine effects in VaD were studied in the VaD
trial studying Exelon (VantagE), a Phase III, double-blind,
placebo-controlled RCT (Moretti et al., 2004). This 24-week,
multicentre study randomized 710 VaD patients aged 50–85
years to rivastigmine capsules (3–12 mg/day) or placebo
(Ballard et al., 2008). Efficacy assessments included global
and cognitive performances, ADLs and neuropsychiatric
symptoms. Rivastigmine was superior to placebo on three
measures of cognitive performance (but no other out-
comes). Cognitive improvement occurred in older patients,
probably likely to have concomitant AD as evidenced by
medial temporal atrophy.
Regarding the use of rivastigmine in patients with
AD+CVD, Kumar et al. (2000) compared the outcomes of
AD patients with or without concurrent vascular risk fac-
tors; cognitive effects were seen in both groups, but patients
with AD and vascular risk had greater clinical benefit. These
findings were confirmed by Erkinjuntti et al. (2002b) in an
open-label extension study of 104 weeks. Compared with
non-hypertensive patients with AD, significant treatment
differences were observed in the hypertensive subgroup on
the Progressive and Global Deterioration Scales (PDS and
GDS). Furthermore, Erkinjuntti et al. (2003b) stratified 725
patients with AD treated with rivastigmine, according to
the presence or absence of arterial hypertension at baseline.
Rivastigmine 6–12 mg/day provided better outcomes than
placebo on the PDS in the hypertensive (p = 0.031) and non-
hypertensive (p = 0.035) subgroups. All patients receiving
rivastigmine 6–12 mg/day had superior CIBIC-plus scores
to those receiving placebo. The additional apparent benefits
on disease progression detected in patients with AD and
hypertension may be linked to drug effects on cerebrovas-
cular risk factors, or to a larger underlying cholinergic defi-
cit in patients with AD and hypertension.
The problems associated with gastrointestinal side effects
requiring slow oral titration of rivastigmine were solved
to a large extent with the use of a dermal patch (Winblad
Therapeutic strategies for vascular cognitive disorders 673
and Machado, 2008). The patch is associated with three
times fewer reports of nausea and vomiting (Winblad and
Machado, 2008). The rivastigmine patch has not been evalu-
ated in VaD.
60.6.2 MEMANTINE
Memantine is a potent antagonist of the N-methyl-
d-aspartate (NMDA) receptor (Farlow, 2004) (see Chapter 52).
Experimentally, memantine inhibits and reverses the abnor-
mal activity of a protein phosphatase (PP-2A) that leads to tau
hyperphosphorylation and to neurofibrillary degeneration in
AD (Li et al., 2004). Memantine is effective and well toler-
ated in patients with severe AD (Reisberg et al., 2003) and was
approved by the FDA for the treatment of moderate-to-severe
AD (Möbius, 2003). Furthermore, Tariot et al. (2004) showed
that in patients with moderate-to-severe AD receiving stable
doses of donepezil, memantine resulted in significantly better
outcomes than placebo in cognition, ADLs, global outcome,
and behaviour. These findings suggest that this dual therapy
could be useful.
Memantine has been used in patients with VaD based
on its experimental efficacy in animal models of ischaemic
lesions. Memantine acts on potentially contributing factors
such as neuronal depolarization, mitochondrial dysfunc-
tion, magnesium effects on NMDA receptors and chronic
glutamatergic overstimulation; it also has shown positive
effects on long-term potentiation and cognitive tests in stan-
dard animal models of impaired synaptic plasticity (Möbius,
1999). The pivotal memantine 9M-Best study by Winblad
and Poritis (1999) in severe dementia included both AD and
VaD patients. A statistically significant effect was detected
in both dementias. Orgogozo et al. (2002) and Wilcock et al.
(2002) completed two 6-month placebo-controlled RCTs of
memantine (20 mg/day) in mild-to-moderate probable VaD,
diagnosed by NINDS-AIREN criteria (Román et al., 1993).
In study MMM 300, Orgogozo et al. (2002) random-
ized 147 patients to memantine and 141 to placebo. After
28 weeks, the mean ADAS-cog scores were significantly
improved relative to placebo: the memantine group gained
an average of 0.4 points versus a decline of 1.6 in the pla-
cebo group, a difference of 2.0 points (p = 0.0016). The
CIBIC-plus that improved or remained stable reached 60%
with memantine compared with 52% with placebo (p =
0.227). The Gottfries–Bråne–Steen (GBS) Scale (Gottfries
et al., 1982) and the Nurses’ Observation Scale for Geriatric
Patients (NOSGER) (Spiegel et al., 1991) total scores at week
28 did not differ significantly between the two groups.
However, the GBS Scale intellectual function sub-score
and the NOSGER disturbing behaviour dimension also
favoured memantine (p = 0.04 and p = 0.07, respectively).
Wilcock et al. (2002) in study MMM 500 random-
ized 277 patients to memantine and 271 to placebo. At 28
weeks, the active group gained 0.53 points and the placebo
declined by 2.28 points in ADAS-cog, a significant dif-
ference of 1.75 ADAS-cog points between the groups (p <
0.05). There were no differences in CGIC, MMSE, GBS or
674 Dementia
NOSGER between groups. Memantine was well tolerated
in both studies. Möbius and Stoffler (2002) performed a
post hoc pooled analysis of these two placebo-controlled
trials of memantine in VaD. Baseline severity, as assessed
by MMSE, showed larger cognitive benefit in patients with
more advanced disease. Also, the cognitive treatment effect
for memantine was more pronounced in the small ves-
sel type group without cortical infarctions by CT or MRI.
The placebo subgroup of patients with large vessel disease
showed less cognitive decline than the other subgroup.
Möbius and Stoffler (2002, 2003) reviewed the results of
these studies of memantine in VaD in a post hoc analysis
and showed that the small vessel disease subgroup of VaD
accounted for most of the outcome (responders) while the
large vessel disease subgroup (non-responders) was not sta-
tistically significant compared with placebo. Solving this
issue would probably require a separate trial of memantine
in small vessel VaD.
In a review, Thomas and Grossberg (2009) concluded
that memantine shows promise for the treatment of patients
with VaD because of its safety and efficacy. However,
Kavirajan and Schneider (2007) performed a meta-analysis
of 6-month RCTs in VaD (three donepezil, two galantamine,
one rivastigmine and two memantine trials), comprising
3093 patients on the study drugs and 2090 patients on pla-
cebo. They found that all drugs produced small but signifi-
cant cognitive effects of uncertain clinical significance in
patients with mild-to-moderate VaD. Compared with pla-
cebo, more dropouts and AEs (anorexia, nausea, vomiting,
diarrhoea and insomnia) occurred with all three ChEIs, but
not with memantine. The authors concluded that the data
were insufficient to support widespread use of these drugs
in VaD. Wong et al. (2009) analysed the cost-effectiveness
of using ChEIs and memantine in VaD and concluded that
treatment with ChEIs or memantine was more effective, but
more costly, than standard care for mild-to-moderate VaD.
60.6.3 CALCIUM CHANNEL BLOCKERS
The main calcium channels blockers used for the treatment
of VaD include nimodipine, nicardipine, lacidipine and
fasudil.
60.6.3.1 Nimodipine
Nimodipine is a dihydropyridine-type CCB used as anti-
hypertensive agent. Due to its highly lipophilic properties it
readily crosses the blood–brain barrier (BBB), affects auto-
regulation of CBF and produces vasodilatation of small cere-
bral blood vessels (Jansen et al., 1991). Nimodipine reduces
the severity of neurological outcome after subarachnoid
haemorrhage (SAH) secondary to ruptured aneurysms,
probably by decreasing cerebral vasospasm, although this
effect has not been demonstrated by angiography or tran-
scranial Doppler (Ohman et al., 1991). In addition to its
vascular effects, nimodipine appears to have nootropic prop-
erties. There is a high density of nimodipine-binding sites in
hippocampus, caudate nucleus and cerebral cortex (Traber
and Gibsen, 1989). Nimodipine binds to slow l-type calcium
receptors, preventing influx of calcium into vascular smooth
muscle cells and into ischaemic neurones (Greenberg et al.,
1990); experimentally, it protects against age-associated
microvascular abnormalities in the rat brain (De Jong et al.,
1990 Mark et al., 1992). Although a neuroprotective effect
has been postulated in stroke patients, nimodipine showed
only a trend for better outcome when used within the first 12
hours of stroke onset (Gelmers and Hennerici, 1990).
A reanalysis of the Scandinavian Trial of Nimodipine
in MID (Pantoni et al., 2000) showed a beneficial effect in
tests of attention and psychomotor performance in the sub-
group of patients with subcortical small vessel VaD, but not
in patients with PSD of the MID type. A pilot open-label
trial of nimodipine in patients with small vessel VaD was
positive (Pantoni et al., 1996). In this study, subcortical VaD
was defined according to ICD-10 criteria (World Health
Organization, 2008), and inclusion criteria required the
patients to have mild-to-moderate dementia (MMSE 12–24,
GDS 3–5), as well as CT evidence of extensive leukoara-
iosis and at least one lacunar infarct. The primary measure
of efficacy was the Sandoz Clinical Assessment – Geriatric
(SCAG) scale (Shader et al., 1974).
Using similar criteria and outcome measures, a large
multicentre, double-blind, placebo-controlled RCT of
nimodipine in subcortical VaD was conducted in Italy and
Spain (Pantoni et al., 2005). Of 242 patients randomized to
nimodipine 90 mg/day or placebo, 230 patients (nimodipine
N = 121, placebo N = 109) were included in the intention-to-
treat analysis. At 52 weeks, there was no difference in the
primary outcome measure (SCAG scale) between the two
groups. However, patients on nimodipine performed better
than placebo in lexical production (p < 0.01), MMSE (p <
0.01) and GDS (p < 0.05). More dropouts and AEs occurred
among the placebo group (cardiovascular and cerebrovas-
cular events, and behavioural disturbances requiring inter-
vention). The authors concluded that nimodipine offers
benefit in subcortical VaD and might protect against car-
diovascular and CVD comorbidities in this high-risk group.
A Cochrane review on nimodipine (López-Arrieta and
Birks, 2002) found no convincing evidence for its efficacy in
AD, VaD or mixed forms of dementia.
60.6.3.2 Nicardipine
Nicardipine is a dihydropyridine-type CCB with high
vascular selectivity, strong antihypertensive activity and
cerebrovascular effects (Amenta et al., 2008). Nicardipine
protects from atherogenesis in experimental vascular injury
(Weinstein and Heider, 1989); has antioxidant effects, pre-
venting endothelial cell damage from free radical injury
(Mak et al., 1995) and inhibits platelet aggregation (Yamada
et al., 1990). Nicardipine, like all CCBs, lowers arterial pres-
sure by reducing peripheral vascular resistance, thereby
decreasing both systolic and diastolic BP and improving
myocardial oxygen supply by vasodilating coronary arteries

(Amenta et al., 2008). Therefore, nicardipine is an anti-
angina and cardioprotective agent (Pepine and Lambert,
1990). CCBs are more effective in BP lowering in patients
older than 55 years or those of black ethnic origin at any
age (Messerli et al., 2007). Amenta et al. (2009) recommend
nicardipine for the treatment of hypertension after acute
ischaemic stroke or intracerebral haemorrhage for the con-
trol of vasospasm in SAH, as well as for stroke prevention
(Martí-Massó and Lozano, 1990).
Amenta et al. (2009) reviewed the effects of nicardipine
on cognition in 24 studies performed primarily in Japan,
Spain and Italy on about 6000 patients with ‘chronic cere-
brovascular insufficiency’ due to several forms of CVD
including PSD and ranging in severity from vascular MCI
to VaD. Positive effects of treatment with nicardipine were
observed in over 60% of patients; more favourable results
occurred in hypertensive patients resulting in decreased
systolic and diastolic BP, improvement of neurological
symptoms and signs, as well as amelioration of cognition
assessed with the SCAG scale, MMSE and other batteries.
The Spanish Group of Nicardipine Study in VaD (Grupo
Español de Estudio de Nicardipino, 1999) conducted a dou-
ble-blind, placebo-controlled RCT to investigate the effect
of nicardipine on cognitive function in patients with VaD.
The effect of daily treatment with nicardipine (20 mg three
times per day) for 1 year was investigated in 156 patients
with cognitive impairment of vascular origin, random-
ized to nicardipine (N = 81) or placebo (N = 75). A total of
142 subjects completed the study (nicardipine N = 73, pla-
cebo N = 60) on intention-to-treat analysis. The primary
efficacy variable was the loss of >10% of the MMSE basal
score; other end points were the Short Portable Mental
Status Questionnaire (SPMSQ) score (Pfeiffer, 1975), func-
tional disability and drug safety. At 1 year, 21.1% of patients
treated with nicardipine had lowered the MMSE score ver-
sus 34.6% with placebo. Favourable effects of nicardipine
were found on females (40.9% versus 10.5%, p = 0.01876),
previously untreated subjects (46.2% versus 13.3%, p =
0.00748) and patients on concomitant antiplatelet treat-
ment (35.0% versus 15.9, p = 0.03836). Survival analysis
found patients on nicardipine took longer to lose cognitive
capacities (p = 0.031, RR 1.15–3.99). In summary, nicardip-
ine significantly delayed cognitive decline, producing better
evolution in females. The drug was remarkably safe and was
well tolerated for 1 year; side effects secondary to vasodila-
tation were short lived and of low intensity.
The largest (N = 6375 patients) nicardipine trial on vas-
cular MCI and VaD was an open, prospective, multicen-
tre, 6-month study to test the efficacy and tolerability of
a single 40 mg/day oral dose of nicardipine retard (slow
release) in patients with cognitive deterioration of vas-
cular origin (González-González and Lozano, 2000). BP,
ADLs and cognition with the SPMSQ score (Pfeiffer, 1975)
were obtained. Nicardipine improved functional capac-
ity in 65.5% of the patients; systolic/diastolic BP decreased
11.3/7.4 mm Hg in hypertensive patients treated with
other antihypertensive drugs and 5.9/4.3 mm Hg in those
Therapeutic strategies for vascular cognitive disorders 675
not taking antihypertensives. Nicardipine was well tolerated
and no major side effects were seen.
Based on this evidence, Amenta et al. (2008, 2009) con-
cluded that the anti-hypertensive effect of nicardipine, its
safety and effectiveness in improving cognition and func-
tional domains make this a recommended drug in the treat-
ment of cognitive impairment of vascular origin.
60.6.3.3 Lacidipine and lercanidipine
Lacidipine and lercanidipine are third-generation calcium
antagonists that cause systemic vasodilatation by block-
ing calcium entry through l-type calcium channels in cell
membranes; these agents also improve carotid atherosclero-
sis (Zanchetti et al., 2004), small vessel disease (Frishman,
2002) and cerebral flow (Semplicini et al., 2000) in hyper-
tensive patients; their use results in less peripheral oedema
than with older dihydropyridine CCBs.
60.6.3.4 Fasudil
Fasudil hydrochloride is a novel intracellular calcium
antagonist, with Rho-kinase inhibitory activity on arte-
rial walls affecting vessel remodelling (Pearce et al., 2004).
Fasudil has been used to prevent and treat vasospasm asso-
ciated with SAH (Suzuki et al., 2008). Kamei et al. (1996)
reported the use of fasudil in the treatment of two patients
with BD using 31P-magnetic resonance spectroscopy and
Xenon-CT. Treatment with fasudil at 30 or 60 mg/day orally
for 8 weeks controlled the fluctuating symptoms in both
patients. Mental tests and imaging also improved.
60.6.4 NOOTROPIC AGENTS
The name nootropic (Greek nous, mind; trophikos, nour-
ishing) describes a category of agents with neuroprotective
capacity against anoxic or oxidative injuries. Piracetam,
oxiracetam and citicoline will be reviewed.
60.6.4.1 Piracetam
Piracetam (2-oxo-1-pyrrolidine acetamide), the first noo-
tropic agent, is a cyclic derivative of γ–aminobutyric acid
(GABA), which can cross the BBB (Hitzenberger et al.,
1998) to concentrate selectively in the brain cortex (Vernon
and Sorkin, 1991). At low doses, piracetam increases both
oxygen and glucose utilization via adenosine triphosphate
(ATP) pathways and the release of some neurotransmit-
ters – in particular dopamine metabolites – while at higher
dosages, it is associated with platelet anti-aggregation and
rheological effects with antithrombotic properties (Moriau
et al., 1993). It enhances the microcirculation by promoting
erythrocyte deformability and reducing adherence to endo-
thelial cells. However, studies of piracetam in acute stroke
have been inconclusive, although improvement of aphasia
in patients treated within 7 hours of stroke onset was seen
(Hitzenberger et al., 1998). Several animal studies showed
676 Dementia
effects of piracetam on memory and facilitation of retention
over 24 hours. A Cochrane review (Flicker and Grimley
Evans, 2001) concluded that the usefulness of piracetam in
patients with AD and VaD in small clinical trials is unclear,
based mainly on subjective Global Impression of Change.
These findings are supported by a larger Russian trial
(Batysheva et al., 2009) on 70 patients (37 women and 33
men, mean age 62 years), including 29 (41.5%) with PSD and
41 (58.5%) with chronic cerebral ischaemia. Improvements
in cognition (MMSE) and behaviour were better at a dose
of 2400 mg/day. Piracetam was well tolerated. A review
of 19 trials in patients with several forms of dementia
(Waegemans et al., 2002) and a protective effect in patients
undergoing coronary artery bypass surgery (Uebelhack
et al., 2003) appear to provide some support for a moderate
effect of piracetam on cognitive impairment.
60.6.4.2 Oxiracetam
Oxiracetam is a structural analogue of piracetam. This
compound has enhancing effects on vigilance and memory.
In comparison with piracetam, oxiracetam exhibits greater
improvement in memory (Itil et al., 1986) and has been
used extensively for the treatment of dementia, including
AD, VaD, MID (Baumel et al., 1989; Dysken et al., 1989),
and mixed forms. Green et al. (1992) failed to demonstrate a
difference from placebo in AD patients. In contrast, Maina
et al. (1989) studied 289 patients with MID in a double-blind
placebo-controlled trial and after 12 weeks of treatment
found that oxiracetam reduced behavioural symptoms.
60.6.4.3 Citicoline
Citicoline, also known as CDP-choline or cytidine-5′-
diphosphatecholine, is a naturally occurring endogenous
nucleoside. Citicoline functions as an intermediate in three
major metabolic pathways (Conant and Schauss, 2004):
(1) synthesis of phosphatidylcholine (lecithin), one of the
major cell membrane phospholipids with an important role
in lipoprotein formation. Citicoline formation is the rate-
limiting step in the synthesis of phosphatidylcholine. (2)
Synthesis of ACh: citicoline by providing choline for this
neurotransmitter could limit choline availability for mem-
brane synthesis (Ulus et al., 1989). (3) Oxidation to betaine,
a methyl donor. The main components of citicoline, choline
and cytidine, are readily absorbed in the gastrointestinal
tract and cross the BBB (Secades and Lorenzo, 2006). As a
dietary supplement, choline is part of the vitamin-B group.
A related product, choline alphoscerate, has also been used
less frequently (Parnetti et al., 2007).
In animal studies, citicoline enhances repair of ischaemic
neuronal injury and increases levels of ACh and dopamine
(Secades and Frontera, 1995; Secades, 2002; Secades and
Lorenzo, 2006; Saver, 2008; Secades, 2011). In aged animals,
citicoline increases dopamine release, improving learning
and memory tasks (Cacabelos et al., 1993). Lee et al. (2009)
showed that citicoline protects against cognitive impairment
in a rat model of chronic cerebral hypoperfusion. Silveri
et al. (2008) demonstrated that citicoline treatment for 6
weeks produced significant increases in phosphocreatine
(+7%), in beta-nucleoside triphosphates (largely brain ATP
[+14%]), and in the ratio of phosphocreatine to inorganic
phosphate (+32%), as well as significant changes in mem-
brane phospholipids in the anterior cingulate cortex.
Based on a large body of experimental animal evidence
(Bustamante et al., 2012), the neuroprotective effects of citi-
coline have been well documented in at least 64 ­animal stud-
ies of stroke therapy. The accepted mechanisms of action of
citicoline are the following: (1) protects cell membranes by
accelerating phospholipid resynthesis, (2) inhibits activation
of certain phospholipases, (3) increases glutamate transport
in astrocytes (Hurtado et al., 2008), (4) increases cholin-
ergic transmission, (5) restores the activity of mitochon-
drial ATPase and membrane Na+/K+ ATPase, (6) increases
­neuronal ATP levels in ischemia, (7) decreases ischaemic
lesion volume, (8) accelerates reabsorption of cerebral
oedema and (9) inhibits apoptosis mechanisms.
In experimental animals, citicoline enhances numerous
neuroregenerative processes including inhibition of apop-
tosis, angiogenesis, neurogenesis, gliagenesis, synaptogen-
esis, and modulation of neurotransmitters; these effects are
similar to those induced by stem cells (Gutiérrez-Fernández
et al., 2012; Krupinski et al., 2012). Citicoline can produce
regrowth of dendritic spines in an experimental stroke
model (Hurtado et al., 2007). Furthermore, Hurtado et al.
(2013) demonstrated in experimental stroke that citicoline
increases SIRT1 protein levels in the brain concomitantly
with neuroprotection. Moreover, resveratrol elicited a
strong synergistic neuroprotective effect with CDP-choline,
suggesting that these two products probably should be
used together. SIRT1 plays a major role in the prevention
of ageing-related conditions, including neurodegenerative
diseases such as Alzheimer’s and Parkinson’s diseases and
amyotrophic lateral sclerosis (ALS).
In a pooled analysis of clinical trials on acute isch-
aemic stroke, citicoline enhanced the possibility of recov-
ery (Dávalos et al., 2002; Saver, 2008). However, the ICTUS
trial (Dávalos et al., 2012) failed to show a beneficial effect
in acute ischaemic stroke. Reviews of the effects of citicoline
in acute stroke patients (Secades et al., 2016; Álvarez-Sabín
and Román, 2013) and post-stroke VCD (Álvarez-Sabín
and Román, 2011) concluded that citicoline may possess
substantial neuroregenerative potential that would explain
better its long-term beneficial effects in post-stroke patients.
Álvarez-Sabín et al. (2013) conducted a study to assess the
effect of citicoline on cognitive function in 347 patients with
acute stroke who received citicoline 2 g/day for 6 weeks. After
6 weeks, they were randomized in two groups of 175 subjects
each: one group stopped citicoline (controls) and the other
received citicoline 1 g/day for 6 months. Cognitive functions
improved 6 months after stroke in the entire group, but in
comparison with controls citicoline-treated patients showed
statistically significant better outcome in attention-executive
functions (OR 1.7, 90% CI 1.1–2.7, p = 0.019) and temporal

orientation (OR 1.7, 90% CI 1.02–2.9, p = 0.042). These results
suggest that citicoline treatment within 24 hours of stroke
onset, following by continuous treatment for 6 months is
safe, and benefits prevention of post-stroke VCD compared
to placebo. Furthermore, continuous citicoline treatment in
post-stroke patients for up to 12 months has excellent toler-
ability and safety and continued improvement in post-stroke
VCD especially in temporal orientation, executive functions
and attention (Álvarez-Sabín et al., 2016).
Citicoline has been used in a number of trials in AD
patients showing consistent moderate improvement of
memory and behaviour (Cacabelos et al., 1993; Álvarez
et al., 1997). A placebo-controlled trial on 30 patients with
VaD showed no evidence of cognitive improvement (Cohen
et al., 2003). Cotroneo et al. (2013) in the IDEALE study
demonstrated modest cognitive effects in 349 patients with
mild VCD. Previously, a Cochrane review (Fioravanti and
Yanagi, 2005) included 14 studies on more than 1000 aged
individuals with symptoms ranging from memory disor-
ders to patients with vascular MCI, VaD or senile dementia.
Studies’ duration ranged between 20 and 30 days, one study
was of 6 weeks’ duration, four studies lasted 2 and 3 months
and one study lasted 12 months. Multiple doses, inclusion
criteria and outcome measures were used. Overall results
(884 patients) showed evidence of benefit of CDP-choline
on memory and behaviour but not attention. There was sig-
nificant improvement on the Global Impression of Change,
in comparison with the placebo group. The effect size was
very large (OR 8.89, 95% CI 5.19–15.22, p < 0.001) indicat-
ing a strong drug effect for improvement under treatment
(Fioravanti and Yanagi, 2005). These authors concluded that
the cognitive effects of citicoline are clearly evident at the
behavioural level and can be easily appreciated with clinical
observation of patients, irrespective of the methods used to
measure them. Citicoline is very well tolerated; more side
effects were seen with placebo than with active treatment.
60.6.5 XANTHINE DERIVATIVES
The main xanthine derivatives used to treat VaD are pent-
oxifylline or oxpentifylline, denbufylline, a phosphodi-
esterase 4 (PDE4) inhibitor, and propentofylline (PPF).
Pentoxifylline has haemorheological effects both on the
microcirculation and on peripheral vascular disease (in par-
ticular for treating intermittent claudication). Pentoxifylline
has immunomodulatory properties, increasing the rate of
neutrophil migration, suppressing monocyte production
of tumour necrosis factor (TNF-α) and inhibiting leuco-
cyte stimulation by TNF-α and interleukin-1 (IL-1). These
properties are strong contributors to its haemorheological
effects (Samlaska and Winfield, 1994). PPF exhibits ade-
nosine-mediated nootropic properties against post-anoxic
neuronal cell damage and glial modulation effects with
inhibition of microglial activation. Bruno et al. (2009)
showed improvement of neurological and neurochemical
deficits in rats subjected to transient brain ischaemia treated
with pentoxifylline.
Therapeutic strategies for vascular cognitive disorders 677
60.6.5.1 Pentoxifylline
Haemorheological alterations are found in AD patients
and in some forms of VaD, such as BD, in comparison with
age-matched controls (Solerte et al., 2000). Abnormalities
included hyperviscosity, increased sedimentation rate, hyper-
fibrinogenemia and increased acute-phase reactants; these
changes correlate with increased levels of TNF-α and IFN-γ.
Pentoxifylline treatment lowers fibrinogen and TNF-α levels.
Black et al. (1992) demonstrated beneficial effects of pentoxi-
fylline in patients with MID. These preliminary findings were
confirmed in the larger, multicentre European Pentoxifylline
Multi-Infarct Dementia Study (1996) that demonstrated sig-
nificant cognitive improvement in the MID form of VaD in
comparison with placebo. Sha and Callahan (2003) reviewed
20 articles on pentoxifylline use in VaD but only four stud-
ies met systematic review criteria. A trend towards improved
cognitive function was found in pentoxifylline-treated
patients. A subgroup analysis of three studies of VaD noted
statistically significant improvement in cognitive function
with pentoxifylline compared with placebo and suggested a
potential therapeutic role for pentoxifylline in VaD.
60.6.5.2 Propentofylline
Beneficial effects on learning and memory were observed
in several European and Canadian double-blind, placebo-
controlled, parallel group RCTs of PPF in AD and VaD
(Kittner et al., 1997; Mielke et al., 1998; Pischel, 1998; Rother
et al., 1998; Kittner, 1999). Despite these results, the clinical
development of PPF was halted.
60.6.5.3 Denbufylline
Denbufylline, a xanthine derivative and PDE4 inhibitor, has
effects such as vasodilatation of cerebral vessels (Willette
et al., 1997) and potent activation of the hypothalamic–
pituitary–adrenal axis. PDE4 is one of the cyclic adenos-
ine monophosphate (cAMP)–specific phosphodiesterases
whose tissue distribution is important in pathologies related
to the central nervous and immune systems. In experimen-
tal animals, denbufylline increases adrenocorticotropic
hormone (ACTH), circulating corticosterone, luteinizing
hormone, corticotrophin-releasing hormone, and cAMP
content of the hypothalamic tissue, but is without effect
on arginine vasopressin (Kumari et al., 1997). Treves and
Korczyn (1999) studied patients with AD, mixed demen-
tia, and VaD treated with denbufylline. No significant dif-
ferences were found in comparison with placebo for the
treatment of AD or VaD, although patients who received
denbufylline tended to improve their cognitive scores.
60.6.6 VASODILATORS
Yesavage et al. (1979) reviewed 102 studies on the use of
vasodilating agents in senile dementias; the postulated effect
of these agents was to counteract ‘hardening of the arteries’.
678 Dementia
Recommendations for most of these agents were based in tri-
als invalidated by small numbers of participants, short open
treatment periods, and variations in diagnostic criteria and
clinical end points. Cochrane (1979) strongly criticized the
poor quality of this evidence. The principal pharmacologi-
cal agents with primary effect on smooth muscle resulting in
vasodilatation are cyclandelate, papaverine, isoxsuprine, cin-
narizine and nafronyl. There were no significant effects with
the use of vasodilating agents in VaD (Cook and James, 1981).
Nicotinic acid (niacin), long used for its vasodilating
properties, has received renewed attention due to its effects
in the treatment of primary hypercholesterolemia and
mixed dyslipidemia. It is the only drug that primarily low-
ers concentrations of non-sterified fatty acids and thereby
lowers very low-density lipoprotein (VLDL) triglycerides.
Nicotinic acid also seems to improve insulin resistance
and stimulate cholesterol mobilization from macrophages,
offering an avenue for regression of atherosclerotic vascular
lesions (Karpe and Frayn, 2004).
60.6.7 ERGOT DERIVATIVES
The main ergot derivatives used for the treatment of VaD
are nicergoline and codergocrine or ergoloid mesylates – a
mixture (in a 3:3:2:1 ratio) of four dehydrogenated mesyl-
ated ergot peptide derivatives, i.e. dihydroergocornine,
dihydroergocristine, dihydro-α-ergocryptine and dihydro-
β-ergocryptine (Wadworth and Chrisp, 1992).
60.6.7.1 Ergoloid mesylates
The metabolic effects of ergoloid mesylates (Hydergine) may
include enhancement of noradrenergic, dopaminergic and
serotoninergic neurotransmission (Weil, 1988) and reduc-
tion of free radicals. Schneider and Olin (1994) reviewed 151
reports on the use of Hydergine in senile dementia, but only
47 of these trials (31%) met strict criteria for meta-analysis. A
Cochrane review (Olin et al., 2001) confirmed that patients
with VaD appeared to benefit more than patients with AD
in terms of cognition, clinical global ratings and combined
measures. However, compared with placebo, efficacy was very
modest. Thus, there are no grounds to recommend its use.
60.6.7.2 Nicergoline
Nicergoline is an ergot derivative that may protect against
degeneration of cholinergic neurones (Giardino et al., 2002).
Nicergoline has a broad spectrum of action (Winblad et al.,
2008): (1) as α1-adrenoceptor antagonist it induces vasodilata-
tion and increases arterial blood flow; (2) it enhances cholin-
ergic and catecholaminergic neurotransmission; (3) it inhibits
platelet aggregation; (4) it promotes metabolic activity, result-
ing in increased oxygen and glucose utilization; and (5) it has
neurotrophic and antioxidant properties. Nicergoline has been
used for the treatment of various dementias, including AD and
VaD (Fioravanti and Flicker, 2001). The therapeutic effects of
nicergoline were evident by 2 months of treatment and were
maintained for 6–12 months. Cognitive assessment (MMSE)
was performed in 261 patients. The difference between treat-
ment and control groups on the MMSE favoured nicergoline;
at 12 months, the effect size was 2.86. Herrmann et al. (1997)
conducted a double-blind placebo-controlled RCT involving
136 patients with MID. After 6 months of treatment, cogni-
tion in the nicergoline group was significantly better than in
the placebo group. Another placebo-controlled pilot study
by Bes et al. (1999) recruited 72 elderly hypertensive patients
with VCI and evidence of leukoaraiosis, randomly assigned to
either nicergoline (n = 36) or placebo (n = 36) for 24 months.
Nicergoline (30 mg twice daily [b.i.d.] for 24 months) was
well tolerated and attenuated cognitive decline. Winblad et al.
(2008) found that up to 89% of patients treated with nicer-
goline 30 mg b.i.d. showed improvements in cognition and
behaviour; patients remained stable after 12 months of treat-
ment. In addition, nicergoline has favourable safety and toler-
ability (Fioravanti et al., 2014).
60.6.8 POSATIRELIN
Posatirelin is a TRH analogue. In a rat experimental model
of brain cholinergic deficit by lesion of the nucleus basa-
lis magnocellularis (nbM), posatirelin treatment rescued
cholinergic neurones of the nbM and their cholinergic
projections to the cerebral cortex (Sabbatini et al., 1998).
Posatirelin has been used in AD and VaD patients (Parnetti
et al., 1995, 1996). VaD patients treated with posatirelin
showed a significant improvement in intellectual perfor-
mance, orientation, motivation and memory as compared
to controls. The drug was well tolerated.
60.6.9 ANTITHROMBOTIC AGENTS
Antiplatelet drugs are effective to prevent TIAs and isch-
aemic stroke (Meschia et al., 2014). Antiplatelet agents
include ASA, sulfinpyrazone, ticlopidine, clopidogrel,
dipyridamole, and orally administered IIb/IIIa inhibitors.
The Antithrombotic Trialists’ Collaboration (Easton, 2003)
assessed the effect of antiplatelet therapy in 135,000 patients.
Therapy reduces the combined odds of stroke, myocardial
infarction or vascular death by 22%, and reduces the odds of
a non-fatal stroke by 25% in patients with or without a history
of stroke. Likewise, among patients with nonvalvular atrial
fibrillation, anticoagulation (International Normalized Ratio
[INR] ≥ 2.0) reduces the frequency, severity and mortality of
ischaemic stroke (Hart, 2003). Substantial progress has been
achieved with the use of new oral anticoagulants, particu-
larly for stroke prevention in atrial fibrillation (January et al.,
2014). However, few trials of antiplatelet agents have been
conducted in patients with VaD.
60.6.9.1 Aspirin
A single population-based study (Sturmer et al., 1996)
showed that ASA users have a slight protection against
cognitive decline (OR 0.97–0.87), but a Cochrane review

(Williams et al., 2000) concluded that there is no evidence
that ASA treats VaD effectively.
60.6.9.2 Triflusal
Triflusal is an antiplatelet agent structurally related to the
salicylates, but it is not derived from ASA. Triflusal and its
metabolite (3-hydroxy-4-trifluoro-methylbenzoic acid or
HTB) produce specific inhibition of platelet arachidonic acid
metabolism (McNeely and Goa, 1998). A single 12-month
open-label trial of triflusal in 73 VaD patients (López-Pousa
et al., 1997) showed fewer declines in MMSE scores in
the active group compared with untreated subjects. More
recently, triflusal was used in patients with amnesic MCI;
257 patients were randomized to receive 900 mg of triflusal
or placebo for 18 months. Triflusal therapy was associated
with a significantly lower rate of conversion to dementia
(Gómez-Isla et al., 2008).
60.6.9.3 Ginkgo
Ginkgo, extract EGb 761 from the G. biloba tree (the ‘maiden-
hair’ tree), has been widely used in several European countries
and in North America for the treatment of ‘chronic cerebral
circulatory insufficiency’ (Kleijnen and Knipschild, 1992;
Gertz and Kiefer, 2004). Ginkgo biloba extracts have vasodi-
lating and antioxidant properties, as well as haemorheological
and nootropic effects, and decrease platelet aggregability and
blood viscosity, but the mechanism of action remains poorly
understood (Zimmermann et al., 2002; Gertz and Kiefer,
2004). Several trials used ginkgo in patients with MID or with
AD plus CVD, with modest positive results (Le Bars et al.,
1997; Kanowski and Hoerr, 2003; van Dongen et al., 2003).
Using Cochrane data, Kurz and van Baelen (2004) showed sig-
nificant but minimal benefit versus placebo with ginkgo treat-
ment only when all doses were pooled. Ginkgo treatment in
the elderly has been associated with SAH and other haemor-
rhagic complications such as subdural haematoma, intracra-
nial and intraocular bleeding (Vale, 1998; Fong and Kinnear,
2003; Meisel et al., 2003). Snitz et al. (2009) conducted the
Ginkgo Evaluation of Memory (GEM) trial and concluded
that compared with placebo, the use of G. biloba, 120 mg b.i.d.,
did not prevent cognitive decline in older adults with normal
cognition or MCI. The minimal therapeutic results should be
tempered by the potential side effects (Brown et al., 2010).
60.6.10 CHOTO-SAN
Choto-san (Gouteng-san) is a Japanese (Kampo) herbal
medicine with apparent neuroprotective effect against glu-
tamate-induced neuronal death (Itoh et al., 1999; Watanabe
et al., 2003). Choto-san was administered for 12 weeks to 10
patients with post-stroke VCI; P3 event-related brain poten-
tials, MMSE and verbal fluency tests significantly improved
with treatment (Yamaguchi et al., 2004). In a larger trial,
Choto-san resulted in improvement of ADLs, global rating
and subjective and psychiatric symptoms (Itoh et al., 1999).
Therapeutic strategies for vascular cognitive disorders 679
60.6.11 JIANNAO YIZHI
Jiannao Yizhi, a Chinese herbal medicine, was studied for
the treatment of VaD (Zhang et al., 2002) in a multicentre,
double-blind, placebo-controlled RCT of 242 patients with
mild-to-moderate VaD; 89 cases were randomized to the
active group (Jiannao Yizhi granules), 106 cases to the west-
ern medicine group and 47 to placebo. MMSE and Blessed
Dementia Scale were used to evaluate the therapeutic effect
after 60 days. Jiannao Yizhi treatment was superior to west-
ern medicine and to placebo (Obulesu and Rao, 2011).
60.6.12 VINPOCETINE
Vinpocetine is a synthetic ethyl ester of apovincamine.
Vinpocetine has been used for cognitive impairment, but
the mechanism of action is unclear. A Cochrane review
(Szatmari and Whitehouse, 2003) of three short-term stud-
ies involving 583 patients with dementia (AD, VaD, mixed)
concluded that patients treated with vinpocetine (30–60 mg/
day) showed modest benefit compared to placebo.
60.6.13 DEHYDROEPIANDROSTERONE
(DHEA)
DHEA is a weakly androgenic adrenal steroid and an inter-
mediary in the biosynthesis of androgens and oestrogens. It
is a neurohormone; small quantities of DHEA are produced
in the brain (Knopman and Henderson, 2003). DHEA or its
sulphate ester metabolite (dehydroepiandrosterone sulphate
[DHEAS]) is the most abundant circulating steroid and
declines in serum and CSF with age. Bicikova et al. (2004)
suggested that levels of these neurosteroids could discrimi-
nate between AD and VaD; however, CSF levels of DHEAS
are low in both AD and VaD (Kim et al., 2003).
DHEA is classified as a dietary supplement; a 6-month,
double-blind RCT of DHEA for AD (Wolkowitz et al., 2003)
showed modest improvement with DHEA but increas-
ing confusion, agitation, and paranoid reactions were
seen among DHEA-treated participants, resulting in high
dropout. A single open-label trial of DHEA in the MID
type of VaD (Azuma et al., 1999) used intravenous DHES
(200 mg/day) for 4 weeks; the treatment markedly increased
serum and CSF levels of DHEAS in seven MID patients;
however, improvement of ADL and emotional disturbances
were seen in only three patients.
60.6.14 CEREBROLYSIN
Cerebrolysin is a peptidergic drug produced from purified
porcine brain proteins, with postulated neurotrophic and
neuroprotective effects (Windisch et al., 1998; Rockenstein
et al., 2003; Plosker and Gauthier, 2009; Gauthier et al.,
2015). A small open-label trial in patients with AD and VaD
(Rainer et al., 1997) showed minimal improvement in cog-
nitive tests and clinical global impression. The main side
effects were nausea and vertigo. A Cochrane review (Chen
680 Dementia
et al., 2013) of six RCTs with a total of 597 participants
showed minimal MMSE and ADAS-cog improvements.
60.6.15 SULODEXIDE
Sulodexide is a medium molecular weight glycosamino-
glycan with effects on plasma viscosity by lowering plasma
fibrinogen concentrations (Lunetta and Salanitri, 1992).
Sulodexide differs from other glycosaminoglycans, like
heparin, by having a longer half-life, reduced effect on sys-
temic clotting and bleeding and increased lipolytic activity.
Oral administration of sulodexide results in the release of
tissue-type plasminogen activator (tPA) and an increase in
fibrinolytic activities. Sulodexide has been used in chronic
venous disease (Andreozzi, 2014), peripheral occlusive arte-
rial disease with claudication (Shustov, 1997) and diabetic
nephropathy (Vilayur and Harris, 2009). Parnetti et al. (1997)
conducted a trial of sulodexide in patients fulfilling NINDS-
AIREN criteria for probable VaD; 46 patients were included
in the active treatment group, compared with 40 in the pent-
oxifylline group. Larger reductions of plasma fibrinogen
levels were seen with sulodexide, and both groups showed
a slight reduction in activated factor VII levels. Dementia
scores improved more in the sulodexide group.
60.6.16 THROMBIN INHIBITORS
There is evidence indicating that hypercoagulable states could
result in increased dementia risk (Mari et al., 1996). Bots
et al. (1998) from the Dutch Vascular Factors in Dementia
Study found that dementia, particularly post-stroke VaD,
was associated with increased thrombin generation. In this
population, increased levels of thrombin–antithrombin
complex (TAT), cross-linked D-dimer and tPA activity were
associated with increased risk of dementia. In addition,
coagulation abnormalities have been described in patients
with BD. Schneider et al. (1987) found high fibrinogen and
hyperviscosity in patients with BD. Iwamoto et al. (1995)
demonstrated increased platelet activation in BD manifested
by increased plasma β-thromboglobulin levels. Tomimoto
et al. (1999, 2001) found coagulation activation leading to
hypercoagulable state in Japanese patients with BD; levels of
fibrinogen, TAT complex, prothrombin fragment 1+2, and
D-dimer were found to be significantly increased, particu-
larly in patients with recent aggravation of their deficits.
There are no RCTs in BD, but these results point toward
several potential therapeutic options (Román, 1999b).
Iwamoto et al. (1995) reported that the use of ticlopidine
hydrochloride in eight patients with BD resulted in lower
levels of platelet activation, without major clinical change.
There is a need for RCTs of ticlopidine and other antiplate-
let agents (e.g. ASA, dipyridamole and clopidogrel, alone or
combined) in BD.
Hyperfibrinogenemia has deleterious effects on
haemorheological conditions in the cerebral microcircula-
tion that result in hyperviscosity and slowing of blood flow
in deep border-zone territories in BD. Therefore, the use
of medications such as pentoxifylline, ancrod (Sherman,
2002) or bezafibrate (Tanne et al., 2001) to lower fibrinogen
levels could be indicated.
Ancrod is a defibrinating enzyme (Sherman, 2002).
Ringelstein et al. (1988) used it in 10 patients with BD.
Subcutaneous ancrod treatment decreased plasma levels
of fibrinogen from 3.26 g/L (SD 1.3) pretreatment (normal
2.5–4.0 g/L) to 1.52 g/L (SD 0.53) after 1 month. Treatment
improved retinal arteriovenous circulation time (abnor-
mally slow pretreatment) and increased CO2-induced cere-
bral vasomotor response by transcranial Doppler. However,
clinical condition and neuropsychological tests were
unchanged, and there was no decrease in stroke recurrences
during 6 months of observation.
In 1968, Walsh observed improved dementia symp-
toms with a treatment based on warfarin anticoagulation
(Walsh et al., 1978). Currently, this treatment is reserved for
patients with nonvalvular atrial fibrillation (Hart, 2003),
heart valve replacement or with anticardiolipin antibody
syndrome. Direct thrombin inhibitors are equally effective;
they inhibit fibrin-bound thrombin, produce a predictable
anticoagulant response and require no long-term monitor-
ing and no dose adjustment, but are irreversible in emer-
gencies. Stroke prevention in patients with atrial fibrillation
is complicated by dementia and cognitive decline (Flaker
et al., 2010).
Since 1993, Walzl (1993, 2000) has developed a haemorhe-
ological treatment called Heparin-mediated Extracorporeal
low-density lipoprotein (LDL)/fibrinogen Precipitation
(HELP) to reduce elevated fibrinogen levels and increased
lipid fractions to control hyperviscosity of plasma and whole
blood and to reduce aggregability or sludging of red blood
cells. HELP was used in 141 patients with the MID type of
VaD. Laboratory and clinical evaluations were performed
before and after treatment. Each HELP treatment reduced
whole blood and plasma viscosity and red cell transit time.
Total cholesterol, low-density lipoproteins, and triglycer-
ides were reduced significantly. Neurological improvement
was confirmed by improved MMSE, Mathew Scale, and
ADL scores. The Italian HELP group continues to use this
method (Stefanutti et al., 2013).
60.6.17 HYPERBARIC OXYGEN
TREATMENT (HBOT)
Vila et al. (1999) reported on HBOT in four BD patients.
Patients received daily sessions of HBOT at 2.5 atmo-
spheres absolute (ATA) for 45 minutes, for a total of 10 days.
Controls received room air at 1.1 ATA. The procedure was
well tolerated. After treatment, noticeable improvements in
gait, urinary symptoms and cognitive tests were observed
in all subjects, with increased independence. This improve-
ment persisted for up to 5 months, after which the previ-
ous deficits reappeared but responded again to repeated
HBOT treatment. Despite the method’s promise, there has
been no independent confirmation of the benefits of HBOT
in BD (Román, 1999c). In China, Xiao et al. (2012) found a

single study (Wang et al., 2009) involving 64 patients who
used HBOT as an adjuvant treatment to donepezil. After
12 weeks, patients on HBOT performed significantly better
than controls on two cognitive tests: MMSE and Hasegawa’s
Dementia Rating Scale.
60.6.18 SPG STIMULATION
The SPG is the source of parasympathetic innervation to
the anterior cerebral circulation. Electrical stimulation of
SPG neurones leads to profound ipsilateral increase in CBF,
augmenting tissue perfusion (Henninger and Fisher, 2007;
Khurana et al., 2009). This method was used in the treat-
ment of acute stroke in ImPACT-I and ImpACT-24 to evalu-
ate the safety and effectiveness of SPG stimulation using the
Ischemic Stroke System (ISS), an implantable neurostimula-
tor (INS). The INS is implanted to all patients through the
greater palatine canal, in a minimally invasive, oral proce-
dure under local anaesthesia. Study patients are unilaterally
implanted with the INS and treated daily for up to 90 days.
Treatment is expected to augment CBF, improve cerebral
perfusion, and halt cognitive deterioration. Preliminary
results in 10 patients (Alladi et al., 2009) confirmed signifi-
cant increase in CBF ipsilateral to the stimulated side and
in the contralateral cerebellum by 18F-fluorodeoxyglucose
(FDG) positron emission tomography (PET) scan, along
with significant improvement in attention, orientation,
memory, ability to execute verbal commands, and executive
function. SPG has also been used to treat cluster headaches.
60.7 GENERAL MEDICAL
MANAGEMENT OF THE PATIENT
WITH VaD
Epidemiological studies confirm the increased risk of
dementia associated with vascular risk factors, especially
hypertension (Launer et al., 1995; Skoog et al., 1996; Kilander
et al., 1998; Launer et al., 2000). In a French population-
based study, Tzourio et al. (1999) found that in 4 years,
untreated hypertension in subjects 59–71 years of age mul-
tiplied by four the risk of cognitive decline (OR 4.3, 95% CI
2.1–8.8) compared with 1.9 (95% CI 0.8–4.4) in those being
treated.
Other important risk factors include diabetes mellitus
(Ott et al., 1999; Stewart and Liolitsa, 1999;), smoking (Ott
et al., 1998), raised homocysteine (Seshadri et al., 2002),
particularly with vitamin B12 deficiency (Hooshmand et al.,
2010, 2012), and mutations of the MTHFR gene (Román,
2015). These vascular risk factors increase the risk of both
VaD and AD. Other than the APOE gene, other genetic and
racial factors are probably important. Zamrini et al. (2004a)
showed that blacks had higher rates of hypertension than
whites in Alabama, whereas whites had a higher incidence
of atrial fibrillation, coronary artery disease, and higher
cholesterol. Therefore, primary and secondary prevention
Therapeutic strategies for vascular cognitive disorders 681
of stroke and CVD appears to be mandatory for dementia
prevention (Lechner, 1998; Erkinjuntti and Gauthier, 2002;
O’Brien et al., 2003; Barnes and Yaffe, 2011; Román et al.,
2012; Willis and Hakim, 2013; Román and Boller, 2014).
The reader is referred to the Guidelines for Primary Stroke
Prevention of the American Heart Association/American
Stroke Association (Meschia et al., 2014) for the prevention
of atherosclerotic cardiovascular disease (Gorelick et al.,
2014).
60.7.1 TREATMENT OF HYPERTENSION
Treating hypertension protects against cognitive decline
even in the absence of stroke (Forette et al., 1998; Clarke,
1999; Forette et al., 2002). No deleterious effects on cogni-
tion, mood and quality of life have been demonstrated with
the treatment of hypertension in the elderly (Applegate et al.,
1994; Starr et al., 1996; Prince et al., 1996; Prince, 1997). On
the contrary, Forette et al. (2002) confirmed that treatment
of systolic hypertension with nitrendipine protects against
dementia in older patients. Compared with placebo, long-
term antihypertensive therapy reduced the risk of dementia
by 55%, from 7.4 to 3.3 cases per 1000 patient-years. After
adjustment for sex, age, education, and entry BP, the relative
hazard rate associated with the use of nitrendipine was 0.38
(95% CI 0.23–0.64, p < 0.001). Treatment of 1000 patients
for 5 years can prevent 20 cases of dementia (95% CI 7–33)
(Forette et al., 1998, 2002). The results of the SPS3 study
(Jacova et al., 2012, 2015) showed that adherence to the anti-
hypertensive treatment is more important than the level of
BP control achieved.
The SCOPE confirmed that the treatment of mild-to-
moderate hypertension in the elderly prevents stroke and
dementia (Lithell et al., 2003). SCOPE enrolled 4964 patients
aged 70–89 years, with systolic BP of 160–179 mm Hg and/
or diastolic BP of 90–99 mm Hg and an MMSE test score
≥24; patients were treated with candesartan, an angioten-
sin receptor blocker, or placebo, plus open-label active anti-
hypertensive therapy added as needed. BP reduction was
slightly better with candesartan, compared with control
therapy; this was associated with a modest, non-significant,
reduction in major cardiovascular events and with a marked
reduction in non-fatal stroke. Cognitive function was well
maintained in both treatment groups in the presence of sub-
stantial BP reductions. Current guidelines (JNC8) should
be consulted for the recommended antihypertensive treat-
ments (James et al., 2014; Farooq and Ray, 2015).
Finally, control of hypertension in patients with stroke
(secondary prevention) also helps to prevent dementia. The
PROGRESS Collaborative Group (2001), an RCT of perin-
dopril, an angiotensin-converting enzyme (ACE) inhibitor
and a diuretic (indapamide) used in 6105 individuals with
previous stroke or TIA showed that after 3.9 years follow-
up BP was reduced, lowering the risks of stroke and other
major vascular events. Dementia was decreased, with a RR
reduction of 12% (Tzourio et al., 2003). Cognitive decline
occurred in 9.1% of the treated group and 11.0% of the
682 Dementia
placebo group (risk reduction, 19%). In summary, treat-
ment resulted in reduced dementia risk and of the cognitive
decline associated with recurrent stroke.
60.7.2 TREATMENT OF HYPERLIPIDAEMIA
WITH STATINS
The most recent recommendations for the management of
hyperlipidaemia suggest a reduction of LDL cholesterols to
below 100 mg/dL, and drug therapy for high-risk patients
whose LDL ranges from 100 to 129 mg/dL (Grundy et al.,
2004). High-risk patients have coronary heart disease or
peripheral vascular disease in the extremities or the vessels
to the brain, or diabetes, or multiple (two or more) risk fac-
tors (e.g. smoking, hypertension) that give them a greater
than 20% chance of having a heart attack within 10 years.
Very high-risk patients are those who have cardiovascular
disease together with either multiple risk factors (especially
diabetes) severe and poorly controlled risk factors (e.g. con-
tinued smoking) or metabolic syndrome (a constellation of
risk factors associated with obesity including high triglyc-
erides and low high-density lipoprotein [HDL]). Patients
hospitalized for acute coronary syndromes or strokes are at
very high risk (Grundy et al., 2004). The most recent guide-
lines recommend statin therapy for those with coronary
heart disease or other high-risk conditions such as diabetes
mellitus or symptomatic carotid atherosclerosis. In these
groups, statin treatment is associated with 20% reduction in
the risk of a first stroke (Gorelick et al., 2014).
The use of statins may reduce the risk of dementia (Jick et al.,
2000; Rockwood et al., 2002; Zamrini et al., 2004b). Jick et al.
(2000) studied 284 patients with dementia and 1080 controls
aged over 50 years; the adjusted RR for those prescribed statins
was 0.29 (95% CI 0.13–0.63, p = 0.002) indicating a substan-
tially lowered risk of developing dementia, independent of the
presence or absence of untreated hyperlipidaemia. Zamrini
et al. (2004b) conducted between 1997 and 2001 a study of
veterans in Birmingham, AL; patients with a new diagnosis of
AD (n = 309) were compared with age-matched non-AD con-
trols (n = 3088). In this group, statins users had a 39% lower
risk of AD relative to nonstatin users (OR 0.61, 95% CI 0.42–
0.87). These results indicate a possible antidementia effect of
statins, perhaps related to anti-inflammatory effects. Positive
effects have been noted in patients with VaD (Giannopoulos
et al., 2014). However, the use of statins in nondemented, non-
hyperlipidaemic patients cannot be recommended (Miller and
Chacko, 2004; McGuinness et al., 2014).
60.7.3 CONTROL OF DIABETES
The abnormalities in carbohydrate, lipid and protein metab-
olism resulting from diabetes mellitus injure blood vessels,
nerves and other tissues. Diabetes increases up to fourfold
the RR for cardiovascular and CVD due to the microvas-
cular (retinopathy, nephropathy, neuropathy, lacunes) and
macrovascular (coronary heart disease, stroke, peripheral
arterial disease) complications. Diabetes produces cognitive
decline, doubling the overall risk of dementia (Ott et al.,
1999; Stewart and Liolitsa, 1999).
Diabetes increases blood viscosity from hyperglycaemia,
endothelial oxidative damage, loss of nitric oxide (NO)–
mediated endothelial functions and alterations of the BBB
(Mooradian, 1997), as a result of excessive glycation as well
as from glycoxidized LDLs. The end result is impairment
of perfusion through the cerebral and retinal microcircula-
tion. In addition, stress-activated pathways such as the Jun-
kinases play a major role in diabetic microangiopathy (Evans
et al., 2002). The most current guidelines for the treatment
of type 2 diabetes are the American-European (Nathan et al.,
2009) and American Diabetes Association (2014) guidelines.
60.7.4 CESSATION OF SMOKING
Smokers double their risk of coronary artery disease, con-
gestive heart failure and peripheral vascular disease, and
increase 1.5 times the risk of stroke and dementia (Ott et al.,
1998). Smoke, in addition to nicotine and carbon monox-
ide, contains a complex mixture of free radicals that cause
morphological irregularities of the endothelium, formation
of blebs, leakage of macromolecules and increased endothe-
lial cell death (Pittilo, 2000). Smoke reduces prostacyclin
release, enhances endothelium-derived vasodilatation, and
decreases NO concentrations and cyclic guanosine mono-
phosphate (cGMP) production, increasing aggregation of
platelets and leucocytes. Smoking worsens atheromatous
plaque formation in carotid arteries and increases hyperten-
sion, blood coagulability, serum viscosity and fibrinogen.
Smokers have worse cognitive performances than non-
smokers including reduced psychomotor speed and reduced
cognitive flexibility. This effect is observed in subjects as
young as 45 years old (Kalmijn et al., 2002). A meta-analysis
of prospective cohort studies (Zhong et al., 2015) demon-
strated that smoking is associated with an increased risk
of dementia. For VaD, the RR was 1.38 (95% CI 1.15–1.66).
For all-cause dementia, the risk increased by 34% for every
20 cigarettes per day (RR 1.34, 95% CI 1.25–1.43). Smoking
cessation decreases the risk to that of never smokers.
60.7.5 DIET
Dietary change with reduced sodium intake is a crucial
component of the treatment of arterial hypertension. The
Dietary Approaches to Stop Hypertension (DASH) diet
(Sacks et al., 2001) is currently recommended by the US
Department of Health and Human Services. This diet is
rich in magnesium, potassium, calcium, protein and fibre
and low in saturated fat, cholesterol and total fat. There is
emphasis on fruits, vegetables, low fat dairy foods, whole
grain products, fish, poultry and nuts. McGuire et al. (2004)
randomized hypertensive patients to advice-only group; to
a group treated with weight loss, increased physical activity,
and reduced sodium and alcohol intake and a third group
that included the latter plus the DASH diet. At 6 months,
compared with the advice-only group, the second group

had a decline of mean systolic BP of 3.7 mm Hg (p < 0.001)
and 4.3 mm Hg for the DASH diet group (p < 0.001). The
study confirmed that hypertension control requires mul-
tiple lifestyle changes including an appropriate eating plan.
Epidemiological data suggested an association between
dietary factors, particularly antioxidants, and cognition
(Deschamps et al., 2001). Similarities in the diets of patients
with AD and VaD have been reported in Japan (Otsuka et al.,
2002), with higher energy intake from fats, in particular poly-
unsaturated fatty acids and decrease in antioxidant vitamins B,
C and carotene. However, in the Honolulu-Asia Aging Study,
midlife intakes of antioxidants, such as beta-carotene, flavo-
noids and vitamins E and C, did not modify late-life dementia
risk, including AD and VaD (Laurin et al., 2004). Likewise, no
effect of fat intake in the development of dementia was found
in the Rotterdam study (Engelhart et al., 2002).
Wald et al. (2002) concluded, based on the evidence
from genetic and prospective studies, that the association
between increased homocysteine and cardiovascular dis-
ease is causal. Despite some disagreement (Homocysteine
Studies Collaboration, 2002), lowering homocysteine con-
centrations by 3 µmol/L from current levels (achievable by
increasing folic acid intake) would reduce the risk of isch-
aemic heart disease (IHD) by 16% (11%–20%), deep vein
thrombosis by 25% (8%–38%) and stroke by 24% (15%–33%).
Román (2015) observed a very high prevalence of MTHFR
mutations in a memory clinic population. DNA analyses of
two MTHFR gene mutations (C667T and A1298C), includ-
ing homozygous and heterozygous polymorphisms, were
recorded in 92.5% of consecutive patients with late-onset
AD+CVD (Román, 2015). Elevation of total serum homo-
cysteine (tHcy) is considered a risk factor for dementia
(Hooshmand et al., 2010, 2012), particularly in association
with low folate and vitamin B12 levels (Clarke et al., 1998).
In the Framingham Study (Seshadri et al., 2002), elderly
subjects (mean age, 76 years) with tHcy above 14 μmol/L
nearly doubled the risk of AD over a period of 8 years, even
after adjustment for multiple factors. A review of cross-
sectional and prospective studies involving >46,000 sub-
jects (Smith, 2008) confirmed the association between high
tHcy and cognitive deficit or dementia. However, elevation
of tHcy is affected by factors including age, diet, supple-
mentation of folic acid and B-group vitamins, smoking,
Helicobacter pylori infection and renal failure, among oth-
ers. Nonetheless, combined treatment with folate and vita-
mins B6 and B12 has been demonstrated effectively to halt
the conversion of MCI to AD (Smith et al., 2010; Douaud
et al. 2013). These results disagree with a Cochrane review
(Malouf et al., 2003) that concluded that in older patients
with mild-to-moderate cognitive decline, supplementation
with 750 μg/day of folic acid, with or without B12, had no
beneficial effects on cognition or mood, although folic acid
plus vitamin B12 effectively reduced serum homocysteine
concentrations. Along the same lines, a trial on the use of
vitamins to prevent recurrent stroke gave negative results
(Toole et al., 2004).
Therapeutic strategies for vascular cognitive disorders 683
Nonetheless, a diet rich in antioxidant phytophenols,
such as those found in fish, olive oil, red wine, and grape
juice, appears to inhibit endothelial adhesion molecule
expression effectively, partly explaining the protection from
atherosclerosis afforded by Mediterranean diets (Carluccio
et al., 2003; Scarmeas et al., 2009a, 2009b; Lourida et al.,
2013; Shen et al., 2015).
60.7.6 CHRONIC INFLAMMATION
Markers of inflammation such as C-reactive protein (CRP)
are important predictors of atherosclerotic disease, par-
ticularly in patients with diabetes (Rader, 2000). Chronic
infections, including periodontal disease and persistent
intracellular infection with Chlamydia pneumoniae have
been associated with increased risk of vascular events
(Kalayoglu et al., 2002).
60.8 PUBLIC HEALTH ASPECTS OF VaD
Population ageing will lead to increasing incidence of stroke
and heart disease. It is predicted that VaD will become the
most common cause of senile dementia, both by itself and
as a contributor to other degenerative dementias (Román,
2002e).
There is growing evidence that preventive measures to
decrease the vascular burden on the brain may also decrease
VaD in the elderly. VaD and AD share with stroke a number
of vascular risk factors. The most important of the modifi-
able factors is hypertension, which explains at least half of
the attributable risk of stroke. As noted, three large RCTs
(Forette et al., 1998, 2002; Lithell et al., 2003; Tzourio et al.,
2003) demonstrated that BP lowering has a significant effect
in decreasing the risk of dementia, including VaD and
AD. Overall, these data suggest that interventions aiming
at reducing the level of vascular risk factors might prevent
dementia. The expected benefit of these interventions could
be estimated from data provided by epidemiological stud-
ies; however, there is a dearth of large population-based
controlled studies to demonstrate the efficacy of preven-
tive interventions at Public Health level (Román, 2003b;
Alperovitch et al., 2004; Williams, 2004). Prevention
appears to be the most promising avenue for decreasing the
incidence of the two most common forms of senile demen-
tia, AD and VaD dementia.
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 6
Part    

Dementia with Lewy Bodies and

Parkinson’s Disease

61 Dementia with Lewy bodies: A clinical overview 703

Ian G. McKeith
62 Pathology of dementia with Lewy bodies 714
Glenda Halliday, Simon Lewis and Paul Ince
63 The treatment of dementia with Lewy bodies 730
John-Paul Taylor
64 Cognitive impairment and dementia in Parkinson’s disease 740
Dag Aarsland, Kolbjørn Brønnick, Milica G. Kramberger and Joana B. Pereira

Dementia with Lewy bodies: A clinical overview
IAN G. MCKEITH
61.1 INTRODUCTION
61.1.1 DEMENTIA WITH LEWY BODIES:
WHAT’S IN A NAME?
Dementia with Lewy bodies (DLB) is now the preferred
term (McKeith et al., 1996) for a variety of clinical diagno-
ses including diffuse Lewy body disease (DLBD) (Kosaka
et al., 1984; Dickson et al., 1987; Lennox et al., 1989),
Lewy body dementia (LBD) (Gibb et al., 1987), demen-
tia associated with cortical Lewy bodies (DCLB) (Byrne
et al., 1991), the Lewy body variant of Alzheimer’s disease
(LBVAD) (Hansen et al., 1990; Förstl et al., 1993) and senile
dementia of Lewy body type (SDLT) (Perry et al.,1990).
Figure 61.1 provides a simple schematic of the relationship
between the various Lewy body (LB) terminologies rec-
ommended currently, and consistency of usage is essential
for a full understanding of the disorder. This chapter con-
siders the evolution of diagnostic concepts and methods;
the pathology and management of DLB are considered in
subsequent chapters.
DLB is important in clinical practice because of the fol-
lowing reasons:
●● It usually has a clinical presentation and course, which
differs from Alzheimer’s disease (AD) and other non-
AD dementias.
●● Functional disability and impairment in quality of life
(QoL) are greater in DLB than AD and generate signifi-
cantly higher costs of care.
●● The management of psychosis and behavioural distur-
bances, which are common in DLB, is complicated by
sensitivity to neuroleptic medication.
●● It may be particularly amenable to cholinesterase
inhibitor treatment.
61
61.1.2 SCALE OF THE PROBLEM
Several studies in a range of settings have suggested that
DLB accounts for just 20% below of all cases of dementia
referred for neuropathological autopsy (McKeith et al.,
2005). Community-based estimates are much more in vari-
able ranging from 0% to 30.5% (Zaccai et al., 2005). A com-
munity study of 85+ year olds found 5.0% met diagnostic
criteria for DLB representing 22% of all demented cases
(Rahkonen et al., 2003), similar to other clinical estimates
(Stevens et al., 2002; Aarsland et al., 2008). A systematic
review reported that DLB accounted for 4.2% of all diag-
nosed dementias in the community, increasing to 7.5% in
secondary care. The incidence of DLB was 3.8% of new
dementia cases. Vann Jones et al. (2014) estimated the inci-
dence of DLB as 3.5 per 100,000 person-years overall (Savica
et al., 2013). In clinical practice, therefore, it is likely that
DLB is significantly under-diagnosed compared to autopsy
findings. Survival in DLB is significantly reduced compared
to AD, but studies have not confirmed a general tendency
to a more rapid cognitive decline. Risk factors for DLB are
unclear as prevalence studies have been too limited.
61.2 DEVELOPMENT OF CLINICAL
DIAGNOSTIC CRITERIA FOR DLB
61.2.1 EARLY CASE REPORTS
When Friedrich Lewy first described the eosinophilic,
neuronal inclusions that we now call Lewy bodies, in
the brain stem of patients with paralysis agitans, he did
not associate the inclusions with cognitive impairment
and psychiatric disorder (Forster and Lewy, 1912). This
was despite half of his sample being clinically demented
703
704 Dementia
Lewy body disease (LBD)
Parkinson’s Lewy body
disease dementias
(PD) (LBDs)
PD dementia Dementia with Lewy
(PDD) bodies (DLB)
50–60 Increasing age 70–80
Figure 61.1 Schematic of the relationship between the
various Lewy body terminologies.
and a quarter having mood disorders, hallucinations and
paranoid delusions (Förstl and Levy, 1991). The first case
reports specifically describing patients with dementia and
LBs did not appear until 1961 when Okazaki et al. (1961)
published two cases, both elderly men presenting cogni-
tive decline and subsequently developing severe demen-
tia. Over the next 20 years, 34 similar cases were reported.
Kosaka et al. (1984) noted a 3:1 male predominance, with
memory disturbance as the presenting feature in 67%,
psychotic states (sic) in 17% and dizziness due to ortho-
static hypotension in 17%. Progressive dementia with
muscular rigidity occurred eventually in 80% although
only 25% of cases were diagnosed with parkinsonism. The
first substantial listing of these Japanese cases in western
literature was done in 1987 by Gibb et al. who added four
new UK cases.
61.2.2 EARLY DIAGNOSTIC CRITERIA
The following year, Burkhardt et al. (1988) listed 34 US cases
and carried out a simple meta-analysis. The most common
presentation was a ‘neurobehavioural syndrome’; memory
impairment and other cognitive deficits were typical, all but
one eventually becoming demented. Psychotic features such
as depression, hallucinations and paranoia were seen in 10
patients (29%), 2 patients being psychotic for many years
before developing other symptoms. Parkinsonian features,
the most common of which was rigidity, were usually over-
shadowed by dementia; in only five cases (15%), there were
no extrapyramidal features present. Duration of illness was
variable (1–20 years) with an end state of severe dementia,
rigidity, akinetic mutism, quadriparesis in flexion and emaci-
ation. The most common reported cause of death was aspira-
tion pneumonia. Based upon these observations, Burkhardt
et al. (1988) were the first to attempt a general description of
the clinical syndrome associated with DLBD, distinguishing
it as separate from Parkinson’s disease (PD) with dementia
(PDD). They concluded that ‘DLBD should be suspected in
any elderly patient who presents with a rapidly progressive
dementia, followed in short order by rigidity and other par-
kinsonian features. Myoclonus may be present.’
Crystal et al. (1990) in a paper entitled ‘Antemortem diag-
nosis of diffuse Lewy body disease’ criticized this approach
on the grounds that ‘extrapyramidal features occur in many
patients with severe AD and since dementia occurs in many
subjects with PD, the clinical criteria for the diagnosis of
DLBD remain unclear’. The authors proposed alternative
criteria of ‘progressive dementia with gait disorder, psychiat-
ric symptoms and a burst pattern on electroencephalogram
(EEG) at the time of moderate dementia’. No particular char-
acteristics of the pattern of cognitive impairment were noted.
Although, these early clinical definitions were important
in drawing attention to the existence of DLB and describing
some of its salient characteristics, neither could be regarded
as satisfactory for clinical diagnostic purposes, since they
lacked detail and were not operationalized in a way which
would allow acceptable inter-rater reliability (Hansen and
Galasko, 1992).
61.2.3 THE NOTTINGHAM GROUP
FOR THE STUDY OF
NEURODEGENERATIVE DISORDERS
The Nottingham group reported the clinical characteristics of
15 new UK cases in considerable detail, the largest individual
series published at that time (Byrne et al., 1989) leading to the
first formal proposal of operational criteria for DCLB (Byrne
et al., 1991). Seven were men in this sample study, the mean
age of onset was 72 years and the mean duration of illness
was 5.5 years. Forty per cent presented symptoms and signs of
idiopathic PD with cognitive impairment occurring 1–4 years
later. A further 20% had parkinsonism and mild cognitive
impairment (MCI) during presentation and the remaining
40% showed motor features later in their illnesses, gait distur-
bance and postural abnormalities being commonest. These
latter cases presented with neuropsychiatric features, only
in various combinations of cognitive impairment, paranoid
delusions and visual or auditory hallucinations. Fourteen of
the 15 people were demented before death, the exception pre-
senting itself with classical PD and later becoming depressed,
irritable and mildly forgetful with frequent falls. Fluctuating
cognition with episodic confusion for which no adequate
underlying cause could be found, was observed in 80% of the
Nottingham cases. Byrne also drew attention to the frequent
occurrence of depression (20%) and psychosis (33%).
61.2.4 THE NEWCASTLE STUDIES
At around the same time, the Newcastle upon Tyne group
identified 14 UK cases with the neuropathological features
of ‘SDLT’ (Perry et al., 1990) accounting for 15% of a series
of dementia autopsies. These SDLT cases had been regarded,
when patients were alive, as clinically atypical ‘caus-
ing much diagnostic perplexity’. Acute onset, fluctuating

course, more rapid deterioration, early and prominent
hallucinatory and behavioural disturbances and associ-
ated mild parkinsonian features were present. Two further
Newcastle series were reported soon after (McKeith et al.,
1992a, 1992b) and depressive symptoms, unexplained falls,
observed disturbances of consciousness and excessive sen-
sitivity to side effects of neuroleptic medication were added
to the list of clinical characteristics with potential to distin-
guish DLB pathology cases from AD.
Based upon these observations, new clinical diagnos-
tic criteria was proposed with an emphasis upon cognitive
dysfunction and neuropsychiatric features, which could
occur in the absence of extrapyramidal motor signs and an
attempt was made to describe the typical course of illness.
The first stage is often recognized only in retro-
spect and may extend back to 1–3 years’ pre-
presentation with occasional minor episodes of
forgetfulness, sometimes described as lapses of
concentration or ‘switching off’. A brief period
of delirium is sometimes noted for the first time,
often associated with genuine physical illness
and/or surgical procedures. Disturbed sleep,
nightmares and daytime drowsiness often per-
sist after recovery.
Progression to the second stage frequently
prompts psychiatric or medical referral. A more
sustained cognitive impairment is established,
albeit, with marked fluctuations in severity.
Recurrent episodes of confusion are accompa-
nied by vivid hallucinatory experiences, visual
misidentification syndromes and topographi-
cal disorientations. Extensive medical screen-
ing is usually negative. Attentional deficits are
apparent as apathy and daytime somnolence
and sleep behaviour disorder may be severe.
Gait disorder and bradykinesia are often over-
looked, particularly in elderly subjects. Frequent
falls occur either due to postural instability or
due to syncope.
The third and final stage often begins with a
sudden increase in behavioural disturbance lead-
ing to requests for sedation or hospital admission
by perplexed and exhausted carers. The natural
course from this point is variable and obscured by
the high incidence of adverse reactions to neu-
roleptic medication. For patients not receiving
or tolerating neuroleptics, a progressive decline
into severe dementia with dysphasia and dys-
praxia occurs over months or years, with death
usually due to cardiac or pulmonary disease.
During this terminal phase, patients show con-
tinuing behavioural disturbances including vocal
and motor responses to hallucinatory phenom-
ena. Lucid intervals with some retention of recent
memory function and insight may still be appar-
ent. Neurological disability is often profound with
Dementia with Lewy bodies: A clinical overview 705
fixed flexion deformities of the neck and trunk and
severe gait ­impairment (McKeith et al., 1992a).
61.2.5 INTERNATIONAL CONSENSUS
CRITERIA
61.2.5.1 First report of the DLB consortium
By the early 1990s, it was becoming apparent that DLB was a
relatively common cause of dementia in old age and that the
several research groups investigating it were adopting differ-
ent terminologies. The Consortium on DLB met in October
1995 to agree on common clinical and pathological methods
and nomenclature. The consensus criteria (McKeith et al.,
1996) described the particular characteristics of the cogni-
tive impairments of DLB in some detail as differing from
the dementia syndrome of AD, in which memory deficits
predominate. In DLB, attentional deficits and prominent
visuospatial dysfunction are the main features (Salmon and
Galasko, 1996). Probable DLB could be diagnosed if any two
of the three key symptoms are present, namely fluctuation,
visual hallucinations or spontaneous motor features of par-
kinsonism and possible DLB if only one is present.
Several retrospective and two prospective studies have
examined the predictive accuracy of these original consen-
sus clinical criteria for probable DLB (McKeith et al., 2000;
Litvan et al., 2003). They suggest that sensitivity of case
detection is generally low at around 40% whereas, specific-
ity is much higher, typically around 90%, suggesting that
the criteria are most useful for confirmation of diagnosis
(low false positive rate) but less helpful for case finding.
61.2.5.2 Second report of the DLB
consortium
The Second International DLB Workshop met in July 1998
(McKeith et al., 1999). The objectives were to review devel-
opments since publication of the consensus guidelines and
to determine whether these were required to be modified
further. It was recommended that the clinical consensus
criteria should continue to be used in their current for-
mat with the addition of two new supportive features,
namely, rapid eye movement (REM), REM behaviour dis-
order (RBD) (Section 61.3.1.3.3) and depression (Section
61.3.1.3.4).
61.2.5.3 Third report of the DLB consortium
In order to address the perceived shortcomings of the origi-
nal diagnostic criteria, the DLB Consortium met again in
2003 to resolve improved methods of identifying cases ante-
mortem. No major amendments to the three core features
of DLB were proposed, but better methods for their clinical
assessment were recommended. A new category of features
‘suggestive’ of DLB was described comprising RBD, severe
706 Dementia

Table 61.1 Criteria for the clinical diagnosis of dementia with Lewy bodies (DLB)
1. Central feature (essential for a diagnosis of possible or probable DLB)
Dementia is defined as progressive cognitive decline of sufficient magnitude to interfere with normal, social or
occupational function. Prominent or persistent memory impairment may not necessarily occur in the early stages but is
usually evident with progression of the disease. Deficits on tests of attention, executive function and visuospatial ability
may be especially prominent.
2. Core features (two core features are sufficient for a diagnosis of probable DLB, one for possible DLB)
Fluctuating cognition with pronounced variations in attention and alertness.
Recurrent visual hallucinations that is typically well formed and detailed.
Spontaneous features of parkinsonism.
3. Suggestive features (if one or more of these is present in the presence of one or more core features, a diagnosis of
probable DLB can be made. In the absence of any core features, one or more suggestive features are sufficient for
possible DLB. Probable DLB should not be diagnosed on the basis of suggestive features alone).
Rapid eye movement (REM) sleep behaviour disorder.
Severe neuroleptic sensitivity.
Low dopamine transporter uptake in basal ganglia demonstrated by single photon emission computed tomography
(SPECT) or positron emission tomography (PET) imaging.
4. Supportive features (commonly present but not proven to have diagnostic specificity)
Repeated falls and syncope.
Transient, unexplained loss of consciousness.
Severe autonomic dysfunction, e.g. orthostatic hypotension, urinary incontinence.
Hallucinations in other modalities.
Systematized delusions.
Depression.
Relative preservation of medial temporal lobe structures on computerized tomography/magnetic resonance imaging
(CT/MRI) scan.
Generalized low uptake on SPECT/PET perfusion scan with reduced occipital activity.
Abnormal (low uptake) meta-iodobenzylguanidine (MIBG) myocardial scintigraphy.
Prominent slow wave activity on electroencephalogram (EEG) with temporal lobe transient sharp waves.
5. A diagnosis of DLB is less likely in the following cases:
In the presence of cerebrovascular disease evident as focal neurological signs or on brain imaging.
In the presence of any other physical illness or brain disorder sufficient to account in part or in total for the clinical
picture.
If parkinsonism only appears for the first time at a stage of severe dementia.
6. Temporal sequence of symptoms
DLB should be diagnosed when dementia occurs before or concurrently with parkinsonism (if it is present). The term
Parkinson’s disease (PD) with dementia (PDD) should be used to describe dementia that occurs in the context of
well-established Parkinson’s disease. In practice, setting the term that is most appropriate to the clinical situation
should be used and generic terms such as Lewy body (LB) disease are often helpful. In research studies that require
distinction between DLB and PDD, the existing 1-year rule between the onset of dementia and parkinsonism, DLB
continues to be recommended. Adoption of other time periods will simply confound data pooling or comparison
between studies. In other research settings, that may include clinico-pathologic studies and clinical trials, both clinical
phenotypes may be considered collectively under categories such as LB disease or alpha-synucleinopathy (AS).

neuroleptic sensitivity and abnormal dopamine transporter
(DAT) neuroimaging. If one or more of these suggestive fea-
tures is present, in addition to one or more core features,
a diagnosis of probable DLB can be made – see Table 61.1.
Possible DLB can be diagnosed if one or more suggestive
features are present in a patient with dementia even in the
absence of any core features. The revised criteria are also
explicit about the importance to be attached to clinical and
radiological evidence of cerebrovascular disease.
These improved criteria have been suggested to detect 25%
more DLB cases than the previous version (Aarsland et al.,
2008) although, a retrospective application of the new criteria
to an autopsy verified sample reported that cases with Braak
stage 5 and 6 Alzheimer pathology were still unlikely to be
detected ante-mortem. Such cases tend to lack core or sugges-
tive DLB features and clinically resemble AD (Weisman et al.,
2007). It has also been shown that the DLB clinical syndrome is
modified by the severity of Alzheimer neuritic pathology, while
β-amyloid load has no effect (Tiraboschi et al., 2015) on it. This
is consistent with the proposal made by the third Consortium
group that the likelihood of a patient having the typical DLB
clinical syndrome is ‘directly related to the severity of Lewy-
related pathology and inversely related to the severity of con-
current AD-type pathology’. Given that AD-type pathology is

frequently present in DLB, there will, therefore, be a significant
number of patients who will always present symptoms difficult
to identify solely on clinical grounds alone. This group, who are
best described pathologically as AD+LB or as LBVAD (Hansen
et al., 1990) can probably be reliably identified by additional
investigations and biomarkers only – see Section 61.4.
61.2.5.4 Future reports of the DLB
consortium
The DLB Consortium met again in December 2015 and is
likely to publish an updated report of the proceedings in 2016.
61.3 DIFFERENTIAL DIAGNOSIS OF
DLB IN CLINICAL PRACTICE
61.3.1 CLINICAL PRESENTATIONS OF DLB
DLB patients may present psychiatric disorders (cognitive
impairment, psychosis or behavioural disturbance), inter-
nal medicine (acute state of confusion or syncope) or neu-
rology (movement disorder or disturbed consciousness).
The details of clinical assessment and differential diagnoses
to a large extent are shaped by these symptoms and specialty
biases (McKeith et al., 1995). In all cases, a detailed history
from patient and reliable informants should document the
time of onset of relevant key symptoms, the nature of their
progression and their effects on social, occupational and
personal function. Functional disability in DLB is generally
greater than in AD patients with similar severity of cogni-
tive impairment. Most of the extra burden is due to motor
impairments that cause difficulty with mobility, feeding
and toileting (McKeith et al., 2006). Given the additional
disabilities associated with DLB, it is not surprising that
care costs have been estimated twice compared to those for
patients with AD (Boström et al., 2007a) and that carers rate
DLB patients’ Qol as significantly worse than that of AD
(Boström et al., 2007b) patients.
61.3.2 COGNITIVE IMPAIRMENT
Although, brief bedside tests of mental status, e.g. Mini-
Mental State Examination (MMSE) may confirm the pres-
ence of cognitive impairment in DLB, total scores are usually
equivalent to AD and unhelpful in differential diagnosis.
More detailed psychometric examination is usually required
to reveal a profile of deficits that helps to identify DLB from
AD or other dementias (Ferman et al., 2006). Prominent
deficits on tests of executive function and problem-solving,
such as the Trail Making Test (TMT) and verbal fluency for
categories and letters, may be useful clinical discrimina-
tors (Salmon and Galasko, 1996), as may disproportionate
impairment on tests of visuospatial performance, present
in up to three quarters of DLB patients at first evaluation
(Tiraboschi et al., 2006). Although, total cognitive and
Dementia with Lewy bodies: A clinical overview 707
self-contained part of the CAMDEX (CAMCOG) scores
were identical in DLB and AD, significant differences were
found in mean scores for the delayed recall subtest (DLB
performing better) and the visuospatial praxis subtest (DLB
performing worse) (Walker et al., 1996). With the progres-
sion of dementia, this selective pattern of cognitive deficits
may be lost, making differential diagnosis based on neuro-
psychological examination difficult during the later stages.
DLB is particularly characterized by increased vari-
ability in performance on cognitive tasks, within and
between patients and when compared to age-matched
controls and patients with AD. This variability is most
evident in executive and attentional tasks. Wide test –
retest variation in performance of timed computer-based
tasks (Walker et al., 2000a) have been proposed as a reli-
able and widely applicable quantified measure, which is
well correlated with clinical expert estimates of fluctuat-
ing performance.
61.3.3 CORE FEATURES
Review of nine studies that report clinical details on 190
autopsies confirmed DLB cases and compared them to
261 AD cases, providing a useful source of frequency rates
of the core features of DLB (Byrne et al., 1989; McKeith
et al., 1992a, 1992b; Förstl et al., 1993; Galasko et al., 1996;
Hely et al., 1996; Klatka et al., 1996; Weiner et al., 1996;
Ala et al., 1997). The wide ranges reported most likely
reflect sampling biases and different methods of symptom
ascertainment.
61.3.3.1 Fluctuation
Fluctuations in cognitive function, which may vary over
minutes, hours or days, occur in 58% of DLB cases at the
time of presentation (range 8%–85%) and are observed at
some point during the course of the illness in 75% (45%–
90%). Substantial changes in mental state and behaviour
may be seen within the duration of a single interview or
between consecutive examinations. Fluctuation includes
and indeed may be based on pronounced variations in
attention and alertness. Excessive daytime drowsiness
with transient confusion on waking commonly occurs.
Episodes may last from a few seconds to several hours and
can be ascertained by caregiver report, observer rating
(Walker et al., 2000b) or using computer-based measures
of variation in attentional performance (Walker et al.,
2000a). Questions such as ‘are there episodes when his/her
thinking seems quite clear and then becomes muddled?’
may be useful opening probes although, up to 75% of car-
ers will respond in the affirmative regardless of AD/DLB
diagnosis (Bradshaw et al., 2004; Ferman et al., 2004).
Objective questions about daytime drowsiness and leth-
argy, daytime sleep of 2 or more hours, staring into space
for long periods and episodes of disorganized speech are
more informative. The presence of three or four features of
this composite occurred in 63% of DLB patients compared
708 Dementia
to 12% of AD patients and 0.5% of normal elderly persons
(Ferman et al., 2004).
61.3.3.2 Visual hallucinations
Visual hallucinations are present in 33% of DLB cases at
the time symptoms present themselves (range 11%–64%)
and occur at some point during the course of the illness
in 46% (13%–80%). Most patients experience complex
hallucinations daily, normally lasting for at least several
minutes. They commonly see people or animals that do
not exist in reality and the experiences are usually per-
ceived as unpleasant. Simple hallucinations are rare.
Neuropsychiatric symptoms commonly coexisting with
hallucinations are apathy, sleep disturbance and anxiety
(Mosimann et al., 2006). Carers are more likely to give
‘don’t know’ answers to mild or moderately demented
patients about visual hallucinations and the use of a semi-
structured interview can increase both the quantity and
quality of information about a symptom, which is present
in the early stages and strongly predictive of a DLB diag-
nosis (Tiraboschi et al., 2006; Mosimann et al., 2008). It is
the persistence of visual hallucinations in DLB (McShane
et al., 1995) that helps distinguish them from the episodic
perceptual disturbances that occur transiently in demen-
tias of other aetiology or during a delirium provoked by an
external cause. It has been suggested that they arise from
a combination of faulty perceptual processing of environ-
mental stimuli and less detailed recollection of experience
combined with intact image generation (Collerton et al.,
2005). Visual hallucinations in DLB are associated with
greater deficits in cortical acetylcholine (Perry et al.,1991)
and predict better response to cholinesterase inhibitors
(McKeith et al., 2004b).
61.3.3.3 Motor parkinsonism
Extrapyramidal signs (EPS) are reported in 25%–50% of
DLB cases at diagnosis and the majority develop some EPS
during the natural course. Up to 25% of autopsy confirmed
cases may, however, have no record of EPS indicating that
parkinsonism is not necessary for a clinical diagnosis of
DLB. Initial suggestions that parkinsonism in DLB is mild
has not been supported by studies finding equal severity
with non-demented PD patients (Louis et al., 1997; Aarsland
et al., 2001) with similar annual progression rates in motor
Unified Parkinson’s Disease Rating Scale (UPDRS) scores
(Ballard et al., 2000). The pattern of EPS in DLB shows an
axial bias with greater postural instability and facial impas-
sivity and a tendency towards fewer tremors consistent
with greater ‘non-dopaminergic’ motor involvement (Burn
et al., 2003). The degree of cognitive impairment appears
to have no influence on the occurrence of EPS, although,
more demented patients may have difficulty in following
instructions on formal motor tests. A modified version
of the UPDRS, which allows for this instruction has been
developed (Ballard et al., 1997).
61.3.4 SUGGESTIVE FEATURES
61.3.4.1 REM sleep behaviour disorder
RBD is a parasomnia characterized by loss of normal skeletal
muscle atonia during REM sleep with resultant motor activ-
ity and ‘acting out of dreams’. Patients demonstrate a variety
of movements ranging from verbal outbursts to pugilistic
movements and even more dramatic motor activity. Injuries
to patients and bed partners are common. Estimates from
prospective studies in specialist centres place the frequency
of RBD at 50%–80% in DLB (Boeve et al., 2004) and it is
uncommon in patients with AD. The diagnosis is made on
clinical grounds and careful questioning of bed partners is
therefore vital. Use of a validated instrument such as the
Mayo Sleep Questionnaire (MSQ), is recommended since
techniques such as video polysomnography (PSG), utiliz-
ing audiovisual footage to confirm the physical features of
RBD in addition to electromyography, electro-oculography,
EEG and oxygen saturation recordings during sleep are
generally unavailable for most patients. The history of RBD
may precede the diagnosis of dementia by several years and
may either persist or diminish following the onset of cogni-
tive decline. REM sleep-wakefulness dissociations charac-
teristic of narcolepsy may explain several features of DLB
including daytime hypersomnolence, visual hallucinations
and cataplexy. Sleep disorders may contribute to fluctua-
tions typical of DLB and their treatment may improve fluc-
tuations and QoL.
61.3.4.2 Severe neuroleptic sensitivity
The hypothesis of an abnormal sensitivity to adverse effects
of neuroleptic medication was based upon the observation
that 57% of a series of DLB patients deteriorated rapidly
after either receiving neuroleptics for the first time or fol-
lowing an increase in dosage (McKeith et al., 1992a, 1992b).
Mortality risk, estimated by survival analysis was increased
by a factor of 2.7. A severe adverse reaction to neuroleptic
medication may be an important diagnostic indicator of
underlying LB disorder but tolerance of neuroleptics does
not rule out DLB. Neuroleptic challenge is never justified
as a diagnostic test and prescribing neuroleptic is routinely
and desirably avoided in patients suspected of having DLB.
Newer atypical antipsychotics used at low dose may be safer
in this regard but sensitivity reactions have been docu-
mented with most and they should be used with great cau-
tion (McKeith et al., 2004a; Aarsland et al., 2005).
61.3.4.3 Low DAT uptake in basal ganglia
Functional imaging of the DAT defines integrity of the
nigrostriatal dopaminergic system and was originally
developed to assist diagnosis of patients with tremor of
uncertain aetiology (Marshall and Grosset, 2003). Positron
emission tomography (PET) and single photon emission

computed tomography (SPECT) ligands are available for
this purpose and both have subsequently been useful in the
discrimination of DLB from AD. 123I-radiolabelled 2 beta-­
carbomethoxy-3 beta-(4-iodophenyl)-N-(3-fluoropropyl)
nortropane (FP-CIT) has been the most investigated and a
sensitivity of 78% for detecting probable DLB with a speci-
ficity of 85% for AD and 94% for controls, has been reported
(O’Brien et al., 2004). A multicentre clinical trial subse-
quently demonstrated similar results across a wide variety
of settings (McKeith et al., 2007) and regulatory approval for
distinguishing probable DLB from AD with FP-CIT imaging
now exists in Europe. The most useful clinical application
of the test however, is probably in cases of possible DLB or
where diagnostic uncertainty is high. A longitudinal study
found that of 12/19 people (63%) who were diagnosed of
possible DLB accompanied by an abnormal DAT scan were
re-diagnosed with probable DLB at 1-year follow-up and
subsequent clinical follow-ups. By contrast, 100% of cases
initially diagnosed as possible DLB but reclassified as AD a
year later had normal DAT scans at first evaluation (O’Brien
et al., 2009).
61.3.5 SUPPORTIVE FEATURES
A detailed discussion of every feature identified as support-
ive of a diagnosis of DLB is beyond the scope of this chap-
ter. Clinical symptoms are summarized briefly below and
investigations including neuroimaging are detailed out in
Section 61.4.
61.3.5.1 Repeated falls, syncope and
transient losses of consciousness
Dementia of any aetiology is probably a risk factor for all
three of these clinical features and it can be difficult to
clearly distinguish between them. Repeated falls may be due
to posture, gait and balance difficulties in DLB and are a
significant cause of hospitalization contributing to reduced
survival (Hanyu et al., 2009). Syncopal attacks in DLB with
complete loss of consciousness and muscle tone and tran-
sient episodes of unresponsiveness without loss of muscle
tone are probably related phenomena representing one
extreme of fluctuating attention and cognition. Episodes of
each type occur in about 20% of DLB cases at primal stages
and up to a half during the whole course of illness (McKeith
et al., 1992a, 1992b). Such episodes frequently lead to a mis-
diagnosis of vascular dementia because of the suspicion of
transient ischaemic attack.
61.3.5.2 Autonomic dysfunction
Autonomic dysfunction that affects both sympathetic and
parasympathetic systems is a significant, common and
often early feature of DLB presenting itself as orthostatic
hypotension, carotid sinus hypersensitivity, reduced secre-
tions (lacrimal, mouth, sweat), urinary retention, erectile
dysfunction and bowel problems, both constipation and
Dementia with Lewy bodies: A clinical overview 709
diarrhoea (Del-Ser et al., 1996). Orthostatic hypotension
and carotid sinus sensitivity appear to occur more com-
monly in DLB than AD or age-matched controls (Kenny
et al., 2004; Allan et al., 2007) and probably contribute to the
high rates of syncope and falls that occur in this population.
61.3.5.3 Systematized delusions and
hallucinations in other modalities
Delusions are common in DLB, occurring in about half of
the patients. They are usually based on recollections of hal-
lucinations and perceptual disturbances and consequently
have a fixed, complex and bizarre content that often contrasts
with the mundane and poorly formed persecutory ideas
encountered in AD, which are based on forgetfulness and
confabulation. Auditory, olfactory and tactile hallucinations
occur lesser often but can present striking features in some
DLB cases leading to initial diagnoses of late onset psycho-
sis (Birkett et al., 1992) and temporal lobe epilepsy (McKeith
et al., 1992a). In such circumstances, severe neuroleptic sen-
sitivity reactions may indicate the true underlying cause.
61.3.5.4 Depression
Depressive symptoms are frequent in most neuropsychi-
atric syndromes and often of little differential diagnostic
value. However, depression was diagnosed at first consul-
tation in 38% of DLB patients compared to 16% with AD
(p < 0.05) and was the primary reason for referral in 60% of
the patients in whom it was present (McKeith et al., 1992a).
Klatka et al. (1996) found depression in 14/28 (50%) DLB,
8/58 (14%) AD and 15/26 (58%) PD cases with autopsy con-
firmation. No particular characteristics of depression have
been described in DLB but apathy and psychomotor retar-
dation are to be expected in this population and may con-
found the assessment of affective state.
61.3.5.5 Differential diagnosis
There are four main categories of disorder that should be
considered in the differential diagnosis of DLB. These are
as follows:
1. Other dementia syndromes
2. Other causes of delirium
3. Other neurological syndromes including PD
4. Other psychiatric disorders
61.3.5.6 Other dementia syndromes
Sixty-five per cent of autopsy confirmed DLB cases meet
the National Institute of Neurological and Communicative
Diseases and Stroke–Alzheimer’s Disease and Related
Disorders Association (NINCDS-ADRDA) clinical criteria
for probable or possible AD (McKeith et al., 1994) and this is
the most frequent clinical misdiagnosis of DLB. Conversely,
710 Dementia
12%–36% of cases meeting NINCDS criteria for a clinical
diagnosis of AD are unexpectedly found to have LB pathol-
ogy at autopsy (Burns et al., 1990; Hansen et al., 1990).
There is a large ‘overlap’ group of patients who have both LB
and Alzheimer pathologies and who cannot easily be clas-
sified by clinical criteria alone. Up to a third of DLB cases
can be misclassified as having vascular dementia by virtue
of symptoms such as fluctuating nature and course of ill-
ness. Pyramidal and focal neurological signs are however,
usually absent.
61.3.5.7 Other causes of delirium
In patients with intermittent delirium, appropriate exami-
nation and laboratory tests should be performed during the
acute phase to maximize the chances of detecting infec-
tive, metabolic, inflammatory or other aetiological factors.
Pharmacological causes are particularly common in elderly
patients. Although, the presence of any of these features
makes a diagnosis of DLB less likely, comorbidity is not
unusual in elderly patients and the diagnosis should not be
excluded simply on this basis.
61.3.5.8 Patients with a previous diagnosis
of PD
Dementia in PD (discussed fully in Chapter 64) is often
similar to DLB with respect to fluctuating neuropsychologi-
cal function and neuropsychiatric features. Such patients
who develop the typical features of DLB only after many
years of motor disability present some problems of classi-
fication. Anti-parkinsonian medications are usually held
responsible for hallucinations and confusion in PD, but
research findings do not fully support this clinical impres-
sion. There has been considerable debate as to whether PD,
PDD and DLB are simply different clinical presentations of
the same underlying biological process, i.e. LB disease and
indeed, whether LB disease might be a better clinical term
to use for the whole spectrum of such phenotypes (McKeith,
2009). The current recommendation is to apply an arbi-
trary 1-year rule that proposes that the onset of dementia
within 12 months of the onset of parkinsonism qualifies as
DLB and more than 12 months of parkinsonism before the
onset of dementia qualifies as PDD (McKeith et al., 2005).
Using diagnostic labels such as PDD and DLB that describe
the order of onset of symptoms is generally helpful in the
diagnosis and management of most clinical cases and the
majority of patients and carers (and clinicians) are able to
understand that the diagnosis is predictable, e.g. DLB is
‘caused by’ LB disease. In some patients, particularly those
with an admixture of neurological and psychiatric symp-
toms occurring in relatively short order, a single label of LB
disease may serve as the best primary diagnosis, qualified
by a secondary descriptive epithet, for example, LB disease
with parkinsonism or LB disease with dementia or LB dis-
ease with parkinsonism and dementia. Clinicians need to
decide which term is the most appropriate for each indi-
vidual patient and carefully explain the terminology to the
patient and his or her caregivers.
61.3.5.9 Other neurological syndromes
Other atypical parkinsonian syndromes associated with
poor levodopa response, cognitive impairment and postural
instability include progressive supranuclear palsy (Fearnley
et al., 1991), multisystem atrophy and corticobasal degen-
eration. The development of myoclonus in patients with a
rapidly progressive form of DLB may lead the clinician to
suspect Creutzfeldt–Jacob disease (CJD). Syncopal epi-
sodes in DLB are often incorrectly attributed to transient
ischaemic attacks, despite an absence of focal neurological
signs. Recurrent disturbances in consciousness accompa-
nied by complex visual hallucinations may suggest complex
partial seizures (temporal lobe epilepsy) and vivid dream-
ing with violent movements during sleep and may meet cri-
teria for RBD.
61.3.5.10 Other psychiatric disorders
If a patient spontaneously develops parkinsonian features
or cognitive decline or shows excessive sensitivity to neu-
roleptic medication, in the course of late onset delusional
disorder, depressive psychosis or hypomania (Birkett et al.,
1992; Mullan et al., 1996), DLB should be considered.
61.4 NEW AND FUTURE CLINICAL
DEVELOPMENTS
61.4.1 RECOGNITION OF DLB AS A
CLINICAL DIAGNOSIS IN FORMAL
CLASSIFICATIONS
Although, the DLB consensus criteria was constructed for
both research and general clinical use, it is only recently
that they have been formally incorporated into the official
diagnostic classification systems. Diagnostic and Statistical
Manual of Mental Disorders, Fifth Edition (DSM-5)
(American Psychiatric Association, 2013) contains catego-
ries to identify major and mild neurocognitive disorder with
LBs that are consistent with the 2006 consensus criteria,
both in the diagnostic features listed and the possible/prob-
able distinction. DSM-5 also contains a separate category of
major and mild neurocognitive disorder due to PD, which
uses the previously stated 1-year rule to distinguish from
DLB. It is anticipated that the International Classification of
Disease, Eleventh Revision (ICD-11) will similarly incor-
porate DLB into the formal dementia subtype classifica-
tion and together these changes should assist case detection
rates, clinical service development and reimbursement and
research funding.

61.4.2 PRE-DEMENTIA AND PRODROMAL
DIAGNOSIS OF DLB
Possibly the most significant clinical development in the
whole dementia field over the last decade has been a shift
away from diagnosing at a mild/moderate symptomatic
stage to prodromal or even pre-symptomatic diagnosis.
The main justification for this shift to earlier diagnosis is
that preventative treatment will only be effective if given
before extensive neurochemical and anatomic pathological
changes have occurred in the brain. It follows that trials of
potential preventative agents will only be possible once reli-
able methods of prodromal diagnosis have been established.
Efforts to start developing diagnostic methods and cri-
teria for LB disease are already under way (Donaghy and
McKeith, 2014). Since we do not yet know why some cases
progress to PD and others to DLB, very early identification
of LB disease would identify individuals at risk of an uncer-
tain future clinical course and progression. Criteria for the
identification of early cases at high risk of progression to
dementia syndromes of the DLB type might be made at a
stage when an individual has at least one clinical feature
suggestive of prodromal DLB, e.g. cognitive or neuropsy-
chiatric features and at least one biomarker supportive of
LB disease. Given the large number of potential prodromal
symptoms and existence of several biomarker candidates,
it is anticipated that formal criteria for prodromal DLB are
still distant. The MCI stage of dementia with Lewy bodies
(MCI-DLB) category is however, already being used infor-
mally in some memory clinic settings with evidence that
non-amnestic MCI subjects are more likely to progress to
DLB rather than AD, particularly, if they have additional
DLB core or suggestive features (Ferman et al., 2013). DSM-5
also contains criteria for ‘mild neurocognitive disorder with
LB’ although, these have not yet been validated.
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Pathology of dementia with Lewy bodies
GLENDA HALLIDAY, SIMON LEWIS AND PAUL INCE
62.1 INTRODUCTION
Dementia with Lewy bodies (DLB) is a primary degenera-
tive dementia sharing features of Parkinson’s disease (PD)
and most often also of Alzheimer’s disease (AD). The diag-
nosis of DLB implies an underlying pathology, the Lewy
body (LB), and all patients with DLB have these inclusions.
LBs are intraneuronal insoluble fibrillar aggregations of the
synaptic protein α-synuclein (Figure 62.1). Causal mutations
in the gene encoding α-synuclein associate with familial PD
(Polymeropoulos et al., 1997), the other major LB disease.
LBs were originally described by Friedrich Lewy over a cen-
tury ago (Lewy, 1913) but the major constituent protein was
only identified as α-synuclein in 1997 (Spillantini et al., 1997).
Lewy described these neuronal inclusions as intracytoplas-
mic, spherical or elongated, eosinophilic masses possessing
a dense core and a peripheral halo, with neurones able to
contain multiple inclusions (Figure 62.1). Patients with a pri-
mary degenerative dementia and these inclusions have DLB.
As described in the preceding chapter, they often also have
clinical features that differentiate them from other demen-
tia syndromes. While the definition of DLB in itself seems
simple, very few patients with DLB have only LB pathology,
and the variety of other pathologies, neurochemical abnor-
malities and patterns of neuronal loss continue to be assessed
and defined, with multiple phenotypes now acknowledged.
LBs develop in many grey matter regions, and LBs are
not the only α-synuclein pathology observed. The majority
of patients with DLB have extensive LBs in limbic and less
so in association cortical regions (Mckeith et al., 2005). LBs
are predominantly found in deeper cortical layers (4, 5 and
6) within small- and medium-sized neurones (Kosaka et al.,
1984). In addition to classical LBs, there is an extensive neu-
ritic component and diffuse cytoplasmic granular staining
(Duda et al., 2002). In fact, neuritic α-synucleinopathy is
now considered the most consistent feature of LB diseases
(Klucken et al., 2003; Duda, 2004). Considerable synaptic
714
62
deposition of α-synuclein has also been identified in DLB
(Kramer and Schulz-Schaeffer, 2007). While this has not been
independently replicated, it is likely that synaptic changes in
α-synuclein occur in DLB, and many new techniques are see-
ing dot-like inclusions in LB disorders consistent with syn-
aptic aggregations, although not as extensively (Kovacs et al.,
2014; Roberts et al., 2015). In addition to neuronal inclu-
sions and aggregates (LBs and Lewy neurites), astrocytes also
aggregate non-fibrillar α-synuclein in brain regions contain-
ing LBs (Braak et al., 2007; Song et al., 2009; Kovacs et al.,
2014) (Figure 62.1). Astrocytes are specialized glial cells that
outnumber neurones by over fivefold and are the main sup-
port cells of the brain, modulating neuronal activity and form-
ing the blood–brain barrier (Sofroniew and Vinters, 2010).
The abnormal increase in α-synuclein in astrocytes appears
to compromise their function. A recent study has also high-
lighted oligodendroglial α-synuclein pathologies in brain-
stem regions in DLB (Seidel et al., 2015). Oligodendroglia
wraps all neuronal membranes and myelinate axons.
Oligodendroglial α-synuclein inclusions have been observed
in PD cases with longer disease durations and more marked
neuronal loss (Wakabayashi et al., 2000) and in the DLB cases
with similar inclusions (Terada et al., 2000), marked to severe
neuronal degeneration in restricted brainstem nuclei was
observed (Seidel et al., 2015). It may be that oligodendroglial
α-synuclein inclusions are a sign of advanced LB disease.
62.2 CURRENT DIAGNOSTIC CRITERIA
FOR/AND THE PATHOLOGY OF
DLB
The DLB Consortium pathological guidelines have evolved
over more than a decade and require the presence of LBs in a
primary dementia syndrome (Mckeith et al., 2005) and were
originally based on the description of LB stages identified
in DLB patients by Kosaka et al. (1988) who identified three
types (brainstem, transitional and diffuse). This DLB staging
 Pathology of dementia with Lewy bodies 715

(a) (b) (d) (e)

50 μm 50 μm 20 μm

(c) (f )

50 μm 20 μm

100 μm 50 μm

Figure 62.1 (See colour insert.) Lewy bodies and Lewy pathologies in Parkinson’s disease. (a) and (b) Haematoxylin and
eosin stained classic Lewy bodies in pigmented dopaminergic neurones of the substantia nigra showing the typical core
and halo structure. Scale in (b) is equivalent for (a). (c)–(f). α-Synuclein immunoreactive pathologies showing (c) and (e)
mature Lewy bodies, (c) and (d) pale bodies and neuronal aggregates and (f) astrocytes containing aggregates.

scheme is virtually identical to that subsequently described
by Braak et al. (2003) for PD, but it differs from a more recent
staging scheme suggested for LB disorders by Beach et al.
(2009). In 2005, the DLB pathological scheme changed from
a staging scheme to give a likelihood ratio that the pathologi-
cal findings were associated with a clinical DLB syndrome,
taking into account both the extent of LB pathologies and
AD-related pathologies, as AD pathologies are very com-
mon in DLB (Mckeith et al., 2005). The practical implemen-
tation of the criteria requires LB pathologies to be identified
with immunohistochemistry and semiquantitatively graded
(Table 62.1), and National Institute on Aging (NIA)–Reagan
diagnostic criteria for AD-related pathologies to be applied
(National Institute on Aging and Reagan Institute Working
Group, 1997). The probability of pathological DLB is then
identified using this information with the higher LB staging
in the presence of less AD pathology more likely to be clini-
cally significant (Table 62.2). While the pathological criteria
have been validated in small samples (Fujishiro et al., 2008),
in large dementia populations a number of cases do not fit
the LB staging scheme (Fujimi et al., 2008; Leverenz et al.,
2008; Zaccai et al., 2008) and modifications have been sug-
gested, including the incorporation of an amygdala only stage
of LB pathologies (Alafuzoff et al., 2009). Note that current
probability criteria for the pathological diagnosis of AD have
recently changed to formally incorporate β-amyloid immu-
nohistochemistry (Montine et al., 2012). The pathological cri-
teria of DLB now need to be formally updated in line with the
AD criteria and to determine which standardized protocol
should be formally adopted.
As indicated by the diagnostic criteria, apart from LBs,
AD-related pathologies are common in DLB. While the
degree of neocortical plaque formation is equivalent to that
found in AD, the presence of neocortical neurofibrillary
tangles is variable and may be infrequent (Table 62.2), with
this variability contributing to variable dementia pheno-
types (Weisman et al., 2007; Tiraboschi et al., 2015). If neu-
rofibrillary tangles and LB pathologies are both present, the
likelihood of clinical expression of DLB is greater at lower
Braak tangle stages (Ballard et al., 2004; Fujishiro et al., 2008;
Tiraboschi et al., 2015). The current diagnostic criteria for
AD with its focus on biological markers of β-amyloid deposi-
tion subsume DLB as a variant of AD (Dubois et al., 2014).
However, the pathological distinctions between AD and
DLB are clear and include:
●● There are rare cases of DLB with no significant

(Uchikado et al., 2006; Leverenz et al., 2008; Zaccai et al., AD-related pathologies.
2008). All modifications suggest fewer regions are required ●● Quantitative and qualitative analysis of the AD-related

for the assessment of LB pathologies without compromising pathologies shows differences between DLB and AD.
accuracy (Harding and Halliday, 1998; Leverenz et al., 2008; ●● While ß-amyloid deposition is similar in both AD and

Alafuzoff et al., 2009) with the latest modification showing DLB, they can be distinguished by their neuronal inclu-
better inter-observer agreement without scoring the severity sion pathology.
716 Dementia

Table 62.1 Methods for the pathological diagnosis of DLB

Assignment of Lewy body type based upon pattern of Lewy-related pathology in brainstem, limbic and neocortical
regions

Brainstem regions Basal forebrain/limbic regions Neocortical regions

IX–X LC SN nbM Amygdala Transentorhinal Cingulate Temporal Frontal Parietal
Lewy body Brainstem 1–3 1–3 1–3 0–2 0–2 0–1 0–1 0 0 0
type predominant
Limbic 1–3 1–3 1–3 2–3 2–3 1–3 1–3 0–2 0–1 0
(transitional)
Diffuse neocortical 1–3 1–3 1–3 2–3 3–4 2–4 2–4 2–3 1–3 0–2
Notes: Brain regions are as defined anatomically in the original consensus report.
Abbreviations: DLB, dementia with Lewy bodies; IX, ninth cranial nerve nucleus; X, tenth cranial nerve nucleus; LC, locus ceruleus; SN,
substantia nigra; nbM, nucleus basalis of Meynert.

Table 62.2 Methods for the pathological diagnosis of DLB

Assessment of the likelihood that the pathologic findings are associated with a DLB clinical syndrome

Alzheimer type pathology

NIA–Reagan NIA–Reagan NIA–Reagan
Low Intermediate High
(Braak stage 0–II) (Braak stage III–IV) (Braak stage V–VI)
Lewy body type pathology Brainstem-predominant Low Low Low
Limbic (transitional) High Intermediate Low
Diffuse neocortical High High Intermediate
Abbreviation: NIA, National Institute on Aging.

DLB also differs in the severity of vascular pathology
compared with AD. Amyloid angiopathy is prevalent in
both AD and DLB (Jellinger and Attems, 2008a, 2008b),
but haemorrhages appear more common in DLB due to
trauma associated with falls, while microinfarcts are less
common (Isojima et al., 2006; Jellinger and Attems, 2008b).
White matter vascular changes are more frequent in AD and
small mini-bleeds occur in both AD and DLB patients with
AD (De Reuck et al., 2011). The extent of LB pathology is
inversely correlated to the extent of most vascular patholo-
gies (atherosclerosis, infarcts and small vessel disease) except
for cerebral amyloid angiopathy, which correlates with the
LB pathology (Ghebremedhin et al., 2010).
It has been recognized for some time that tar DNA bind-
ing protein 43 (TDP-43) proteinopathy forms the basis for
many cases of frontotemporal dementia (Neumann et al.,
2006), and it has been reported that TDP-43 proteinopathy
can present with clinical features mimicking DLB (Claassen
et al., 2008). In AD, TDP-43 deposition is commonly present
as a minor component of the pathology, especially in hip-
pocampus and amygdala (Wilson et al., 2011; Youmans and
Wolozin, 2012). Between 30% and 60% of DLB cases with AD
have similar TDP-43 pathology (Nakashima-Yasuda et al.,
2007; Arai et al., 2009) with a subset of TDP-43 inclusions
colocalizing with LB (Higashi et al., 2007). Approximately
5% have associated hippocampal sclerosis (Aoki et al.,
2015). Few cases with pure DLB have TDP-43 pathology
(Nakashima-Yasuda et al., 2007; Yokota et al., 2010; Wilson
et al., 2013). The TDP-43 pathology in DLB is most associ-
ated with coexisting AD pathology.
62.3 PREVALENCE OF LB IN
AGEING POPULATIONS AND
PATHOLOGICAL PHENOTYPES
Data from large cohorts of older brain donors, including
population-based studies have identified LBs in asymptom-
atic people and also in different distributions (Parkkinen
et al., 2003; Zaccai et al., 2008, 2015). The UK popula-
tion-based study showed some degree of synucleinopathy
in 37% of 207 elderly people (Zaccai et al., 2008, 2015).
Similarly, a Japanese population-based study reported
α-synucleinopathy with a prevalence of 22.5% at autopsy,
which included 41% who were demented during life
(Wakisaka et al., 2003). These findings are comparable to
work from Finland (Parkkinen et al., 2003) and also from
the United States (Beach et al., 2009). The different distri-
butions of LBs in these populations have led to an alternate
theory of progression through olfactory and limbic brain
regions in addition to that from the brainstem through to
the cortex (Beach et al., 2009) and have also lead to the con-
cept of different phenotypes of DLB (Table 62.3).
As detailed in Table 62.3, three main DLB phenotypes
can be identified based on the amount of LB and AD
 Pathology of dementia with Lewy bodies 717

Table 62.3 Phenotypes of cases with different pathological combinations of LB and AD pathologies

Feature Pure DLB DLB + AD AD + amygdala LB Pure AD

Severity of amyloid β deposition High High High High
Severity of tau deposition (Weisman et al., 2007) Low High High High
Severity of LRP (Uchikado et al., 2006) Highest Intermediate Low Absent
Frequency of ApoE-4 and odds ratio ~30% ~40%–50% NA ~35%
(Tsuang et al., 2005, 2013) 6.1 12.6 NA 9.9
Frequency of GBA mutation (Clark et al., 2009; 10%–28% ~5% NA 1%–10%
Tsuang et al., 2012) 7.6 4.6 NA 1.1
Odds for male gender (Nelson et al., 2010) 2.9 2.9 NA 0.66
Odds for depression (Lopez et al., 2006) NA 3.83 8.56 0.96
Memory function (Kraybill et al., 2005; Initially Poor Poor Poor
Nelson et al., 2009) preserved
Executive function/attention (Kraybill et al., Poor Poor NA Initially preserved
2005)
Functional decline (Kraybill et al., 2005) Steady Rapid NA Steady
Median survival and survival after dementia NA 78 and 7.3 years, NA 85 and 8.5 years,
(Williams et al., 2006) adjusted for adjusted for
gender and gender and
ApoE ApoE
Abbreviations: LB, Lewy body; AD, Alzheimer’s disease; LRP, low-density lipoprotein receptor-related protein; GBA, β-glucocerebrosidase;
NA, not available; ApoE, apolipoprotein E.

pathologies. At present, the prevalence of these different
phenotypes is not clear, as the amygdala-only LB pheno-
type appears to be very prevalent – 60% of cases with AD
(Hamilton, 2000) – but has not been assessed at a popula-
tion level. The pure DLB phenotype is considered the least
prevalent and the DLB + AD phenotype has previously
been known as the ‘common form’ of DLB or the ‘LB vari-
ant of Alzheimer’s disease’ (Hansen et al., 1990). Pure DLB
has more preserved memory at onset, the most severe LB
pathology and less tau deposition, as well as the lowest fre-
quency of apolipoprotein E (ApoE) ε4 genotype and the
highest frequency of β-glucocerebrosidase (GBA) mutations
(Table 62.3). Compared with AD, DLB + AD has LB pathol-
ogy, a higher frequency of both ApoE ε4 genotype and GBA
mutations as well as depression, with a more rapid func-
tional decline (Table 62.3). The amygdala-only phenotype
has the highest rate of depression (Table 62.3). While these
phenotypes are separable pathologically with evidence of
clinical and genetic differences, more work is needed to dif-
ferentiate these phenotypes further, particularly clinically.
62.4 NEUROIMAGING CHANGES AND
NEURONAL LOSS IN AUTOPSY
CONFIRMED DLB
62.4.1 DOPAMINE TRANSPORTER AND
NEUROMELANIN IMAGING AND
RELATED CELL LOSS
In addition to revising the pathological definition of DLB
in 2005, the DLB Consortium also revised guidelines
on neuroimaging, which highlight underlying patholo-
gies (Mckeith et al., 2005). Positron emission tomography
(PET) and single-photon emission computed tomography
(SPECT) imaging using dopamine transporter ligands
were recommended due to reduced striatal uptake in DLB
patients compared with AD (Mak et al., 2014). This suggests
that there is a loss of dopaminergic neurones in the substan-
tia nigra and their projections to the striatum in DLB that
is similar to that observed in PD and different from AD. A
multicentre study confirmed the routine clinical utility of
using dopamine transporter ligands to assist with the diag-
nosis of DLB showing over 85% accuracy in diagnosing DLB
with high inter-rater agreement (Mckeith et al., 2007). A
longitudinal study shows that such scans detect abnormali-
ties in the dopaminergic system prior to symptom onset
(Siepel et al., 2013). Of importance, in patients followed lon-
gitudinally to autopsy, sensitivity was 88% and specificity
was 100% in diagnosing DLB using dopamine transporter
imaging, proving that such imaging substantially enhances
the diagnosis of DLB (Walker et al., 2007). Although it is
suggested that a proportion of DLB cases do not have dopa-
mine transporter abnormalities (Siepel et al., 2013), these
studies have not been confirmed at autopsy.
At autopsy, the loss of neurones in the substantia nigra is
generally not as severe while more LB are often seen com-
pared to PD, although some DLB cases do show substantia
nigra neuronal loss and LB formation in the PD range (Iseki
et al., 2005; Tsuboi and Dickson, 2005). This potentially
suggests that synaptic damage is greater than the absolute
loss of neurones in DLB compared with PD. Neuronal loss
and increasing LB severity are related (Oinas et al., 2009),
also suggesting that more LBs, as seen in DLB, may protect
neuronal cell bodies but not terminals. Importantly, the loss
718 Dementia
of the dopaminergic pigmented neurones of the substantia
nigra can be visualized using magnetic resonance imaging
(MRI) (Kitao et al., 2013) providing another tool for future
studies to assess differences between the loss of synapses
with dopamine transporter labelling and neuronal cell bod-
ies with MRI.
62.4.2 MEDIAL TEMPORAL LOBE
ATROPHY AND RELATED CELL
LOSS
Medial temporal lobe atrophy has been identified as a
highly accurate diagnostic marker for autopsy confirmed
AD (sensitivity 91%, specificity 94%), and does not relate to
the severity of plaque or LBs in the temporal lobe (Burton
et al., 2009). Patients with a high or intermediate pathologic
likelihood of DLB using the 2005 consensus criteria have
normal hippocampal volumes (Kantarci et al., 2012) and
greater atrophy rates in the hippocampus and amygdala cor-
relate with AD-type pathology in DLB patients (Nedelska
et al., 2015a). These studies show that medial temporal lobe
changes are much more likely to relate to AD pathologies in
DLB than to LB pathologies.
In patients with pure DLB, neuronal loss in the amygdala
is severe (Yamamoto et al., 2006) and there is selective loss
of neurones in only the lower pyramidal layers of the presu-
biculum in DLB compared with PD or AD (Harding et al.,
2002b). In the hippocampus proper, there is a reduction in
the small interneuronal population that contains parvalbu-
min immunoreactivity (Bernstein et al., 2011) suggesting
some changes in calcium regulation. These changes appear
to be additional to any changes associated with concomitant
AD in patients with DLB; however, it should be noted that
the AD changes are overwhelming compared to the DLB
changes noted.
62.4.3 CORTICAL ATROPHY AND
RELATED CELL LOSS
Overall cortical atrophy is more pronounced in DLB com-
pared with PD, but AD has more temporal and frontal lobe
atrophy than DLB (Beyer et al., 2007). Glucose PET imag-
ing shows hypometabolism in temporoparietal regions and
occipital regions in DLB with occipital hypometabolism dif-
ferentiating DLB (Kasanuki et al., 2012; Toledo et al., 2013;
Mak et al., 2014). Neuronal loss in temporoparietal regions
is milder in DLB compared with AD, with no difference
in the degree of cell loss in these regions in DLB patients
with or without AD pathology (Kasanuki et al., 2012). This
suggests that the severity of AD pathology is independent
of neuronal loss in DLB, with confirmation that amyloid
Pittsburgh compound B (PiB) imaging detects all types of
amyloid plaques in DLB (Kantarci et al., 2012). Amyloid PiB
imaging in DLB is not related to the severity of hypome-
tabolism (Ishii et al., 2015) confirming this notion. No cell
loss is observed in occipital cortex (Kasanuki et al., 2012),
but diffusion tensor imaging shows significant white matter
abnormalities, which differentiate DLB from AD (Nedelska
et al., 2015b). These data again suggest that neuronal cell
bodies are spared in DLB but that significant abnormalities
occur to their processes.
In addition to the more selective hypometabolism of
the occipital cortex in DLB, a new signature abnormality
on glucose metabolism is called the cingulate island sign,
where there is a higher ratio of posterior cingulate to pre-
cuneus and cuneus metabolism (Graff-Radford et al., 2014).
The regions of lower metabolism have been shown to have
cortical thinning in DLB (Delli Pizzi et al., 2014a). DLB
cases with this metabolic signature have a high or interme-
diate pathologic likelihood of DLB using the 2005 consensus
criteria and lower neuritic pathologic stages (Graff-Radford
et al., 2014), although changes in these regions of the brain
have yet to be assessed pathologically. The cingulate island
sign is independent of positive findings on amyloid PiB
imaging (Graff-Radford et al., 2014).
62.4.4 OTHER REGIONS OF NEURONAL
LOSS IDENTIFIED
Unfortunately, many studies on other regions of neuronal
loss, particularly those assessing subcortical regions, have not
assessed appropriate comparison groups, and so it is difficult
to determine whether any changes noted are more related to
AD-type pathologies or LB pathologies, and whether patients
with PD and no dementia also have similar neuronal loss.
Below is a summary of regions where multiple studies have
assessed the same region using different methods.
Greater structural changes in the thalamus is observed
in DLB compared with AD (Delli Pizzi et al., 2014b) and
thalamic pathology is substantial in DLB, particularly in
the midline (innervate medial temporal and prefrontal cor-
tices) and anterior (innervate frontal and parietal cortices)
intralaminar nuclei (Brooks and Halliday, 2009). These
thalamic regions regulate cortical synchrony, informa-
tion transmission and cognition (Saalmann, 2014). Recent
studies have identified neuronal loss in the hypothalamic
sleep-­associated centres (Kasanuki et al., 2014; Benarroch
et al., 2015), but such loss does not appear to differ between
patients with DLB and AD (Kasanuki et al., 2014).
Severe loss of cholinergic neurones in the basal fore-
brain that innervate the medial temporal lobe is observed
in patients with DLB compared with AD (Fujishiro et al.,
2006), and there is greater atrophy of the entire cholinergic
basal forebrain region in DLB (Kim et al., 2011), although this
may occur in a region-specific fashion (Grothe et al., 2014).
Patients with a high pathologic likelihood of DLB using the
2005 consensus criteria have atrophy of the cholinergic dorsal
mesopontine grey matter nuclei (Kantarci et al., 2012) and a
loss of the main cholinergic projection from the dorsal meso-
pontine region to the thalamus has been identified in DLB
but not AD using acetylcholinesterase (AChE) PET (Kotagal
et al., 2012b). Neuronal loss has been observed in this region
in some (Schmeichel et al., 2008), but not all (Hepp et al.,

2013), cases with DLB. Of interest, amyloid deposition is only
observed in this region in DLB (Hepp et al., 2013).
62.4.5 SYNAPTIC LOSS
Synaptic loss has been proposed to be a major process in
the pathogenesis of DLB linked to the role of oligomeric
α-synuclein acting as a synaptotoxin (Kramer and Schulz-
Schaeffer, 2007). This finding has been replicated using other
synaptic markers in the medial temporal lobe (Mukaetova-
Ladinska et al., 2009), occipital (Mukaetova-Ladinska et al.,
2013) and frontal lobes (Whitfield et al., 2014), suggesting
that LB pathology does primarily affect synapses more than
neuronal cell bodies.
62.5 NEUROTRANSMITTERS AND
NEUROCHEMICAL CHANGES IN
DLB
As discussed above, neuronal loss specific to DLB is more
similar to PD and involves the cholinergic and dopami-
nergic systems, but is also overlaid with changes associated
with AD, at least in a proportion of cases. In addition to the
frank loss of neurones, neurotransmitter receptor changes
in postsynaptic neurones also occur, as detailed below. Such
changes have relevance for neurotransmitter replacement
therapies.
62.5.1 DOPAMINERGIC SYSTEMS
As discussed above, the loss of dopaminergic neurones in
the substantia nigra and their input to the striatum is highly
accurate at identifying patients with DLB from AD. As the
membranes of these neurones contain the dopamine trans-
porter, neuroimaging using this ligand is a very effective
way of seeing this change, as discussed above. There are
multiple dopamine receptors (D1–D5) that can be classed
into two major categories, D1-like receptors (D1 and D5)
that are very widespread in the brain, and D2-like recep-
tors (D2, D3 and D4) that autoregulate dopaminergic
neurones as well as occurring selectively postsynaptically
(Beaulieu and Gainetdinov, 2011). Receptor loss occurs
when the neuronal structures containing them degener-
ate, as discussed, but can also occur with drug treatments.
Agonists that activate receptors can decrease receptor den-
sity, whereas antagonists that block receptor activity or a
reduction in neurotransmitter can increase receptor den-
sity. In this context, it is of interest that D1 receptors do not
change substantially in DLB, even in regions of significant
dopamine denervation (Sun et al., 2013). However, D2-like
receptors are upregulated in the striatum and thalamus in
DLB (Piggott et al., 2007a; Sun et al., 2013), particularly in
those treated with neuroleptic medications, which antago-
nize dopamine receptors, with such changes associated with
an increase in extrapyramidalism (Piggott et al., 2007a). In
Pathology of dementia with Lewy bodies 719
contrast to the increase in subcortical D2 receptors, there is
a substantial decrease in cortical D2 receptors (Piggott et al.,
2007b), most likely due to the denervation of the cortex by
dopaminergic neurones. The severity of cortical D2 recep-
tor loss correlates with the severity of cognitive decline and
psychiatric symptoms, as well as with increasing LB pathol-
ogy, and is likely to explain the intolerance of DLB patients
to D2 antagonistic neuroleptic medications (Piggott et al.,
2007b). Importantly, such changes are not observed in pure
AD cases (Piggott et al., 2007b).
62.5.2 CHOLINERGIC SYSTEMS
As discussed above, there is a loss of the major cholinergic
neurones innervating the cortex and subcortical structures
in DLB, with subcortical denervation and more marked
hippocampal denervation differentiating DLB from AD.
There are two major classes of cholinergic receptors, nico-
tinic receptors located on postsynaptic neurones, and mus-
carinic receptors located on neurones and blood vessels
(Greig et al., 2013). In addition to the same type of receptor
changes as discussed above, enzymatic changes that regu-
late acetylcholine metabolism can also impact on choliner-
gic function, with certain drugs increasing cholinergic tone
targeting this aspect selectively (Greig et al., 2013).
Cortical nicotinic receptors are fast-acting choliner-
gic receptors that are reduced equally in DLB, AD and
PD (Perry et al., 1990b), a dysfunction that correlates
with a decline in executive function (Colloby et al., 2010).
However, in DLB there is an increase in nicotinic recep-
tors in the occipital lobe, a change most pronounced in
patients with recent visual hallucinations, linking cholin-
ergic changes in the occipital lobe to visual hallucinations
(O’Brien et al., 2008). Such a receptor change suggests most
marked cholinergic denervation in the occipital lobe in DLB
compared to the other cortical regions. In contrast to nico-
tinic receptors, muscarinic receptors affect neurones over
a longer time frame. In DLB and PD, muscarinic receptors
are elevated in the cortex (Teaktong et al., 2005), even in the
occipital lobe (Colloby et al., 2006), in contrast to AD (Perry
et al., 1990b), again reflecting possible upregulation of post-
synaptic receptors in response to cholinergic denervation.
The increase in muscarinic receptors in the cingulate cortex
relates to the severity of psychosis (Teaktong et al., 2005).
In contrast, muscarinic receptor density in the striatum is
lower in DLB and parallels low D2 receptor density (Piggott
et al., 2003), suggesting that these receptors may be located
on the same structures that have degenerated, which is the
dopamine terminals, as described above.
Neocortical choline acetyltransferase (ChAT) activ-
ity, the enzyme necessary for acetylcholine production, is
lower in DLB than in AD, and similar to that observed in
demented PD (Mukaetova-Ladinska et al., 2013). This data
is consistent with the structural loss of cholinergic neu-
rones, as discussed above. The other enzyme that has been
studied in detail is AChE, the main enzyme that degrades
acetylcholine. Cortical activity of AChE is significantly
720 Dementia
reduced in probable DLB compared with probable AD
(Shimada et al., 2009; Klein et al., 2010; Shimada et al.,
2015), although this is not as consistent early in these dis-
eases where there is a more consistent deficit in patients
with amnestic cognitive impairment (Marcone et al.,
2012). In patients with probable DLB, the greatest differen-
tial reduction is observed in the posterior cingulate cortex
(Shimada et al., 2015). This suggests there is less degrada-
tion and increased acetylcholine transmitter cortically as
DLB takes hold, particularly in the posterior cingulate
cortex, which may be the basis of the cingulate island sign
discussed above. Perhaps surprisingly, reducing AChE
activity further with the use of inhibitors produces sig-
nificant clinical benefit in DLB (Mori et al., 2012), suggest-
ing that decreasing acetylcholine degradation further and
enhancing cholinergic transmission in general is benefi-
cial. Of interest, glucose metabolism has been reported to
be either increased (Fong et al., 2011) or decreased in DLB
following AChE inhibition (Satoh et al., 2010), which may
perhaps relate to diagnostic overlap with AD (where cho-
linesterase inhibitors increase perfusion [Chaudhary et al.,
2013]), as none of these studies have had pathologic confir-
mation of diagnosis.
62.6 MOLECULAR AND ANATOMICAL
PATHOLOGY CORRELATES OF
CLINICAL FEATURES IN DLB
Research has attempted to identify key brain structures
where pathology underpins the major and minor clinical
features of DLB. Parkinsonism is securely attributable to
degeneration of the nigrostriatal dopaminergic pathway.
Neurochemical and anatomical substrates for other clini-
cal hallmarks such as visual hallucinations, fluctuating
consciousness and rapid eye movement (REM) behavioural
sleep disorder (RBD) remain poorly characterized.
62.6.1 COGNITIVE DECLINE IN DLB
While mild cognitive impairment is recognized in around
50% of PD patients at their time of diagnosis (Foltynie et al.,
2004), the progression to dementia is generally seen over
5–20 years depending on their age of disease onset (Hely
et al., 2008). In contrast, significant cognitive decline from
onset is the clinical hallmark of DLB. Attributing specific
molecular and pathological changes as the substrate of
cognitive decline in DLB is complicated by the frequent
coexistence of AD-type pathologies. However, some recent
studies show that the degree of cognitive decline correlates
positively with the severity of cortical α-synuclein pathol-
ogy, but also to the severity of β-amyloid and tau deposition
in DLB (Howlett et al., 2015). This differs from the regional
pattern of α-synuclein pathology, which is independent of
the risk of dementia (Zaccai et al., 2015). Other molecu-
lar markers have been associated with cognitive decline,
including synaptic markers (Whitfield et al., 2014) and
dynamin1 (Vallortigara et al., 2014).
62.6.2 PARKINSONISM
The pathological and neurochemical basis of mild parkin-
sonism in DLB are the most satisfactorily characterized
aspect of DLB pathology. The presence of nigral dopamine
neurone loss with reduced presynaptic dopamine trans-
porter activity in the striatum now form the basis for a
clinical diagnostic strategy to distinguish DLB from other
dementia syndromes, as discussed above.
62.6.3 VISUAL HALLUCINATIONS
The presence of visual hallucinations is common to both
DLB and PD with dementia. However, it is well recognized
clinically that visual hallucinations and other psychotic fea-
tures such as paranoia, emerge as early as in the first year of
DLB but not generally seen for several years in the course
of PD (Hely et al., 2008). One of the obvious candidate
regions expected to correlate with visual hallucinations in
DLB would be the components of the visual pathways. There
has been some speculation on the contribution of pathology
in the retina to hallucinations in DLB, but recent studies
show a lack of either AD or LB pathologies in the retina of
patients with AD or LB diseases (Ho et al., 2014). However,
DLB patients appear to have greater atrophy of the retinal
nerve fibre layer compared with AD or PD (Moreno-Ramos
et al., 2013) and large pale synaptic inclusions between the
photoreceptors and retinal horizontal cells (Maurage et al.,
2003; Devos et al., 2005), consistent again with abnormali-
ties in axonal and synaptic structures in DLB. The pale
synaptic inclusions in DLB occur only in patients with hal-
lucinations, suggesting a specific and less common associ-
ated retinopathy (Devos et al., 2005). Visual information
from the retina is relayed to the cortex via the thalamus
with the main rely nucleus being the lateral geniculate.
There are no pathological features in the lateral geniculate
relay to the occipital cortex in DLB, in contrast to AD where
some degeneration is observed (Yamamoto et al., 2006;
Erskine et al., 2016). However, microstructural changes
(Delli Pizzi et al., 2014b) and α-synuclein pathologies
(Yamamoto et al., 2006; Brooks and Halliday, 2009) occur
in both the posterior thalamic regions projecting between
the occipital and parietal cortices as well as in the medial
thalamic regions projecting to the amygdala, differentiat-
ing DLB patients from AD. Hallucinations particularly
related to microstructural changes in the posterior tha-
lamic regions (Delli Pizzi et al., 2014b), while unconscious
visual information is transferred from the thalamus to the
amygdala, and α-synuclein pathology and microstructural
changes in the amygdala in conjunction with the loss of
dopaminergic neurones is also associated with the presence

of visual hallucinations (Harding et al., 2002a; Yamamoto
et al., 2006; Kalaitzakis et al., 2009a; Kantarci et al., 2010;
Zaccai et al., 2015). A requirement for visual hallucinations
is a relative reduction in the activity/perfusion of the occipi-
tal cortex (Shimada et al., 2009; Firbank et al., 2015) and
there is some evidence of a reduction in vascular endothe-
lial growth factor and capillary density in the occipital lobe
in DLB compared with AD (Miners et al., 2014). Of note,
primary visual cortex in the occipital lobe is spared from
α-synuclein pathologies and abnormalities, and is there-
fore not used diagnostically (Table 62.1), although some LB
pathology may be seen in secondary visual cortices in DLB
patients (Yamamoto et al., 2006). These secondary visual
regions have been shown to be dysfunctional with thinned
cortices in DLB patients with visual hallucinations (Taylor
et al., 2012; Delli Pizzi et al., 2014a). These data show only
subtle changes in primary visual pathways in DLB patients
with hallucinations, although more severe LB pathology
and dysfunction in secondary visual relay pathways as well
as in pathways relaying visual information to limbic brain
regions associates with visual hallucinations.
A number of other regional brain changes are docu-
mented as associated with visual hallucinations in DLB.
In patients with visual hallucination there is an increased
burden of α-synucleinopathy in the parahippocampal
cortices, claustrum and insula (Harding et al., 2002a;
Yamamoto et al., 2006; Kalaitzakis et al., 2009a, 2009b),
with the amount of α-synuclein pathology in these regions
correlating with that observed in secondary visual cortices
(Yamamoto et al., 2006). The insula has been identified as
a core region of degeneration/atrophy using neuroimaging
in patients with visual hallucinations and associates with
hypometabolism in the anterior cingulate and parahippo-
campal cortices (Blanc et al., 2014; Heitz et al., 2015). In DLB
patients with complex hallucinations, hypometabolism in
parahippocampal/inferior temporal cortices is especially
pronounced (Heitz et al., 2015). Decreased cortical cholin-
ergic activity appears to be important in DLB patients with
hallucinations (Perry et al., 1990a), with AChE inhibitors
that enhance cholinergic transmission and posterior cor-
tical perfusion highly effective against this clinical feature
(Satoh et al., 2010; Ukai et al., 2015).
More recent developments in our understanding of
visual hallucinations have come from an appreciation of
the role of higher order neural networks rather than think-
ing of more simplistic neural circuits or neurotransmit-
ters (Onofrj et al., 2013). Much of this thinking has arisen
from functional neuroimaging studies that have identified
functional networks that co-activate in response to specific
internal and exogenous demands (Smith et al., 2010; Laird
et al., 2011; Fornito and Harrison, 2012) and also in the
absence of an external task (Biswal et al., 1995). Evidence
from functional MRI experiments in non-demented PD
patients with and without visual hallucinations has sug-
gested that, there is a breakdown in the communication
between the attentional (Default Mode, Dorsal and Ventral
Pathology of dementia with Lewy bodies 721
networks) and visual networks of the brain, allowing for
the generation of incorrect perceptions (Shine et al., 2014a).
This construct is consistent with the brain changes identi-
fied above and allows an appreciation that the generation
of hallucinations can arise from pathology across multiple
regions with contributions from various neurotransmitters
(Onofrj et al., 2013; Shine et al., 2014b).
62.6.4 FLUCTUATION IN CONSCIOUS
LEVEL
The neuroanatomical structures that are key to regulation
of consciousness are not well characterized and candidate
brain regions have not been established in DLB. Through
serendipitous experiments, the claustrum has recently been
identified as the central hub of a network that subserves
consciousness (Koubeissi et al., 2014) and as described
above this region has significant LB pathology in DLB
(Yamamoto et al., 2006; Kalaitzakis et al., 2009a, 2009b).
The claustrum connects to many parts of the cortex, and to
the hippocampus, amygdala and caudate nucleus, allowing
it to have widespread coordination of the cerebral cortex.
During disruptions of consciousness by stimulation of the
claustrum, there is increased electroencephalogram (EEG)
signal synchrony in medial parietal and posterior frontal
networks (Koubeissi et al., 2014). Increased EEG signal syn-
chrony in these regions distinguishes DLB from AD, PD
and elderly controls with many studies demonstrating its
utility in clinical practice (Kai et al., 2005; Andersson et al.,
2008; Bonanni et al., 2008; Roks et al., 2008; Liedorp et al.,
2009; Micanovic and Pal, 2014; Lee et al., 2015). A recent
study suggests that EEG signal synchrony measures are
100% accurate in predicting conversion from mild cognitive
impairment to DLB within 3 years (Bonanni et al., 2015). It
is of interest that in a small study, AChE inhibitors reduced
the EEG synchrony in DLB but not AD patients (Kai et al.,
2005). Pathologically, there are no differences in the sever-
ity of cortical cholinergic degeneration or LB pathologies in
DLB patients with or without fluctuations in consciousness
(Ballard et al., 2002; Harding et al., 2002a), but a reduc-
tion in temporal lobe nicotinic receptors has been demon-
strated (Ballard et al., 2002). Such a reduction is unlikely to
explain the efficacy of AChE inhibitors, and the relationship
between EEG abnormalities and neurochemical changes
and pathology in the claustrum in DLB should be pursued
further.
62.6.5 RAPID EYE MOVEMENT SLEEP
BEHAVIOUR DISORDER
In the 2005 consensus on DLB diagnosis (McKeith et al.,
2005), an additional suggestive clinical feature for DLB was
introduced – RBD, where patients experience dream enact-
ment. The prevalence of RBD in DLB patients has not been
determined, but its inclusion in the diagnosis of DLB is help-
ful in association with other core clinical features (Ferman
722 Dementia
et al., 2011), indicating it is not more highly prevalent than
these features. In longitudinal studies, RBD appears to be
highly specific for an underlying α-synuclein pathology (not
necessarily DLB) (Iranzo et al., 2013; Schenck et al., 2013),
although analysis of large cohorts of patients with dementia
shows that RBD more frequently occurs in a variety of other
dementia types (AD, frontotemporal dementia and vascu-
lar dementia) compared with DLB (Pistacchi et al., 2014).
Further studies are required to determine the prevalence of
RBD in patients with DLB and other types of dementia. This
will assist in identifying the underlying brain regions and
pathologies associated with RBD. In this context, RBD con-
verters to DLB have occipital hypometabolism (Fujishiro
et al., 2013) and awake EEG signal synchrony (Inoue et al.,
2015) similar to that for DLB described above, and DLB
patients with RBD have more severe occipital hypoperfusion
(Chiba et al., 2014). Cross-sectionally, patients with RBD are
similar to DLB patients in their dopamine cell loss and stri-
atal denervation (Rupprecht et al., 2013) and their choliner-
gic denervation (Kotagal et al., 2012a) with similar severities
of brainstem LB pathology (Dugger et al., 2012) but more
cortical LB pathology (Murray et al., 2013; Postuma et al.,
2015). Cross-sectional neuroimaging shows that patients
with RBD have greater neuronal degeneration in the locus
caeruleus that correlates with increased muscle tone dur-
ing REM sleep (Garcia-Lorenzo et al., 2013), although by
end-stage, degeneration in this region or in the cholinergic
pedunculopontine tegmental nucleus is similar in patients
with or without RBD (Dugger et al., 2012). This suggests
that noradrenergic degeneration is not isolated to RBD but
is more severe at earlier disease stages. The specificity of any
of these or other pathologies for the clinical phenomenon of
RBD rather than another core feature associated with such
pathologies requires significantly more work.
62.7 PATHOGENESIS OF DLB AND
OTHER SYNUCLEINOPATHIES
Most research on LB formation is driven by mechanisms
associated with PD, although genetic association studies
show similar associations to α-synuclein and genes associ-
ated with lysosomal dysfunction (Bras et al., 2014). In addi-
tion to depositing α-synuclein, impairment in lysosomal
pathways is a characteristic of most cells that aggregate
α-synuclein (Tofaris, 2012; Dehay et al., 2013). Lysosomes
degrade proteins and other cellular molecules via three
pathways, microautophagy (small invagination of the mem-
brane), chaperone-mediated autophagy (CMA, selectively
tagged molecules for lysosomal degradation) and macro-
autophagy (walling off of large cellular compartments, like
mitochondria, with specialized membranes that then fuse
with lysosomes). There is strong evidence for selective CMA
dysfunction associated with increased α-synuclein accumu-
lation (see Bourdenx et al., 2014 for review). α-Synuclein is
normally released from neurones and can be taken up by
neighbouring cells for degradation in lysosomes (see Lee
et al., 2014 for review). Under stress conditions, α-synuclein
is mainly released from neurones via unconventional exocy-
tosis in vesicles in an oligomeric form, but is also observed in
exosomes (although inhibition of their formation increases
α-synuclein secretion) (see Lee et al., 2014 for review).
Experimental studies have shown that preformed α-synuclein
fibrils and oligomers can be internalized by cultured neu-
rones via endocytosis and that direct transfer of α-synuclein
between cells in culture and in animal models occurs (see
Lee et al., 2014 for review). In cell culture, the α-synuclein
transferred from donor cells to recipient cells can form inclu-
sions consistent with LB pathologies, and animal models
show that α-synuclein pathology can spread throughout the
brain (Masuda-Suzukake et al., 2013). These studies suggest
that lysosome dysfunction is important for LB formation and
that once LB form, they can spread throughout the brain.
62.8 SUMMARY
LB formation is much more highly prevalent in dementia
patients with AD-type pathology than previously recog-
nized, although it is clear that DLB has specific and identifi-
able pathologies that warrant its recognition as the distinct
disorder. Compared with AD, the loss of dopaminergic
neurones is profound while the medial temporal lobe is less
affected. Pathological comparisons with end-stage PD show
largely similar degenerative changes that differ in their
tempo and order of onset. This review has identified synap-
tic and axonal pathologies as particularly prominent in DLB
compared with both AD and PD, and genetic associations
suggest that dysfunction of lysosomes plays an important
role. Further research with more consistent comparisons
between patients with DLB, AD and PD are required to
unravel the separate and overlapping factors critical for
these different disorders.
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The treatment of dementia with Lewy bodies
JOHN-PAUL TAYLOR
63.1 INTRODUCTION
The management of dementia with Lewy bodies (DLB) is not
easy. Clinicians face a daunting multiplicity of symptoms
where the treatment of one symptom can potentially exac-
erbate another. Classic examples of these include the use of
dopaminergic medications to help ameliorate motor symp-
toms but which conversely exacerbate or cause psychiatric
symptoms; in a similar vein, the use of cholinesterase inhibi-
tors (ChEIs) may improve cognition, yet lead to unacceptable
urinary urgency and incontinence. However, this should not
engender treatment nihilism, as often, with well-informed
and balanced management plans, patients with DLB can do
very well. Indeed, as discussed in Section 63.2.2, treatment
effects for ChEI can be noticeably greater in DLB patients
than in patients with Alzheimer’s disease (AD).
Practical management of DLB, reflecting the widespread
impact of the core pathology of alpha-synuclein across mul-
tiple neural systems (both peripheral and central), often
means that clinicians need to consider a wide range of con-
current treatments targeting different symptom clusters
(Figure 63.1).
The key to this process is making sure that the patient and
patient’s family have a clear understanding of the condition
and its myriad of symptoms. In the clinical consultation,
asking direct questions in each of the symptom domains
can unearth what seem like apparently unrelated yet trou-
bling problems and allow patients, families and caregivers to
rank these in order of priority and severity so that a rational
management plan can be chalked out for the patient. Frank
discussions on the benefits versus side effects of particular
interventions can also help determine what symptoms are
perhaps most important to patients and their families.
Experienced multidisciplinary teams (e.g. geriatricians,
psychiatrists, neurologists, physiotherapists, nurse special-
ists etc.) working in close collaboration probably represent
the idealized service model to deal with the wide array of
730
63
symptoms and prevent multiple concurrent clinic/hospital
attendances, although local resources will dictate what is
pragmatically possible.
In this chapter, we focus on DLB management. However,
clinical uncertainty often exists in terms of whether the
diagnosis of the dementia is DLB or Parkinson’s disease
with dementia (PDD; see Chapter 64). While such delin-
eation is important for research, from a clinical perspec-
tive there are significant overlaps in the treatments, which
are applied to both conditions and thus, management
suggestions described here also have broad applicability
to PDD.
63.2 PHARMACOLOGICAL
INTERVENTIONS
63.2.1 GENERAL PRINCIPLES
Prior to adding in any new medications, it is worthwhile
reviewing the patient’s current medicines and rationalize
these in conjunction with their prescribers, e.g. physical
health specialists or primary care physicians. This is par-
ticularly important in DLB as polypharmacy (particularly
with drugs that have psychotropic effects such as opiates,
antihistamines, anticonvulsants, benzodiazepines etc.)
can exacerbate or mimic DLB related symptoms such as
worsening confusion, sedation and behavioural distur-
bances, as well as contribute to risk of falls in the patient.
In particular, be alert to those drugs with potent central
anticholinergic effects – generally, these should be avoided
in patients with DLB. However, one should also be aware
that there is increasing evidence that even drugs with mild
anticholinergic effects (e.g. opiates, digoxin, beta-blockers
etc.), which are often prescribed in old age, additively, can
have a deleterious effect on cognition, worsen long-term
functional outcomes in dementia and increase the risk
 The treatment of dementia with Lewy bodies 731

Cognitive
impairment and
cognitive
fluctuations

Autonomic
dysfunction, e.g.
Depression,
OH, urinary
anxiety, apathy
symptoms,
constipation etc.

DLB
symptoms

Psychosis, especially
Parkinsonism visual
hallucinations

Sleep
disturbances, e.g.
RBD, insomnia,
daytime
somnolence etc.

Figure 63.1 Examples of symptom clusters in dementia with Lewy bodies (DLB). OH, orthostatic hypotension; RBD, rapid
eye movement sleep behaviour disorder.

of mortality (Jewart et al., 2005; Fox et al., 2011; Kalisch
Ellett et al., 2014; Gray et al., 2015). Furthermore, from
a DLB perspective, drugs with an anticholinergic effect
may also obviate any therapeutic benefit of any prescribed
ChEI.
Another challenge in DLB is the inherent variabil-
ity in symptom severity, which can make it difficult to
determine any positive or negative response to treatment.
Pragmatically, for the initiation of new medications in
patients with DLB, the established mantra of starting low
and going slow is a sensible approach. Careful upward titra-
tion with regular monitoring of the mental and physical
state can help as well as only introducing one treatment at a
time to determine response while being mindful to the fact
that any short-term worsening may be related to the disease
itself rather than the treatment.
63.2.2 CHOLINESTERASE INHIBITORS
There is extensive evidence to suggest that unlike AD, there
is relatively less neuronal loss but relatively more profound
cholinergic loss in DLB (Tiraboschi et al., 2002) and this
provides the scientific basis that restoration of cholinergic
function by blocking acetylcholine breakdown by cholines-
terases in the synaptic cleft, and prolonging its postsynaptic
effect may be an effective method by which to treat cognitive
and neuropsychiatric symptoms of DLB.
Supporting this assertion is the observation that, in gen-
eral treatment, effect size for cognitive impairment appears to
be larger in Lewy body dementias (LBDs) than AD (Samuel
et al., 2000; Emre et al., 2007). All three currently prescribed
ChEIs, donepezil, rivastigmine and galantamine have
been tested in DLB with improvements noted in cognition
(Rolinski et al., 2012; Stinton et al., 2015; Wang et al., 2015).
A recent meta-analysis (Stinton et al., 2015) across a combina-
tion of eight major trials of either rivastigmine or donepezil
in DLB and PDD suggested that, on average, the Mini-Mental
State Examination (MMSE) improved by 1.26 points (95%
confidence interval [CI] 0.66–1.86) with cognitive benefits
favouring donepezil in DLB and rivastigmine in PDD.
Post-mortem studies have suggested that visual hal-
lucination occurrence is also associated with more pro-
found cholinergic deficits (Perry et al., 1990) and this
aligns with clinical trial data demonstrating improvement
in this symptom in DLB with rivastigmine and donepezil
(McKeith et al., 2000; Emre et al., 2004; Mori et al., 2012).
Notably, the presence of visual hallucinations appears to
predict a better cognitive response to ChEI, perhaps, as
a result of greater cholinergic deficits in those individu-
als who experience those (McKeith et al., 2004). Other
732 Dementia
psychiatric domains that may also improve with ChEI
in DLB include apathy, delusions, depression and cogni-
tive fluctuations (McKeith et al., 2000; Mori et al., 2012).
Behavioural symptoms such as agitation and aggression
can sometimes improve with ChEI, particularly, if there is
a clear cognitive component driving them; however, ChEI,
as alerting agents, can, on rare occasions, paradoxically
aggravate agitation in DLB patients.
Functionally, ChEI use in both DLB and PDD has been
associated with improvements in activities of daily living
(ADLs) and clinical global impression and reductions in
caregiver burden scales (Aarsland et al., 2002; Emre et al.,
2004; Dubois et al., 2012; Mori et al., 2012). Even if improve-
ments are not evidenced, absence of deterioration data have
tended to favour the use of ChEI in DLB with one study
(Mori et al., 2012) observing a lack of clinical decline in a
treated donepezil group (96% with no decline) versus pla-
cebo group (50% with no decline) over the 3-month trial
period.
Discerning whether one ChEI is better than another in
DLB is less clear, as there are no direct comparison trials
to favour one agent over another. Double-blind randomized
controlled trial (RCT) evidence exists for rivastigmine and
donepezil, whereas there has been only one uncontrolled
trial in DLB with galantamine (Edwards et al., 2007). Thus,
while from an efficacy perspective, there is no evidence to
suggest that any one ChEI is better than another in DLB
(Bhasin et al., 2007; Stinton et al., 2015), the relative lack of
high-quality data for galantamine has perhaps biased cur-
rent clinical practice towards the use of rivastigmine and
donepezil in DLB.
Overall, ChEIs appear to be tolerated reasonably in
patients with DLB. Notable side effects, however, include
gastrointestinal symptoms, sleep disturbance, dizziness,
urinary frequency, insomnia, leg cramps, hypersalivation
and increased lacrimation. Sleep disturbances may respond
to prescribing ChEI in the morning (or giving second dose
in the afternoon for twice daily preparations) and gastroin-
testinal symptoms arising after ChEI initiation may settle
over a few days. Sometimes, anti-emetics may be needed
and 5-HT3 antagonists such as ondansetron or granis-
etron might be suggested as helpful by some clinicians
(Boot, 2015).
Symptomatic bradycardia and conduction delays as a
result of Lewy body disease related to cardiac dysautono-
mia and are perhaps more serious, albeit, rare side effects of
ChEI in DLB (Ballard et al., 2006). Some authorities advo-
cate the use of baseline electrocardiograms to check for any
pre-existing issues and for some patients permanent cardiac
pacemakers may be required although whether this should
be done specifically to allow the patient to undergo ChEI
treatment is controversial (Boot, 2015).
Finally, despite the reciprocal interplay between dopa-
mine and acetylcholine in the striatum, only a minority of
patients appear to have exacerbations of their motor symp-
toms with ChEI treatment (Thomas et al., 2005).
With regard to side effects, meta-analyses have suggested
that there is perhaps a tendency for more adverse events with
rivastigmine than donepezil (Stinton et al., 2015). However,
rivastigmine now comes as a transdermal patch also, which
appears to have a lower proclivity for gastrointestinal side
effects and may have benefits in terms of providing a more
sustained release (Emre et al., 2010a).
When and if, one should withdraw ChEI in DLB is not
clear; certainly, if there are side effects there may be a clear
need to do this. Sudden withdrawal of ChEI in DLB (and
PDD), however, has been associated with worsening neu-
ropsychiatric symptoms and marked declines in cognition
(Minett et al., 2003) and even switching from one ChEI to
another may have negative sequelae (Bhanji and Gauthier,
2005), so careful cross-tapering may be required in these
instances.
There are limited data for the long-term effect of ChEI
treatment in DLB although benefits appear to be sustained
for up to 2 years (Grace et al., 2001; Werner et al., 2006; Mori
et al., 2015) and use of ChEI may delay nursing home admis-
sion (Rongve et al., 2014). Intriguingly, meta-analyses have
also suggested that across the LBD spectrum, ChEI use may
be associated with reduced mortality with odds ratio of 0.28
(CI 0.09–0.84) (Rolinski et al., 2012).
There is also some tentative evidence to suggest that there
may be added benefits to patients by increasing ChEI doses
above the recommended maximum, albeit, at an increased
likelihood of side effects (Pakrasi et al., 2006). There have
been no systematic trials to suggest that higher than recom-
mended doses are truly beneficial.
63.2.3 MEMANTINE
Memantine, N-methyl-d-aspartate (NMDA) antagonist has
been trialled in DLB but results have not been conclusive.
One study by Aarsland et al. (2009) included 72 patients
with either PDD or DLB of mild-to-moderate severity who
were randomized to 20 mg of memantine or to placebo for
24 weeks. Key findings included a significant benefit for
memantine over placebo in the primary outcome measure
of the Clinical Global Impressions of Change (CGIC), which
appeared stronger in PDD than DLB. There was no effect
on secondary outcome measures such as neuropsychiatric
symptoms or ADLs, although attentional speed did appear
better on memantine while parkinsonian symptoms did not
worsen. In a second larger study by Emre et al. (2010b), 199
patients with DLB or PDD were randomized to memantine
20 mg or placebo. However, while the primary outcome
measure of CGIC was lower in the memantine group, this
did not reach significance except in the DLB group, who also
demonstrated improvements in their total Neuropsychiatric
Inventory (NPI) scores. Cognitive scores and other sec-
ondary outcome measures were not statistically different
between treatment and placebo groups.
It is likely that patient heterogeneity played a large role
in the above studies and introduced a degree of response

variability. In addition, notably, in the Aarsland et al. (2009)
study, concurrent use of ChEI was allowed, whereas they
were not in the Emre et al. (2010b) trial, which may have
influenced the findings.
Overall, these mixed data provide some tentative evi-
dence that memantine might be beneficial, but it is equivocal
whether it helps patients with DLB and/or PDD and it remains
unclear what symptom domains would be best targeted by
the memantine. Clearly, further studies are needed in this
area, making use of different designs with responder analy-
ses to clarify the utility of memantine in DLB. Longitudinal
data from a subsample of the patients in the Aarsland et al.
(2009) trial have suggested that early treatment and positive
clinical response to memantine might predict longer survival
in patients with DLB and PDD (Stubendorff et al., 2014) and
a secondary analysis of reaction time data has favoured the
use of memantine in terms of improvements in attention in
DLB and PDD patients (Wesnes et al., 2015).
Practically, despite some case reports suggesting
increased agitation in DLB (Ridha et al., 2005), the major
trials described above indicate that memantine is generally
a well-tolerated agent and thus, it may be worth trialling in
selected patients, particularly, those in whom ChEI are con-
traindicated or cannot be tolerated.
63.2.4 DOPAMINE REPLACEMENT
Use of levodopa/carbidopa in Parkinson’s disease (PD) is well
established; however, their use in LBD and, in particular, DLB
is less clear due to a lack of adequate trial data. Uncontrolled
studies have demonstrated acute and chronic improvements
in motor functioning and reductions in tremor for individuals
with DLB and PDD with levodopa (Bonelli et al., 2004; Molloy
et al., 2005; Goldman et al., 2008; Onofrj et al., 2013). Motor
improvements in response to levodopa treatment appear more
common in PDD (65%–70%) than DLB (32%–50%) (Bonelli
et al., 2004; Onofrj et al., 2013; Stinton et al., 2015).
A major challenge with levodopa use in DLB is the
increased risk of psychotic symptoms such as hallucina-
tions; certainly about one-third of those who derive motor
benefits also experience worsening of their psychotic symp-
toms (Goldman et al., 2008).
There are little or no data for the use of other anti-­
parkinsonian agents such as amantadine, catechol-O-­
methyltransferase (COMT) inhibitors, rotigotine selegiline
etc. in DLB although their tolerability is likely to be poor
and their propensity towards causing psychosis and compul-
sive symptoms significantly limits their use in DLB (Stinton
et al., 2015). Thus, treatment of any motor symptoms in DLB
is typically recommended to be limited to a levodopa mono-
therapy regime.
63.2.5 ANTIPSYCHOTICS
Alternatives to ChEI for the management of behavioural
symptoms include the use of antipsychotics, but these
agents, particularly typical antipsychotics (e.g. haloperidol)
The treatment of dementia with Lewy bodies 733
can provoke profound neuroleptic sensitivity reactions in up
to 50% of DLB patients and these reactions have been asso-
ciated with significant morbidity and mortality (McKeith
et al., 1995). Given the frequent occurrence of cardiac
denervation in DLB (King et al., 2011), QT prolongation
may also be a risk. Across the dementia landscape, there
have been significant concerns about the use of antipsy-
chotics in dementia, not in the least as a result of evidence
suggesting significant increases in mortality, cerebrovascu-
lar disease and cognitive decline associated with the use of
these medications (Wang et al., 2005; Schneider et al., 2006;
Ballard et al., 2009).
Specific evidence for the utility of antipsychotics in DLB
is also lacking. A secondary analysis of an RCT of olanzap-
ine in AD where patients were reclassified retrospectively
as DLB (Cummings et al., 2002) found that this antipsy-
chotic leads to reductions in hallucinations and delusions;
however, this finding was balanced with marked intolerance
of DLB patients to olanzapine even when treated with low
doses (Marsh et al., 2001).
Risperidone has also been trialled in an RCT of 31 DLB
patients (Culo et al., 2010). Similar to olanzapine, this anti-
psychotic led to a worsening in psychiatric and cognitive
symptoms with marked withdrawals in the study.
Clozapine has an evidence base for efficacy in PD with
psychosis (Eng and Welty, 2010) and has also been tried in
PDD (Lee et al., 2007), but there is no evidence for its use
in DLB; aside from the obvious risk of agranulocytosis it is
likely that side effects such as drooling, sedation, tremors,
constipation and delirium, which have been reported in PD/
PDD patients taking clozapine would also limit the utility of
clozapine in DLB.
A favourite antipsychotic choice of clinicians, at present,
for DLB, appears to be quetiapine, given its lower tendency
for side effects. However, evidence for efficacy in treatment
of agitation or psychosis in DLB is limited with regard to
this drug (Takahashi et al., 2003; Kurlan et al., 2007).
In the context of the above, given the relative burden of
side effects to possible efficacy, a high level of caution needs
to be applied to the use of antipsychotics in DLB. They
should only be considered as a second or third option when
other therapeutic avenues have been exhausted and in gen-
eral, they should not be used to treat non-specific agitation
or behavioural disturbances but should only be reserved for
those patients with clear psychosis as these symptoms are
the ones most likely to respond to an antipsychotic (Ballard
et al., 2004).
63.2.6 ANTIDEPRESSANTS, ANXIOLYTICS
AND STIMULANTS
Depression and anxiety are common symptoms in DLB
affecting up to approximately two thirds (59%) and one-
third (27%) of patients, respectively (Fritze et al., 2011;
Boot et al., 2013). However, there is a paucity of evidence
regarding what treatments might be helpful for these symp-
toms in DLB. One small trial in DLB of citalopram versus
734 Dementia
risperidone in terms of neuropsychiatric/behavioural ben-
efits found more than 70% of participants withdrew from
the study due to worsening of psychiatric symptoms or side
effects (Culo et al., 2010).
There are some unpublished data in PDD to support the
use of duloxetine, escitalopram and trazodone in treating
depression but little of such other kind of data are available
(Stinton et al., 2015). Pragmatically, avoidance of tricyclics,
given their anticholinergic properties, is sensible; low dose
trials of selective Serotonin re-uptake inhibitors (SSRIs),
Serotonin-norepinephrine re-uptake inhibitors (SNRIs)
(duloxetine, venlafaxine) or noradrenergic and specific
serotonergic antidepressants (NaSSAs) (mirtazapine) may
represent reasonable alternatives for treatment of depres-
sion and/or anxiety. One should also be cautious regard-
ing the use of benzodiazepines and pregabalin for anxiety
in DLB, given the propensity of these medications to cause
sedation, falls and increased confusion.
Notably, depression was one of four symptoms in an aggre-
gate NPI symptom score, which demonstrated improvement
in the major ChEI trials in DLB (McKeith et al., 2000; Mori
et al., 2012). Thus, it is possible that ChEI may also have a
role to play in treating depression in DLB patients.
Apathy is another major, yet often unrecognized symp-
tom in DLB. It can have significant impacts on patients and
their families (Bjoerke-Bertheussen et al., 2012). If apathy
is part of a depressive constellation, it may respond to anti-
depressant treatment although, again evidence is lacking
for any specifically efficacious agent. Alternatively, apathy
as part of impaired arousal clustered with daytime somno-
lence/drowsiness may respond to ChEI.
Stimulants such as methylphenidate, modafinil/
armodafinil have also been advocated by some special-
ists with case series data, suggesting the latter agents may
lead to global improvements as well as increased wakeful-
ness and attention in DLB (Varanese et al., 2013). However,
data are limited to make recommendations about the use of
stimulants in DLB and the marked side effect propensity of
these agents is a significant factor limiting their use.
63.2.7 SLEEP MEDICATIONS
Sleep disturbances are common and troublesome symp-
toms in DLB and often have significant impacts on carers
(Galvin et al., 2010a). The archetypal sleep symptom in
DLB is REM sleep behaviour disorder (RBD), which affects
approximately 70% of DLB patients (Ferman et al., 2011).
Pharmacological management of RBD has focused on the
use of low dose clonazepam (0.5 mg–1.0 mg nocte) and while
there is case series data to support its efficacy (Massironi
et al., 2003), there is a lack of trial data. Furthermore, the
potential for significant side effects by use of benzodiaze-
pines in a fall-prone dementia group such as DLB is a con-
cern and benzodiazepines can also worsen any concurrent
sleep apnoea (Postuma et al., 2012).
Some clinicians use melatonin for RBD and other sleep
disturbances in DLB. The evidence for efficacy of this
circadian modulator is anecdotal in DLB but other data in
PD and related disorders suggest it might be effective (Boeve
et al., 2003; Dowling et al., 2005). Overall, given its low side
effect profile, melatonin may be reasonable first choice in
DLB for treatment of RBD.
Restless legs and periodic limb movements can also be
an issue in DLB and treatment can be a challenge; in PD
these symptoms can be treated with dopamine agonists,
gabapentin, pregabalin and benzodiazepines, but the pro-
clivity of these medications for significant side effects in
DLB limits their use.
63.2.8 MEDICATIONS FOR AUTONOMIC
SYMPTOMS IN DLB
There are a wide range of autonomic symptoms in DLB
ranging from orthostatic hypotension, urinary and sexual
dysfunction, dysphagia and gastroparesis to constipation,
altered sweating and sialorrhoea. These symptoms are often
neglected in clinical settings which focus on cognitive, neu-
ropsychiatric or motor symptoms; yet autonomic-related
problems can be severe and functionally limiting for people
with DLB. It is important to enquire after these symptoms
as treatment of them can have significant positive impacts
on the quality of life (QoL) of patients and their carers.
First-line treatment of autonomic symptoms is typically
non-pharmacological (Table 63.1) and rationalizing; if pos-
sible, other medications that can exacerbate these symptoms
is also an important consideration. For example, orthostatic
hypotension may be worsened by anti-parkinsonian drugs,
antidepressants, antihypertensives etc. However, if these
measures fail, then pharmacological interventions may be
required. For orthostatic hypotension, fludrocortisone or
midodrine may be used, although, these may need to be ini-
tiated and monitored by a specialist. As noted above, car-
diac sympathetic innervation can be compromised in DLB
leading to syncope in some patients which, in some cases,
may require a pacemaker.
For troublesome sialorrhoea, anticholinergics should
be avoided, given their negative effects on cognition; botu-
linum toxin injections offer a good alternative to salivary
glands. There is also evidence in PD for glycopyrrolate in
the treatment of sialorrhoea (Arbouw et al., 2010), although
there is no trial data in DLB.
For constipation symptom in PD, there are exten-
sive management guidelines (Seppi et al., 2011) and these
are also, probably applicable to DLB. For example, in PD
patients, macrogol had demonstrable efficacy in an RCT
(Zangaglia et al., 2007) and similarly, lubiprostone also
appears to have a good evidence base for improving consti-
pation (Ondo et al., 2012).
Urinary symptoms including urge and nocturia can be
particularly challenging as ChEI can exacerbate urinary
symptoms making the situation difficult to manage and urge
incontinence medications have centrally had anticholiner-
gic effects; newer drugs such as solifenacin, darifenacin and
trospium that have less proclivity to cross the blood–brain
 The treatment of dementia with Lewy bodies 735

Table 63.1 Examples of symptoms in DLB and their possible non-pharmacological management

Symptom Non-pharmacological advice

Cognitive fluctuations and
reduced arousal
Visual hallucinations
Parkinsonism and falls
REM sleep behaviour
symptoms
Constipation
Urinary incontinence
Orthostatic hypotension
Abbreviations: DLB, dementia with Lewy bodies; REM, rapid eye movement.
May respond to enhanced environmental novelty (e.g. new places) and improving social
interactions (e.g. attendance at day care centres may help). Occupational therapy
input may be useful in helping to develop cognitive and social remediation strategies.
Can be exacerbated by eye disease and environmental issues. Correcting for refractive
errors, cataract removal, providing improved illumination and removal of patterned
furnishings that can provoke illusionary experiences may all be helpful. For some,
focusing attention on the visual hallucination experience (especially in cognitively less
impaired individuals) may reduce them. Others find looking away from visual
hallucination and then looking back at where the hallucination was can cause them to
disappear.
A physiotherapy assessment may clarify if there are any modifiable contributors to poor
mobility, which could be treated, e.g. frailty, arthritis. Occupational therapists can
advise on home modifications, e.g. fitting of grab bars, railings etc.
These symptoms are often more distressing for spouses than the patient themselves and
it may be necessary for bed partners to sleep separately, although, this often needs to
be sensitively discussed.
If the patient is at risk of injury or falling out of bed, lowering the bed/putting the
mattress on floor is an option. Using a sleeping bag may be beneficial and removal of
dangerous/sharp objects in the bedroom is advisable.
High fibre diets, encouraging fluid intake, regular exercise and use of stool softeners
may help.
Avoid excessive fluid intake including fizzy, acidic or caffeinated drinks. Regular voiding
pattern and incontinence pads may help some. If symptoms are particularly
troublesome, seeking advice from an incontinence nurse and/or urologist may be
appropriate.
Advise the patient to be careful about the increase in fluid and salt intake. Compression
hosiery may be suitable for some. Advise the patient to take time to rise from a supine
to standing position. For orthostatic hypotension occurring early in the morning,
raising the head of the bed can help.

barrier may be better (Kessler et al., 2011; Pagoria et al.,

2011) in such cases. Mirabegron, a beta-3 adrenergic ago-
nist, may be alternative for urinary urgency although there
is no evidence for its use in DLB.
63.3 NON-PHARMACOLOGICAL
TREATMENTS
Systematic evaluation of non-pharmacological interven-
tions in DLB is lacking and most recommendations are on
the basis of anecdote, clinical experience, case study and
analogy of treatment benefits in other conditions that over-
lap to some degree with DLB (e.g. PD or AD). Examples of
possible non-pharmacological strategies, based on clinical
experience and anecdotal evidence which may help DLB
symptoms are described in Table 63.1. Broadly, multifaceted
and tailored behavioural strategies and caregiver training
programmes for agitation and behavioural disturbances
and which are applicable to a range of dementias should also
be considered (Gitlin et al., 2012; Kales et al., 2015).
63.4 FUTURE THERAPIES
As is evident from the previous sections, there is a dearth of
high-level evidence in the treatment of DLB. The strongest
evidence is the use of ChEI, specifically rivastigmine and
donepezil for cognitive impairment, cognitive fluctuations,
neuropsychiatric symptoms and global improvements in
function. ChEIs, therefore, probably represent good first-
line and broad-spectrum treatment options in DLB.
However, even with ChEI, there is still a relative lack
of data in terms of the number of trials and numbers of
participants within these studies compared to those trials
which have been carried out in AD. Another major chal-
lenge in DLB trials is a high degree of heterogeneity in
patient response to interventions and this is typified by the
mixed results seen in the major memantine trials (Aarsland
et al., 2009; Emre et al., 2010b). Specific aetio-pathological
processes, perhaps in the distribution of alpha-synuclein
and rate of pathological change, which leads to divergences
in the clinical phenotype, for example, in some leading to
the manifestation of PD/PDD and in others, DLB, are likely
736 Dementia
to be important factors. Better patient stratification on the
basis of biomarkers is likely to be highly relevant for future
DLB trials.
Targeting neurotransmitter systems other than the cho-
linergic system may hold promise. As noted earlier, there are
limited trial data to support the notion that improvements
in the noradrenergic system using agents such as amodi-
final may have benefits related to improved alertness and
decreased drowsiness. In PD, a recent double-blind RCT
Phase III study of pimavanserin, a serotonin 2A receptor
inverse agonist, suggested that this agent may help amelio-
rate psychotic symptoms (Cummings et al., 2014); whether
mechanistically this medication may have benefits in DLB
remains an intriguing unanswered question.
Deep brain stimulation (DBS) has been used with success
to treat motor symptoms in PD and there are ongoing trials
focusing on the stimulation of the nucleus basalis of Meynert
in DLB patients with cognitive impairment as a novel
approach to enhance cognition (ClinicalTrials.gov, 2015).
Furthermore, non-invasive stimulation techniques such as
transcranial magnetic stimulation (TMS) have demonstrated
some antidepressant effects in DLB (Takahashi et al., 2009).
As a final point, the prevalence of DLB is estimated to
be about 4%–7% of dementia diagnoses (Vann Jones and
O’Brien, 2014) depending upon the clinical sample, which
contrasts with the higher prevalence of Lewy body disease
of up to 20% in dementia cases evidenced on post-mortem
(McKeith et al., 2005). Thus, one of the main obstacles pro-
viding best care to DLB patients is obtaining the initial
diagnosis and this is reflected in the fact that often, patients
with DLB attend numerous different specialist services
prior to obtaining a diagnosis and it is estimated that, cur-
rently, only one in three DLB cases is correctly diagnosed,
even after referral to specialist dementia services (Galvin
et al., 2010b). The remaining cases are typically to be misdi-
agnosed as being AD or vascular dementia (VaD) cases, or
given another psychiatric diagnosis instead. Specialist train-
ing in the diagnosis and use of biomarkers may improve this
situation.
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Cognitive impairment and dementia in
Parkinson’s disease
DAG AARSLAND, KOLBJØRN BRØNNICK, MILICA G. KRAMBERGER AND
JOANA B. PEREIRA
64.1 INTRODUCTION
Parkinson’s disease (PD) is a common neurodegenerative
disorder affecting about 1.5% of people aged 65 or older (de
Rijk et al., 1997). PD is defined pathologically as cell loss
in the pigmented dopaminergic cells of the substantia nigra
pars compacta and synuclein pathology (Lewy neurites and
Lewy bodies) in the surviving cells. In addition, cholinergic
forebrain nuclei and other brain stem nuclei including the
serotonergic raphe nuclei and the noradrenergic locus coe-
ruleus are usually affected. The topographical progression
subsequently involves the anteromedial temporal meso-
cortex, including the transentorhinal region, and reaches
into adjoining high-order sensory association areas and
important limbic structures such as amygdalae and hippo-
campus (Braak et al., 2003). The cardinal clinical features of
PD are resting tremor, bradykinesia, rigidity and postural
abnormalities. However, owing to the wide distribution of
neurodegeneration, it is not surprising that a wide range of
non-motor symptoms occur as well, including neuropsychi-
atric symptoms and autonomic dysfunction.
The treatment of PD involves dopamine replacement
therapy with l-3,4-dihydroxyphenylalanine (l-DOPA) and
several dopamine agonists, including the selective dopa-
mine D3 receptor agonists ropinirole and pramipexole. In
addition, the monoamine oxidase inhibitors selegiline and
rasagiline with a potential neuroprotective effect may slow
disease progression. Deep cerebral stimulation with the
implantation of electrodes can be very helpful for selected
patients. A wide range of behavioural side effects can occur
during drug and surgical treatments.
It is now increasingly recognized that PD is a neuro-
psychiatric disorder and not merely a movement disorder.
Independent of the motor symptoms of PD, dementia and
740
64
other neuropsychiatric symptoms affect the quality of life,
contribute to caregiver distress and increased risk of nurs-
ing home placement, and is associated with more psychiat-
ric symptoms such as depression and hallucinations, higher
mortality and functional disability and higher risk for drug
toxicity. This chapter discusses the epidemiology, pathophys-
iologic mechanism, clinical presentation and management of
cognitive impairment and dementia in patients with PD.
64.2 COGNITIVE IMPAIRMENT IN PD
Cognitive impairment is common in PD and has a major clin-
ical impact on the patient, carers and society (Svenningsson
et al., 2012). Although the risk for cognitive decline increases
with disease duration, mild cognitive impairment (MCI)
can be detected in a considerable proportion: around 20%,
already at the diagnosis of PD (Foltynie et al., 2004; Aarsland
et al., 2009; Litvan et al., 2011; Weintraub et al., 2015). It is
usually but not always (see below) a progressive decline, and
thus the early and mild changes tend to progress to dementia
even to severe dementia in many patients.
64.2.1 DIAGNOSIS OF COGNITIVE
IMPAIRMENT IN PD
It is crucial that clinicians seeing PD patients screen for cog-
nitive impairment throughout the disease course. The cog-
nitive profile in PD varies but is usually distinct from the
profiles seen in Alzheimer’s disease (AD) and other demen-
tias. Executive control impairment is paramount, including
deficits in working memory (Possin et al., 2008), set-shifting,
planning, error monitoring (Willemssen et al., 2009), response
inhibition (Wylie et al., 2005) and dual tasking (Brown et al.,

1991). Memory impairment is also common (Weintraub,
2004; Brønnick et al., 2011), although may partly be second-
ary to executive/attentional deficits (Higginson et al., 2003).
Visuospatial dysfunction is another hallmark of the cognitive
profile in PD (Aarsland et al., 2009; Litvan et al., 2011).
The motor symptoms and apathy can make the diagnosis
of cognitive impairment and dementia difficult in PD, and
both overdiagnosis and underdiagnosis may occur (Litvan
et al., 1998). Cognitive rating scales should be used, taking
into account the disabilities from motor symptoms. Screening
tests such as the Mini-Mental State Examination (MMSE)
may be employed, although instruments including execu-
tive dysfunction, such as the Dementia Rating Scale and the
Montreal Cognitive Assessment (MoCA) are more sensitive to
the early cognitive disorders in PD. Neuropsychological tests
are required for a reliable diagnosis of MCI (see Section 64.3.1).
Particular care should be taken to distinguish between cogni-
tive impairment due to confusional states from drug toxicity or
other diseases. Criteria to diagnose dementia in PD have been
proposed (Emre et al., 2007), and a practical guide to assist in
the diagnosis of Parkinson’s disease with dementia (PDD) has
been published (Dubois et al., 2007).
There is considerable clinical and pathological overlap
between dementia with Lewy bodies (DLB) and PDD. A
diagnosis of PDD should be made in patients who are diag-
nosed as PD and develop dementia after at least 1 year with
motor symptoms. If dementia develops before or within
1 year after the diagnosis of PD, a diagnosis of DLB should
be made (McKeith et al., 2005), although this time window
is rather arbitrary. There is a debate whether they represent
distinct diseases or rather two syndromes on a spectrum of
Lewy body diseases, and there are no major clinical conse-
quences related to this differentiation.
64.2.2 MECHANISMS UNDERLYING
COGNITIVE IMPAIRMENT IN PD
The heterogeneous cognitive deficits in PD probably reflect
differing forms and location of neuropathological involve-
ment. Relatively mild executive impairment, usually pres-
ent very early in the course of the disease, is related to
the dopaminergic deficits, caused by either disruption of
nigrostriatal circuitry with altered outflow of the caudate
nuclei to frontal cortex via thalamus (Rinne et al., 2000)
or diminished dopamine activity in the frontal projections
consequent to degeneration of mesocortical projections
(Mattay et al., 2002). Loss of cells in the cholinergic nucleus
basalis of Meynert and cortical cholinergic losses of similar
degrees as in AD have been reported, and these changes are
more pronounced in PD patients with dementia compared
with non-demented patients (Perry et al., 1993; Tiraboschi
et al., 2000). There is also evidence linking the cortical nor-
adrenergic system to extradimensional shift performance,
whereas, in general, visuospatial deficits may be dependent
on acetylcholine rather than dopamine, and these deficits
are also associated with the emergence of visual hallucina-
tions (Kehagia et al., 2010).
Cognitive impairment and dementia in Parkinson’s disease 741
Morphological changes involved in cognitive impair-
ment and dementia include cortical and limbic Lewy bodies
(Aarsland et al., 2005), but also Alzheimer-like changes, and
the alpha-synuclein, amyloid and tau-related changes seem to
act in a synergistic way (Compta et al., 2011). Consistent with
the heterogeneous clinical pattern, the underlying pathology
is heterogeneous, with some patients exhibiting early and
widespread cortical neurodegeneration and an aggressive
clinical course, whereas others have less cortical involvement
and a slower decline (Ballard et al., 2006; Halliday et al., 2008).
64.2.3 CLINICAL FACTORS ASSOCIATED
WITH COGNITIVE DECLINE IN PD
The median time to dementia in PD is 10 years, but there
are wide variations in the time from onset of PD to demen-
tia. Age, advanced parkinsonism and MCI are predictors of
dementia in PD (Svenningsson et al., 2012). Rigidity and
symptoms ­mediated mainly by non-dopaminergic systems,
such as speech, gait and postural disorders, are particularly
related to subsequent development of dementia, whereas
patients with a tremor-dominant pattern have a lower risk
(Alves et al., 2005). The relationship with age and severity of
parkinsonism seems to be due to their combined effect rather
than separate effects (Levy et al., 2002). In addition, halluci-
nations, rapid eye ­movement (REM) sleep behavior disorder
(Boot et al., 2012), early severe olfactory dysfunction (Anang
et al., 2014), orthostatic blood pressure drop, abnormal colour
vision and baseline gait dysfunction are clinical predictors for
global cognitive decline (Anang et al., 2014).
64.2.4 GENETICS OF COGNITIVE
IMPAIRMENT IN PD
Some, but not all, studies have found an association between
dementia and apolipoprotein (ApoE) ε4 in PD (Williams-Gray
et al., 2009), whereas the ε2 allele may be protective (Berge
et al., 2014). A positive association of dementia with the H1
haplotype of the microtubule-associated protein tau (MAPT)
gene has been noted (Goris et al., 2007). Others have not
reported this association and also failed to find an association
with the synuclein gene (Mata et al., 2014).
64.2.5 IMAGING AND COGNITIVE
DECLINE IN PD
Structural brain imaging with magnetic resonance imag-
ing (MRI) has become a powerful technique to assess neu-
rodegeneration in vivo in PD. Using a range of imaging
analyses, a pattern of widespread cortical atrophy in fron-
tal, temporal, occipital and parietal regions has been found
in patients with dementia (Burton et al., 2004; Melzer et al.,
2012; Zarei et al., 2013). Limbic structures such as the hippo-
campus (Apostolova et al., 2010) and the amygdala (Junqué
et al., 2005; Bouchard et al., 2008) in addition to the caudate
(Almeida et al., 2002), putamen and thalamus (Summerfield
et al., 2005) are also atrophied in PDD. In PD patients with
742 Dementia
MCI, less extensive grey matter loss or cortical thinning
have been found, mainly confined to prefrontal, temporal
and parietal regions (Melzer et al., 2012; Pereira et al., 2014).
Brain structure has been consistently associated with impair-
ment in specific cognitive functions, with hippocampal atro-
phy correlating with verbal memory deficits in both PDD
(Laakso et al., 1996) and PD-MCI (Beyer et al., 2012).
Diffusion tensor imaging (DTI) has also been used to
detect abnormalities in white matter microstructure in PD.
Reductions of fractional anisotropy, indicating white mat-
ter integrity loss, have been reported in the longitudinal
fasciculi, internal capsule (Hattori et al., 2012), posterior
cingulate bundles (Matsui et al., 2007) as well as other tracts
(Melzer et al., 2013) in PDD. In PD patients with MCI, a
pattern of white matter abnormalities involving the corona
radiata, uncinate and corpus callosum was identified in the
absence of significant grey matter changes (Agosta et al.,
2014), suggesting that white matter abnormalities might
precede grey matter atrophy in PD.
A number of studies have also applied functional MRI
(fMRI) to assess the functional network characteristics of
PD at the resting state. In patients with dementia, reduced
functional connectivity between regions of the default
mode and visual networks has been found (Rektorova et al.,
2012), while in patients with MCI decreased connectivity in
the fronto-parietal, dorsal attention and default-mode net-
works (Amboni et al., 2014; Baggio et al., 2015) are amongst
some of the most consistent findings.
Several studies have explored amyloid pathology in PD
in vivo using 11C-Pittsburgh compound B positron emis-
sion tomography (PIB PET). In a subgroup of patients with
dementia in PD, increased amyloid load has been found and
seems to be associated with Alzheimer-like characteristics
both for clinical phenotype and cerebrospinal fluid (CSF)
(Maetzler et al., 2009). Most studies show low amyloid bur-
den in PD-MCI patients that is comparable to that observed
in healthy controls, although there is some evidence sug-
gesting that amyloid might have a greater value in predicting
cognitive decline over time in PD (Gomperts et al., 2013).
Although both structural and functional imaging tech-
niques may assist in the diagnostic workup of patients with
parkinsonism and cognitive impairment, the final diagno-
sis must be based on the history and clinical examination
including routine supplementary tests.
64.2.6 CSF AND OTHER BIOMARKERS OF
COGNITION IN PD
There is much focus on identifying biomarkers, which can
assist in the diagnosis and, even more importantly, predic-
tion of cognitive decline in PD (Mollenhauer et al., 2014).
In addition to imaging techniques reviewed above, many
studies have explored CSF biomarkers. CSF can be useful
in predicting development of AD. Since Alzheimer’s-type
brain lesions that contain amyloid beta (Aβ) proteins and
neurofibrillary tangles are associated with dementia in
PD, CSF biomarkers for assessing Aβ and tau levels may be
considered diagnostic and possibly predictive markers for
PDD. Indeed, CSF biomarkers are among the most promis-
ing biomarker candidates for cognitive impairment in PD.
Patients with PDD have lower CSF levels of Aβ1–42 com-
pared with patients with PD without cognitive impairment
or age-matched control subjects (Siderowf et al., 2010; Alves
et al., 2014) and have also shown to predict future cognitive
decline (Siderowf et al., 2010). Inconsistent findings have
been reported for levels of total tau (t-tau) and phosphor-
ylated tau (p-tau), reporting slightly lower or unchanged
levels compared with normal controls. Many studies have
attempted to measure alpha-synuclein levels in CSF in PD,
and decreased levels have been found (Kang et al., 2013). The
variation is large, and there is overlap with normal controls,
and it has yet proven difficult to correlate alphasynuclein-
levels with cognitive decline in PD.
Several studies have also explored blood-based mark-
ers, and promising results have been shown for epidermal
growth factor but need to be replicated (Mollenhauer et al.,
2014). There is also evidence that electroencephalogram
(EEG) may be a marker of cognitive impairment in PD
(Bonanni et al., 2008).
64.3 MCI IN PD
64.3.1 CLASSIFICATION AND DIAGNOSIS
A task force commissioned by the Movement Disorders
recently proposed graded criteria for the clinical diagnosis
of MCI in PD (Litvan et al., 2012). These include subjec-
tive and objective evidence of cognitive impairment, and
no significant functional impairment due to the cogni-
tive decline. The diagnosis of PD-MCI can be made using
screening instruments, which are validated for PD, for
example MOCA, or a small battery of cognitive tests at level
1, whereas two standardized neuropsychological tests for
each of the five cognitive domains (memory, executive, lan-
guage, visuospatial and attention) are required for a diag-
nosis at level 2. The criterion ‘subjective cognitive decline’
can be difficult to ascertain in PD; due to the combined
motor features both over- and under-reporting has been
shown. Another challenge is to draw the line between MCI
and dementia based on functional impairment, since both
motor and cognitive symptoms can contribute to cognitive
impairment. The Parkinson’s Disease-Cognitive Functional
Rating Scale (Kulisevsky et al., 2013) has been reported to be
helpful in this regard.
64.3.2 THE COURSE OF MCI IN PD
The annual decline on MMSE in PD is one point, but with wide
interindividual variations (Aarsland et al., 2004). There is now
convincing evidence that PD patients with MCI have a shorter
time to dementia than those with normal cognition, shown
in several large longitudinal cohort studies (Williams-Gray

et al., 2007; Pedersen et al., 2013). There is some evidence
that tests with a more posterior cortical basis (e.g. visuospatial
tests) predicted more rapid cognitive decline compared with
fronto-striatal tests (Williams-Gray et al., 2007). This cogni-
tive dissociation was paralleled by a genetic dissociation: poly-
morphisms of the microtubule-associated protein tau (MAPT)
gene, but not catechol O-methyltransferase (COMT) gene,
was associated with dementia (Goris et al., 2007), whereas a
­polymorphism of the COMT gene was associated with atten-
tional dysfunction and underlying frontal activation, but not
dementia risk (Williams-Gray et al., 2008).
64.4 DEMENTIA
64.4.1 EPIDEMIOLOGY OF DEMENTIA
IN PD
Dementia develops in a considerable proportion of patients
with PD. In a systematic review including 13 studies with
1767 patients, a point prevalence of 31.3% (95% confidence
interval 29.2–33.6), was found, and between 3% and 4% of
patients with dementia in the general population were due to
PD, with an estimated prevalence of PDD in the general pop-
ulation aged 65 and over of 0.3%–0.5% (Zaccai et al., 2005).
In two community-based studies, the annual incidence
was 95.3 (Aarsland et al., 2001) and 112.5 per thousand
(Marder et al., 1995), indicating that about 10% of PD
patients develop dementia per year, although during the
first years the incidence may be lower (Williams-Gray et al.,
2007). The risk for developing dementia is nearly six times
higher than in non-PD subjects (Aarsland et al., 2001). In
the Sydney study, de novo PD patients were followed for
up to 20 years, with 75% being diagnosed with dementia
in the follow-up period (Hely et al., 2008). Since differen-
tial mortality among demented and non-demented was not
adjusted for, the cumulative prevalence is likely to be even
higher. In the Stavanger study, based on a prevalence sam-
ple, the 8-year cumulative prevalence of dementia was cal-
culated to be 78% after controlling for attrition due to death
(Aarsland et al., 2003), and a high likelihood of dementia
and mortality for the higher age groups has been shown
(Buter et al., 2008).
64.5 TREATMENT OF COGNITIVE
IMPAIRMENT IN PD
The cholinergic loss in dementia in PD, an increase of mus-
carinic receptor binding (Perry et al., 1993) and less neu-
rodegenerative changes in neocortex compared with AD,
indicate that cholinergic drugs may be useful. A large-scale
placebo-controlled trial over 24 weeks showed that rivastig-
mine can improve cognition, activities of daily living and
neuropsychiatric symptoms in patients with PDD (Emre
Cognitive impairment and dementia in Parkinson’s disease 743
et al., 2004). The response is particularly marked in those
with visual hallucinations (Burn et al., 2006), and an open-
label extension study suggests sustained benefits for up to
48 weeks (Poewe et al., 2006). Similar, but somewhat less
robust findings were reported for donepezil (Dubois et al.,
2012). These findings have received further support from
meta-analyses (Rolinski et al., 2012; Wang et al., 2014) In
addition to the typical side effects including gastrointestinal
problems, worsening of tremor may occur in some patients,
but is usually mild and transient. Whereas all PD patients
with dementia should be treated with a cholinesterase
inhibitor, there is yet no convincing evidence for PD-MCI.
Changes in the glutamatergic system have been reported
in PD. Memantine, a partial N-methyl-d-aspartate (NMDA)
antagonist, suggested benefit in PDD was found to have
a significant effect in a small placebo-controlled study
(Aarsland et al., 2009), and some effect was also reported
in a larger multicentre study (Emre et al., 2010); but overall,
the evidence is inconsistent (Wang et al., 2014). Memantine
is usually well tolerated.
Neuropsychiatric symptoms such as psychosis, apathy
and depression are common in PD and are particularly
common in PDD (Aarsland et al., 2014). There is good evi-
dence for using clozapine for hallucinations, and a recent
study found effect after pimavanserin, a selective serotonin
5-hydroxytryptamine receptor 2A (5-HT2A) inverse agonist
(Cummings et al., 2014). As is the case in DLB, PD patients
are particularly sensitive to the motor but also cognitive side
effects of antipsychotic agents. There is also good evidence
for drug treatment against depression, including paroxetine,
venlafaxine and nortriptyline (Rocha et al., 2013). Non-
specific measures such as reviewing and removing drugs
that may cause worsening of cognition, that is, anticholin-
ergic agents, and treating comorbid conditions, are thus of
importance. Informing the patient and family about the risk
of progressive worsening of cognitive functioning and emer-
gence of psychiatric symptoms is also important.
64.6 CONCLUSIONS
Cognitive impairment and dementia are very common in PD
patients, with important clinical consequences for them and
their carers. Clinicians need to focus on cognitive impair-
ment and other neuropsychiatric symptoms in addition to the
motor symptoms in order to provide optimal care for patients.
The underlying aetiology and the clinical presentation of cog-
nitive impairment in PD are highly variable, and the noso-
logical classification of dementia in PD and its relationship to
other dementias, in particular DLB, is not yet clarified. The
complex clinical presentation in these frail and elderly indi-
viduals poses considerable challenges for the clinical manage-
ment. Rivastigmine is approved for treatment of dementia in
PD, and emerging evidence indicates that memantine may be
useful as well. The identification of multimodal biomarkers,
including clinical, biochemical, neuroimaging and genetic
744 Dementia
markers will provide crucial insight into the pathophysiology
of cognitive impairment in PD and future disease-modifying
therapies (Lin and Wu, 2015).
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 Part     7
Focal Dementias and Other
Neuropsychiatric Syndromes Involving
Cognitive Decline

65 Frontotemporal dementia 749

Peter J. Nestor
66 Pick’s disease: Its relationship to progressive aphasia, semantic dementia and frontotemporal dementia 759
John Hodges
67 The genetics and molecular pathology of frontotemporal lobar degeneration 771
David M.A. Mann
68 Semantic dementia 783
Julie S. Snowden and Matthew Jones
69 Primary progressive aphasia and posterior cortical atrophy 795
Jonathan D. Rohrer, Sebastian J. Crutch and Jason D. Warren
70 The cerebellum and cognitive impairment 812
Elsdon Storey and Evelyn A. Lindsay
71 Delirium: A clinical overview 823
Andrew Teodorczuk and Daniel Davis
72 Depression with cognitive impairment 832
Sarah Shizuko Morimoto, Genevieve S. Yuen, Stephen Beres and George S. Alexopoulos
73 Schizophrenia, cognitive impairment and dementia 846
Flavie Waters, Andrew Ford and Osvaldo P. Almeida
74 Dementia in intellectual disabilities 852
Jennifer Torr
75 Alcohol-related dementia and Wernicke–Korsakoff syndrome 857
Stephen C. Bowden and Simon J. Scalzo
76 Huntington’s disease 868
Phyllis Chua, Samantha Loi and Edmond Chiu
77 Uncommon dementias (including the prion diseases) 885
Matthew Jones and David Neary

Frontotemporal dementia
PETER J. NESTOR
65.1 INTRODUCTION
Clinical understanding of frontotemporal dementia
(FTD) has improved immensely over recent decades.
For instance, the entry in the 1983 edition of the Oxford
Textbook of Psychiatry for Pick’s Disease, one of the major
pathologies underpinning FTD, stated, ‘There are no
specific clinical features to separate Pick’s disease from
Alzheimer’s, and the distinction is generally made at
autopsy not in life’. In contrast to what is now known,
this statement could barely be further from the truth but
highlights that if one applies the simplistic algorithm of
noting progressive decline; falling below a cut-off on some
global measure of cognition and excluding non-degener-
ative pathologies with a brain scan, then all degenerative
dementias can seem similar.
A seminal step in putting FTD on the map as a clini-
cal diagnosis – rather than just a spectrum of pathological
diagnoses – was the publication of the Lund–Manchester
criteria (1994) that employed the term ‘frontotemporal
dementia’. Neary et al. (1998) subsequently revised these cri-
teria proposing frontotemporal lobar degeneration (FTLD)
as the umbrella term for patients presenting with any of
the recognized clinical variants. According to this system,
those with a predominantly neuropsychiatric syndrome
characterized by behavioural change were labelled ‘fron-
totemporal dementia’; the other two variants in this clas-
sification that affect language and conceptual knowledge
were labelled ‘progressive non-fluent aphasia’ and ‘semantic
dementia’, respectively – these two categories are covered in
Chapters 68 and 69.
It should be noted, however, that ‘FTD’ as a label is
used inconsistently; some follow the Neary (1998) scheme
in which FTLD is the umbrella term for the group of dis-
eases and ‘FTD’ is the syndromic subgroup with behav-
ioural changes while other use ‘FTD’ as the umbrella term
65
in which case the behavioural form is typically referred to
as ‘behavioural variant FTD’ (bvFTD). This last term was
used in the more recent diagnostic guidelines proposed by
Rascovsky et al. (2011) that unlike the earlier Neary criteria
focused exclusively on the behavioural presentation (Table
65.1) rather than FTLD as a whole. Other terms for the clini-
cal syndrome that have been used in the past include ‘fron-
tal variant FTD’ or ‘dementia of frontal type’. For simplicity,
this chapter will use the term ‘FTD’.
FTLD is unique among the neurodegenerative dementias
in that, as already shown, it is not a single clinical entity. It is
also, however, not a single pathological entity. The unifying
feature of this group of clinical syndromes and pathologies
is that they are degenerative and that they have a predilec-
tion for the frontal and rostral temporal lobes. It is also now
well recognized that FTD can coexist with amyotrophic lat-
eral sclerosis (ALS) – people initially diagnosed with ALS
can later develop FTD and vice versa or the two syndromes
can occur contemporaneously. Furthermore, in some of the
genetic forms, one can find cases with ALS and others with
FTD in the same kindred.
65.2 DEMOGRAPHICS
The age of onset of FTD typically ranges from late forties to
early sixties with a mean in the late fifties (e.g. Rascovsky
et al., 2011). Prevalence estimates suggest rates in the order
of 10–20/100,000 (Onyike and Diehl-Schmid, 2013). It is
likely to be the second commonest cause of degenerative
dementia under the age of 65 years after Alzheimer’s dis-
ease (AD). Survival estimates suggest a median of around
10 years from symptom onset (Roberson et al., 2005;
Nunnemann et al., 2011) though this may be significantly
shortened with comorbid ALS. Males and females appear to
be affected equally.
749
750 Dementia

Table 65.1 International consensus criteria for the behavioural form of FTD.
I. Neurodegenerative (must be present for a diagnosis of FTD):
A. Shows progressive decline of behaviour and/or cognition by observation or history (provided by a knowledgeable
informant)
II. Possible FTD (Three of the following must be present; symptoms must be persistent or recurring not single or rare events):
A. Early behavioural disinhibition (one of following must be present):
A.1. Socially inappropriate behaviour
A.2. Loss of manners or decorum
A.3. Impulsive, rash or careless actions
B. Early apathy or inertia (one of the following must be present):
B.1. Apathy
B.2. Inertia
C. Early loss of sympathy or empathy (one of the following must be present):
C.1. Diminished response to other people’s needs and feelings
C.2. Diminished social interest, interrelatedness or personal warmth
D. Early perseverative, stereotyped or compulsive behaviour (one of the following must be present):
D.1. Simple repetitive movements
D.2. Complex, compulsive or ritualistic behaviours
D.3. Stereotypy of speech
E. Hyperorality and dietary changes (one of the following must be present):
   E.1. Altered food preferences
E.2. Binge eating, increased consumption of alcohol or cigarettes
E.3. Oral exploration or consumption of inedible objects
F. Neuropsychological profile: executive/generation deficits with relative sparing of memory and visuospatial functions
(all must be present):
F.1. Deficits on executive tasks
F.2. Relative sparing of episodic memory
F.3. Relative sparing of visuospatial skills
III. Probable FTD (all of the following must be present):
A. Meets criteria for possible FTD
B. Exhibits significant functional decline (by caregiver report or as evidenced by Clinical Dementia Rating Scale or
Functional Activities Questionnaire scores)
C. Imaging results consistent with FTD
C.1. Frontal and/or temporal lobe atrophy on MRI or CT
C.2. Frontal and/or temporal lobe hypometabolism (PET) or hypoperfusion (SPECT)
IV. FTD with definite FTLD pathology
A. Meets criteria for possible or probable FTD
B. Histopathological evidence of FTLD on biopsy or at necropsy
C. Presence of a known pathogenic mutation
V. Exclusion criteria for FTD (A and B must be answered negatively for an FTD diagnosis. C can be positive for possible
FTD but must be negative for probable FTD):
A. Pattern of deficits better explained by other non-degenerative nervous system or medical disorder
B. Behavioural disturbance is better accounted for by a psychiatric diagnosis
C. Biomarkers strongly indicative of Alzheimer’s disease or other neurodegenerative process
Source: Rascovsky, K. et al., Brain, 134, 2456–2477, 2011.
Notes:  Note the emphasis on ‘early’ emergence of clinical features in Section II. This separates the behavioural features of FTD from those
that can occur late in the course of other degenerative dementias; the authors proposed within the first 3 years to denote ‘early’.
Abbreviations: FTD, frontotemporal dementia; MRI, magnetic resonance imaging; CT, computed tomography; PET, positron emission
tomography; SPECT, single-photon emission computed tomography; FTLD, frontotemporal lobar degeneration.

prominent early features. This contrasts to AD, for instance,

65.3 CLINICAL FEATURES
The hallmark of FTD is change in behaviour with neglect of
personal care. While such changes can accompany any form
of degenerative dementia, the key is that in FTD they are
in which behavioural symptoms occur typically later in the
course of the illness while the early clinical course is domi-
nated by cognitive difficulties.
Behavioural changes manifest as being self-centred
and mentally rigid. Disinhibition is a prominent feature

manifesting with such things as being overfamiliar with
strangers including sharing very personal information.
It can also include making embarrassing remarks such as
about the weight or appearance of others or comments of
a sexual nature. While sexually disinhibited comments are
not uncommon, it is notable that patients typically show
a lack of libido and typically do not engage in sexual acts.
Disinhibition in women with FTD can, however, make
them vulnerable to sexual advances from strange men.
Loss of empathy and failure to understand the emotional
states of others is typical; spouses often report, for instance,
that the patient appeared emotionally unaffected by a fam-
ily bereavement. In the case of serious illness in a spouse,
the patient may appear more concerned about the impact on
themselves, for instance, getting agitated about not having
their meals prepared.
Stereotypic behaviours are characteristic with the patient
developing very fixed routines such as walking precisely
the same route at the same time of day; clock-watching,
for instance, expecting to eat meals at precisely the same
time each day; hoarding useless items; checking repeatedly
that doors and windows are locked and so on. Stereotipes
in speech are also common, such as the use of repetitive
catchphrases in conversation. Becoming fixated on eating
the same types of foods is also very common. Often a prefer-
ence for sweet foods emerges that can be extreme and lead
to considerable weight gain. Excessive consumption of alco-
hol may also occur and can make care considerably more
difficult. The manner of eating is also often disturbed with
patients eating very quickly and overfilling their mouths;
having very poor table manners; taking food from the plates
of others and so on. It is not uncommon to hear relatives
complain of ‘pouching’ – i.e. overfilling the mouth such that
the cheeks bulge out like those of a hamster eating.
Apathy is possibly the most frequently reported symp-
tom, although from a diagnostic perspective it is prob-
ably the least helpful in that it is a prominent feature of all
forms of degenerative dementia as well as in depression. The
behavioural features that are most specific for FTD tend to
be stereotypic behaviours and change in food preference
(Bozeat et al., 2000).
Patients characteristically lack insight into their illness
meaning that in order to obtain a full picture of the behav-
ioural disturbance, an informant’s account, from one who
lives with the patient if at all possible, is mandatory. It is also
desirable that the informant interview takes place without
the patient – for instance while the patient has their cogni-
tive examination – as many find giving a full picture of the
manifestations of the behavioural disturbance embarrass-
ing in the patient’s presence.
Psychotic features (delusions and hallucinations) are suf-
ficiently unusual in FTD to be a prompt to consider other
diagnoses. They do, however, occur in a minority of cases
and if present, are typically associated with ubiquitin-
staining pathological inclusions such as FTD-ALS, C9orf72
mutations or fused-in sarcoma protein (FUS) pathology
(Sections 65.8 and 65.9).
Frontotemporal dementia 751
65.4 EXAMINATION
Careful observation of the patient’s behaviour during the
consultation will typically identify abnormalities. For
instance, fatuous giggling, use of stereotypic catch phrases
or echolalia; signs of disinhibition such as kissing staff
members or not respecting the personal space of others;
environment-bound behaviour such as attention shifting
to events outside a window in the street or looking over
the examiner’s shoulder at the computer monitor; impul-
siveness such as losing patience with the consultation and
leaving the room to pace the corridor or insisting that it is
time to go home. Conversely, repeatedly returning to the
room when the informant interview is taking place is also
common.
The general neurological examination is often unre-
markable, particularly in the early stages of the illness.
Primitive reflexes such as grasp and palmo-mental reflexes
are often present. To this end, it is worth noting that the lat-
ter is frequently criticized for the lack of specificity because
it is often an incidental finding in the elderly. This is not the
case in middle age, however, so should be taken seriously as
a sign of frontal pathology with patients in their fifties or
younger.
Because of the association of FTD with ALS, a careful
motor examination looking for features of the latter such
as wasting, fasciculation and brisk tendon reflexes should
always be undertaken. Extra-pyramidal signs of rigidity
and akinesia may be present, though they are usually a fairly
late feature.
65.5 NEUROPSYCHOLOGY/COGNITIVE
PROFILE
A dysexecutive syndrome is often, albeit erroneously, con-
sidered the hallmark of FTD. Although it forms an axis in
the diagnostic criteria proposed by Rascovsky et al. (2011),
it is notable that in applying these criteria, one can reach a
diagnosis of possible, probable or even definite FTD without
this neuropsychological profile; it is not a mandatory fea-
ture (Table 65.1). There has possibly been some backwards
reasoning in the belief of the primacy of a dysexecutive syn-
drome in FTD – i.e. there is frontal degeneration, therefore,
they must be dysexecutive. Empirical evidence for a focal
dysexecutive syndrome in FTD is, however, rather hard to
find. Typically, studies looking at comparisons between AD
and FTD struggle to find significant differences, even at a
group level, let alone changes that are robust enough to sup-
port an individual diagnosis.
Nevertheless, it has been proposed (Hornberger, Piguet
et al., 2010) that the best neuropsychological tests of executive
function for discriminating FTD from AD are reverse digit
span, letter fluency (generating as many words as possible
in a minute beginning with a specific letter) and the Hayling
752 Dementia
test in which subjects are presented with a sentence that has
the last word missing; this missing word is strongly implied
from the rest of the sentence, e.g. ‘Last night I watched an
interesting film on ____’ and one has to suppress the salient
urge to say ‘television’ and instead supply a word that does not
make sense.
Memory is often assumed to be relatively preserved in
FTD when compared with AD, though again, empirical
evidence indicates that this is not necessarily the case in
that FTD patients can display comparable levels of mem-
ory impairment to AD (Hornberger, Savage et al., 2010).
Memory impairment can even be the prominent early
­clinical feature, although, in such circumstances, the char-
acteristic behavioural profile may emerge later (Graham
et al., 2005).
Similar cognitive test scores between FTD and other forms
of dementia do not necessarily imply a similar neural sub-
strate for the impairment – for instance, one can score badly
on a cognitive test simply by not engaging in the task. One
often sees a rather patchy pattern of deficits across a range of
cognitive domains in FTD and one is left with the impression
that a lack of interest on the part of the patient is playing a
role. As with the clinical examination, it is the behaviour of
the patient during testing, rather than the scores themselves,
that often points to FTD: answering impulsively without
appearing to be particularly engaged in the testing; becom-
ing fixated on some tests or arbitrarily deciding to give up
for no apparent reason. In fact, distractibility means that it
is not uncommon for FTD patients to be untestable because
the simply fail to engage in any formal testing.
The reason for stressing the rather messy and haphaz-
ard approach that many FTD patients exhibit in neuropsy-
chological testing is that in this author’s experience, one
of the commonest reasons for an incorrect diagnosis of
FTD is the belief that FTD is diagnosed on the basis of a
focal dysexecutive syndrome on neuropsychological test-
ing. The problem is that so-called executive tasks, although
weighted to the frontal lobes compared with other tests,
really require the whole brain to be functioning. As such,
non-specific neurological insults typically show up with
impairments on executive tasks. In this regard, a miscel-
lany of neurological disorders can cause an apparent dys-
executive test pattern. Examples of referral to our clinic
with a previous incorrect FTD diagnosis include epilepsy,
multiple sclerosis, depression and head injury – all having
been misdiagnosed as FTD on neuropsychological grounds
in spite of a complete absence of any of the typical behav-
ioural features.
65.6 FALSE-POSITIVE DIAGNOSES
In addition to the problem of misdiagnosing FTD on the
basis of neuropsychological performance without consider-
ing the patient’s behavioural features, there is also the risk
of misdiagnosing FTD on the basis of apparent behavioural
features themselves – this scenario has often been referred
to as the FTD phenocopy syndrome.
As already discussed, one can only appreciate the full
range of behavioural changes from an informant’s testi-
mony. If one relies exclusively on the informant’s account,
however, problems can occur. There is potential for an infor-
mant to be led by probing to zealously for specific behav-
iours; particular danger arises where the diagnosis has been
suggested by a previous medical assessment and the infor-
mant, seeking information from the internet, unwittingly
fills in the blanks after reading the clinical features – for
instance, over-interpreting a request for a second slice of
birthday cake as sustained emergence of a sweet food prefer-
ence and so on. Although these issues can exaggerate symp-
toms to give a false impression of FTD, they cannot explain
what brings such patients to medical attention in the first
place, and therefore, what their actual diagnosis might be.
Patients with an apparent phenocopy of FTD are typically
male, have good cognitive performance, normal imaging
and remain stable over time (Kipps et al., 2009). It appears
that the answer is likely to be multifactorial with person-
ality traits, relationship problems and life events being the
most important factors (Gossink et al., 2016).
To ensure that a false-positive diagnosis is not made, one
should consider the informant-based symptom profile as
mandatory but not rely on it exclusively. It must be supple-
mented by empirical evidence – does the patient behave like
someone with FTD in the consulting room (Section 65.4)?
Do they have imaging features of FTD (Section 65.7.1)? Is
there evidence of impairment on cognitive testing, accept-
ing the caveat that this will typically not take the form of
an isolated dysexecutive syndrome (Section 65.5)? One
further caveat is that patients with the C9orf72 mutation
(Section 65.9.1) can have a very indolent disease with unre-
markable imaging (Devenney et al., 2014). Also, as with all
forms of degenerative dementia, sometimes it can be diffi-
cult to decide in the early stages and, in such circumstances,
­evidence of progression with longitudinal follow-up is the
key – to this end, evidence of progressive decline on cogni-
tive testing is particularly useful.
65.7 INVESTIGATIONS
65.7.1 IMAGING
Structural and nuclear imaging can be particularly ­helpful
in FTD (Varma et al., 2002). A pattern of d ­ isproportionate
frontal and rostal temporal lobe atrophy has diagnostic pre-
dictive value for FTLD in general, t­ ypically with the empha-
sis being on the frontal lobes in FTD. Atrophy is often gross
and unmistakable, but even in more subtle degrees, a clear
pattern of disproportionate frontal atrophy – compared
with occipito-parietal regions – is evident (Figure 65.1).
Magnetic resonance imaging is the preferred modality but
computerized tomography is often adequate.
 Frontotemporal dementia 753

Figure 65.1 Magnetic resonance imaging (MRI) scan in frontotemporal dementia (FTD) showing frontal atrophy with
relative preservation of posterior regions. On the sagittal image, this gradient is clearly seen with the widening of sulci
rostrally (i.e. more cerebrospinal fluid [CSF]) that is not evident in occipital lobe and precuneus. Note also the patient had
hippocampal atrophy (arrows) – this is quite typical in FTD and highlights that a cursory inspection of the medial temporal
lobes in isolation could mislead the viewer to think of Alzheimer’s disease.

In cases where the structural imaging findings are equiv-
ocal, nuclear imaging with fluorodeoxyglucose positron
emission tomography (FDG-PET) will often show meta-
bolic changes in the frontal lobes (Figure 65.2). Cerebral
perfusion imaging with hexamethylpropyleneamineoxime
(HMPAO)-single-photon emission computed tomography
(SPECT) can also be useful in this setting though it is less
sensitive than to FDG-PET.
Completely normal imaging, particularly a normal FDG-
PET, should make one very cautious about diagnosing FTD.
65.7.2 MISCELLANEOUS INVESTIGATIONS
It has been known for many years that visual reading of
electroencephalography (EEG) is essentially unremarkable
in FTD (e.g. Neary et al., 1988) – in particular, there is per-
severation of the occipital alpha rhythm. EEG still occasion-
ally has a role, in that, suspected FTD with an abnormal
EEG should prompt a search for other causes (Figure 65.3).
Electromyography is often indicated to exclude/confirm
denervation related to ALS. Cerebrospinal fluid, although
now a routine investigation in many places as a marker of
Alzheimer pathology, has not yet become a standard clini-
cal investigation to support a positive diagnosis of FTD.
Genetic testing is often highly relevant in FTD; the known
mutations are discussed further in Section 65.9.
65.8 PATHOLOGY
Atrophy is most evident in frontal and rostral temporal
lobes with neuronal loss predominantly in the superficial
cortical layers (see Chapter 67 for an in-depth discussion).
Histopathologically, FTD is associated with either tau-pos-
itive inclusions or inclusions staining with ubiquitin. These
two histopathologies occur with approximately equal fre-
quency in FTD (e.g. Rohrer et al., 2011); in sporadic disease,
it is usually impossible to predict whether a patient will have
tau or ubiquinated inclusions in life. The key exception to
this is FTD with clinically manifesting ALS where pathol-
ogy is always tau-negative/ubiquitin positive.
Tau-positive (FTLD-tau) pathology can be subdivided
by the number of microtubule-binding domains in the pro-
tein into three-repeat (3R) or four-repeat (4R) pathologies.
The major forms of FTLD-tau include Pick’s disease (3R)
(Chapter 66), those with tau mutations (3R and 4R) and,
rarely, argyrophilic grain disease (4R). The tauopathies, cor-
ticobasal degeneration and progressive supranuclear palsy
pathology (both 4R) can also be found occasionally in cases
that were diagnosed as FTD in life, though these patholo-
gies are more commonly noted with non-fluent aphasic pre-
sentations of FTLD (Josephs et al., 2011).
FTD with ubiquitin-staining inclusions was typically
referred to as FTLD-U until the substrate to which the
stain bound was identified. It was subsequently discov-
ered that, in the vast majority, this was a transactive
response DNA-binding protein 43 (TDP-43) pathol-
ogy (Neumann et al., 2006). TDP-43 pathology (FTLD-
TDP) is, in turn, divided into subtypes (A–D) based on
the histological pattern (Mackenzie et al., 2011), although
interrater agreement for subtype classification can be
somewhat variable (Alafuzoff et al., 2015). Clinical FTD
is mostly associated with types A and B, the latter being
typical of FTD-ALS. Type D is specifically designated for
754 Dementia

Figure 65.2 (See colour insert.) Fluorodeoxyglucose positron emission tomography (FDG-PET) scan from a patient with
FTD whose structural imaging did not show convincing evidence of disproportionate frontal atrophy. Note the clear evi-
dence of asymmetric frontal hypometabolism (arrows).

(a)

(b)

(c)

Figure 65.3 (See colour insert.) Use of electroencephalography (EEG) in the investigation of suspected FTD. This 63-year-
old male presented with marked changes in personality and comportment, typical of those seen in FTD, that had evolved
over the preceding 8 months. FDG-PET, shown as a parametric map of hypometabolism (a), revealed a marked prefrontal
hypometabolism. His EEG was grossly abnormal with a considerable delta-wave activity (b). This is not compatible with
FTD. His diagnosis was presumed to be an autoimmune encephalitis, and after treatment with high-dose methylpredniso-
lone both his FTD-like behavior and EEG (c) improved dramatically.

the pathology of Valosin-containing protein (VCP) gene
mutations (Section 65.9.6).
Following the discovery of TDP-43, it was noted that
not all FTLD-U cases had this pathology. A minority that
were negative for TDP-43 were designated atypical FTLD-U
(aFTLD-U) and were found subsequently to have FUS
pathology (Neumann et al., 2009). In a pathological series
of FTD, it has been estimated that about 5% have FUS and
in a clinical series of FTD possibly around 3% (Snowden
et al., 2011). FUS pathology, in turn, also has two further
pathological variants – neuronal intermediate filament
inclusion disease (NIFID) and basophilic inclusion body
disease (BIBD) both of which can be associated with FTD.
Collectively, the FUS-related pathologies are designated
FTLD-FUS (Mackenzie et al., 2010). Aside from FTLD-TDP
and FTLD-FUS, there remain rare cases with ubiquitin-
binding pathology that has neither TDP-43 nor FUS as its
substrate; these are designated FTLD-ubiquitin proteasome
system (FTLD-UPS) (Mackenzie et al., 2010). The pathology
associated with the charged multivesicular body protein 2B
(CHMP2B) mutation (Section 65.9.7) is an example of this.
Finally, cases may exhibit frontotemporal neurode-
generation with no specific histological inclusions. This
is referred to as dementia lacking distinctive histology
(DLDH) and was more commonly reported in the era before
routine staining for ubiquitin inclusions – in other words,
the majority of such cases in the historical literature likely
had a form of FTLD-U but without the appropriate stains to
identify them as such. Nevertheless, there probably remains
a small number that have DLDH (Cairns et al., 2007).
65.9 GENETICS
Compared with other degenerative dementias, there is an
increased likelihood of monogenetic mutations causing
FTD. That said, it is difficult to put a precise figure on genetic
prevalence because most estimates have come from regional
samples, often from a single centre; there is quite possibly also
a reporting bias in that regions with a few genetic cases might
be less likely to publish prevalence data. Estimates of preva-
lence typically are of the order of 20%–30%. Notably, the
FTD phenotype, as opposed to the language presentations of
FTLD, is most likely to occur with an autosomal-dominant
mutation (Rohrer et al., 2009). Given that FTD is relatively
less common compared with AD and that only a minority
of cases appear to have autosomal-dominant disease, even
a single large kindred in a clinical catchment area can skew
estimates of genetic prevalence. In contrast, it is often the case
that an individual clinic may have very few or even no genetic
cases based on the genetic epidemiology of the region.
Genetically determined disease should always be consid-
ered when assessing a patient with FTD, and, obviously, the
greatest clue is family history. To this end, it is important to
consider that with late-onset dementia – of any type – being so
common, many will have an apparently positive family history
Frontotemporal dementia 755
for dementia that is not necessarily relevant to FTD. On the
other hand, if FTD was present in previous generations, it is
unlikely to have been diagnosed as such. Enquiring specifi-
cally about the age of onset and symptoms, if known, can be
particularly useful pointers to suggest a forebear had FTD.
Of the current known genes, the chromosome 9 open
reading frame 72 (C9orf72) mutation is probably the most
prevalent cause of familial FTD. Tau and progranulin (PGRN)
mutations are also important causes though there appears,
from reported series, to be considerably more geographical
variability in their occurrence. Several further gene muta-
tions, namely TAR DNA-binding protein (TARDBP), VCP
and CHMP2B, have been associated with FTD but appear
to be very rare. The pathology of tau mutations is obviously
FTLD-tau, all of the remainder have FTLD-TDP with the
exception of CHMP2B that is FTLD-UPS (see Section 65.8).
Several studies have looked for differences between the
genetic forms of FTD in clinical profile, imaging and so on.
The following list highlights some of the key clinical features
to consider as ‘red flags’ that relate to specific mutations.
65.9.1 C9orf72 (CHROMOSOME 9)
This hexanucleotide repeat expansion (DeJesus-Hernandez
et al., 2011; Renton et al., 2011) is also associated with ALS.
ALS can coexist with FTD in the same patient or can exist
in the kindred simply as ALS. The presence of ALS in the
kindred of a patient with FTD makes this mutation highly
likely. Another feature of this mutation is that although cases
typically display the poor prognosis of FTD and ALS, reports
are emerging of very slowly progressive cases with disease
duration exceeding two decades (e.g. Suhonen et al., 2015).
65.9.2 TAU (CHROMOSOME 17)
When this mutation was first discovered, emphasis was
placed on the coexistence of FTD with parkinsonism
(FTDP-17) (Hutton et al., 1998). Parkinsonism, particularly
occurring later in the disease course, is not uncommon in
clinical FTD in general and so is probably not particularly
helpful in making a specific pathologic or genetic prediction.
More relevant to clinical dementia differential diagnosis,
however, is that tau mutations can present with prominent
memory disturbance and profound hippocampal atrophy
making it easy to mistake this mutation for AD.
65.9.3 PGRN (CHROMOSOME 17)
These mutations (Baker et al., 2006; Cruts et al., 2006) are
typically not associated with a sufficiently unique pheno-
type to separate it from FTD in general. Visual hallucina-
tions have been reported in up to 25% of cases (Le Ber et al.,
2008), so if present, these offer a possible clue being so rare
in FTD otherwise. Marked hemispheric asymmetry of atro-
phy pattern has also been emphasized in some studies (Le
Ber et al., 2008; Rohrer et al., 2010), though this is, arguably,
not uncommon in FTD in general.
756 Dementia
65.9.4 FUS (CHROMOSOME 16)
These mutations have been identified in ALS without
dementia (Vance et al., 2009), convincing evidence that
such mutations can also cause FTD remains to be estab-
lished. Nevertheless, it is included here because FUS pathol-
ogy (aFTLD-U) – without a FUS gene mutation – is seen in
FTD and has some distinctive clinical features (Neumann
et al., 2009). This pathology is associated with a very young
onset FTD, typically in the thirties and forties, markedly
ritualistic/stereotypic behaviour and a relatively high preva-
lence of psychotic delusions and hallucinations (MacKenzie
et al., 2008; Snowden et al., 2011).
65.9.5 TARDBP (CHROMOSOME 1)
These mutations, first identified in ALS (Sreedharan et al.,
2008), can be associated with ALS/FTD (e.g. Chiò et al.,
2010), though from the number of reported cases this
appears to be a rare cause of FTD. In addition to FTD, lan-
guage disorders have been reported though it appears that
behavioural disturbance is the norm (Floris et al., 2015).
65.9.6 VCP (CHROMOSOME 9)
Mutations in this gene give rise to a phenotype of FTD with
inclusion body myopathy and Paget’s bone disease (Watts
et al., 2004).
65.9.7 CHMP2B
This mutation (Skibinski et al., 2005) located on chromo-
some 3, and thus known as FTD-3 prior to the gene dis-
covery, is essentially restricted to a large kindred from the
Jutland peninsula of Denmark.
65.10 TREATMENT
Treatment of FTD is supportive in that there are no evi-
dence-based treatments that change the course of the ill-
ness. A clinical psychologist with experience of FTD can be
an invaluable asset both to support the caregiver but also
to offer behavioural strategies that minimize the burden of
care. In particular, environmental manipulations aimed at
minimizing burden of care by reducing the impact of stim-
ulus-bound behaviour can be useful. This can even include
exploiting stimulus-bound behaviour for a positive out-
come – for instance, by setting out potential activities, such
as placing broom in the middle of a room, a patient may
start sweeping and so on.
There is no evidence that the drugs licensed for the
­treatment of AD, cholinesterase inhibitors and meman-
tine, offer benefit in FTD. Memantine, in particular,
was the s­ubject of the largest placebo-controlled trial of
a symptomatic therapy in FTD to date, and the results
were entirely negative (Boxer et al., 2013). Although
­placebo-controlled trial evidence is largely lacking, selec-
tive serotonin reuptake inhibitor (SSRI) medications are
often prescribed to deal with disturbing behaviours. In a
small randomized, placebo-controlled trial, trazodone was
associated with some improvements in behaviour (Lebert
et al., 2004), while another using paroxetine showed no
benefit (Deakin et al., 2004). Anecdotally, low-dose topira-
mate may be ­useful to ameliorate abnormal eating behav-
iour (Nestor, 2012).
65.11 CONCLUSIONS
FTD is an important form of dementia in, predominantly,
middle age. The massive impact it has on personality and
behaviour make it, arguably, the most distressing of the
degenerative dementias in terms of caregiver burden. The
relative youth of patients combined with the non-cognitive
disturbances of FTD are a major challenge to support ser-
vices that are typically geared to older patients and cogni-
tive manifestations.
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Pick’s disease: Its relationship to progressive
aphasia, semantic dementia and
frontotemporal dementia
JOHN HODGES
66.1 INTRODUCTION
Considerable advances continue to be made in our under-
standing of the group of neurodegenerative diseases that
present itself with focal cognitive deficits arising from cir-
cumscribed pathology of the frontal and/or temporal lobes,
most commonly referred to collectively as Pick’s disease
(PiD) or frontotemporal dementia (FTD). However, the lit-
erature on these conditions is filled with a confusing pleth-
ora of terms, which can make these developments difficult
to follow for the non-expert. Central to this problem is a
lack of clarity as to the intended level of description (clinical
syndrome versus clinicopathological entity versus specific
histological diagnosis) and a lack of concordance between
these levels. For example, while some labels denote a clini-
cal syndrome without specific histological implications
(e.g. progressive aphasia, semantic dementia or dementia
of frontal type), others denote specific neuropathological
entities (e.g. PiD or familial tauopathy), hybrid clinico-
pathological entities (e.g. FTD) or even specific genetic dis-
orders (e.g. FTD with parkinsonism linked to chromosome
17). Recent differences in opinion over terminology are
well illustrated by the titles of the following books, all pub-
lished in the last decade: Pick’s Disease and Pick Complex
(Kertesz and Munoz, 1998), Frontotemporal Dementia
(Pasquier et al., 1996), Fronto-Temporal Lobar Degeneration:
Fronto-Temporal Dementia, Progressive Aphasia, Semantic
Dementia (Snowden et al., 1996) Frontotemporal Dementia
Syndromes (Hodges, 2007). This lack of clarity is acknowl-
edged and efforts to rationalize terminology and achieve
clinicopathological and nosological consensus have been
66
made (Brun et al., 1994; Neary et al., 1998; McKhann et al.,
2001; Kertesz et al., 2003b).
The aims of this chapter are to review the evolution of
the terms used to describe this spectrum of disorders, to
highlight recent advances and examine areas of continuing
controversy. While my own bias is to prefer the term PiD for
this group of disorders – which is more readily understood
by carers and parallels our use of the label Alzheimer’s dis-
ease (AD) – the current tide of opinion is to use FTD as an
umbrella term for the overall clinical syndrome.
66.2 WHAT DID PICK ACTUALLY
DESCRIBE?
In 1892, Arnold Pick, working in Prague, reported a
71-year-old man with progressive mental deterioration and
unusually severe aphasia, who at post-mortem had marked
atrophy of the cortical gyri of the left temporal lobe (Pick,
1892; Girling and Berrios, 1994). Pick wanted to draw atten-
tion to the fact that local accentuation of progressive brain
atrophy may lead to symptoms of local disturbance (in
this instance aphasia). He also made specific predictions
regarding the role of the mid-temporal region of the left
hemisphere in the representation of word meaning. In sub-
sequent papers, he described four further patients with left
temporal atrophy (Girling and Berrios, 1997) or frontotem-
poral atrophy (Pick, 1901; Girling and Markova, 1995). It
was only in his 1906 publication that Pick turned his atten-
tion to bilateral frontal atrophy with resultant behavioural
disturbance.
759
760 Dementia
Several points should be emphasized, which is as follows:
●● Pick’s primary interest in these patients was their
language disorder, particularly, the clinicoanatomical
correlates of aphasia.
●● He did not claim to have discovered a new disease,
merely novel phenomena arising from asymmetric
degeneration.
●● He did not describe distinct neuropathological changes
in his patients with focal atrophy.
●● Both the major syndromes now included under the
rubric of FTD (dementia of frontal type and semantic
dementia) were clearly reported by Pick.
In view of these monumental contributions, it is sad that
Pick has been relegated to a minor place in the modern ter-
minology of FTD.
The histological abnormalities associated with PiD were,
in fact, described a few years later by Alzheimer (1911) who
recognized changes distinct from those found in the form
of cerebral degeneration later associated with his name.
Alzheimer recognized both argyrophilic intracytoplasmic
inclusions (Pick bodies) and diffusely staining ballooned
neurones (Pick cells) in association with focal lobar atro-
phy. A comprehensive review of 20 patients with the litera-
ture of aphasia due to focal lobar atrophy written soon after
Alzheimer’s description (Mingazzini, 1914), did not use the
label PiD, which was introduced by Gans some 8 years later
(Gans, 1922). The term was then taken up by Onari and
Spatz (1926), but Carl Schneider (1927) is probably most
responsible for its popularization.
Unfortunately, however, Schneider concentrated on the
frontal lobe component of the syndrome and thus began
the neglect of the temporal lobe syndromes. He distin-
guished three clinical phases, the first characterized by
impaired judgement and behaviour, the second by local
symptoms and the third by generalized dementia. Many
papers describing PiD then appeared in the 1930s and
1940s, which again mainly focused on the frontal lobe
aspects of the disorder.
After World War II, interest in PiD faded, together with
a general waning of interest in the cognitive aspects of
neurology. The focus of interest in English language pub-
lications became the neuropathology and later the genet-
ics of PiD. This resulted in a gradual change in the criteria
for PiD, which evolved to include the necessity for specific
pathological changes (i.e. focal atrophy with Pick cells and
or Pick bodies). Indeed, some authors went as far as to claim
that AD and PiD were clinically indistinguishable in one’s
lifetime (Katzman, 1986). In continental Europe, however,
there remained a strong interest in the clinical phenomena
of the dementias; PiD remained an in vivo diagnosis based
on a combination of clinical features suggestive of frontal
and/or temporal lobe dysfunction and focal lobar atrophy
(Mansvelt, 1954; Tissot et al., 1975). This controversy con-
tinues and has contributed to the adoption of the many
labels to describe patients with the clinical syndrome of
progressive frontal or temporal lobe degeneration (Baldwin
and Förstl, 1993).
66.3 REDISCOVERING PID: FROM
DEMENTIA OF THE FRONTAL
TYPE AND PROGRESSIVE
APHASIA TO FTD
66.3.1 DEMENTIA OF FRONTAL TYPE
A renaissance of interest in the focal dementias occurred
in the 1980s. Workers from Lund (Brun, 1987; Gustafson,
1987) reported on a large series of patients with frontal lobe
degeneration out of which only a small proportion of whom
had Pick cells and Pick bodies – the remainder had very
similar findings but without specific inclusions (i.e. focal
lobar atrophy with severe neuronal loss and spongiosis) –
the Lund group preferred to adopt the term ‘frontal degen-
eration of non-Alzheimer type’. At approximately the same
time, Neary et al. (1986) in Manchester began a series of
important clinicopathological studies of patients with pre-
senile dementia. They, likewise, found a high proportion
of cases with a progressive frontal lobe syndrome that had
neither specific changes of AD (plaques and tangles) nor
specific Pick pathology. They introduced the term ‘demen-
tia of frontal type’. Over the next few years other groups
described very similar cases under the labels ‘frontal lobe
degeneration’ (Miller et al., 1991) and ‘dementia lacking
distinct histological features’ (Knopman et al., 1990). My
own preferred term for this group of patients is behavioural
variant of FTD (bvFTD). (Davies et al., 2006; Kipps et al.,
2007; Rascovsky et al., 2007; Hornberger et al., 2008; Kipps
et al., 2009a).
In the advanced stages of the disease, patients with this
disorder present no diagnostic difficulty. They have the triad
of the following:
●● A profound change in personality and behaviour
●● Neuropsychological impairments indicative of selective
or disproportionate frontal pathology
●● Appropriate changes on structural and/or functional
brain imaging
Diagnosing early cases is by no means easy and one of
the challenges is to develop better methods of early, accurate
detection (Gregory et al., 1999). Since patients are typically
unaware of the insidious changes noted by others, we rely
upon carer-based assessments. One undoubted advance in
the area has been therefore, the development of standard-
ized carer interviews such as the Neuropsychiatric Inventory
(Cummings et al., 1994), the Cambridge Behavioural
Inventory (Wedderburn et al., 2008) and the Frontal
Behaviour Inventory (Kertesz et al., 1997, 2000, 2003a). Recent
 Pick’s disease: Its relationship to progressive aphasia, semantic dementia and frontotemporal dementia 761
work has focused on specific behaviours that can discriminate
patients with bvFTD and semantic dementia from patients
with AD, such as disinhibition, loss of empathy, changes in
appetite, food preferences and eating habits (Ikeda et al.,
2002) or the presence of stereotypes (Nyatsanza et al., 2003).
An international effort has culminated in the publication
of consensus guidelines for the diagnosis of bvFTD, which
appear to be robust (Rascovsky et al., 2011).
Many patients with bvFTD, who visit psychiatrists,
acquire a label of functional psychiatric disorder (including
simple schizophrenia, depression and obsessive-compul-
sive disorder) because despite gross behavioural changes
other aspects of cognition are typically preserved (Ames
et al., 1994; Gregory and Hodges, 1996; Miller et al., 1997).
This is understandable in terms of the site of pathology
in bvFTD, the orbital and mesial frontal lobes, which are
critically involved in social judgement, motivation, risk
assessment and compulsive behaviour (Cummings, 1999).
By contrast, dorsolateral frontal regions, which have been
the focus of classic neuropsychological studies, are spared
in the early stages of the disease. The development of
quantifiable tasks sensitive to orbital and mesial frontal
function has begun with paradigms involving probability
and gambling (Rogers et al., 1998; Rahman et al., 1999),
emotion processing (Keane et al., 2002; Piguet et al., 2011;
Kumfor et al., 2013) and ‘theory of mind’ (ToM) tasks,
such as detection of social faux pas (Gregory et al., 2002;
Torralva et al., 2007) and the discrimination of sincere
from sarcastic statements (Kipps et al., 2009b; Rankin
et al., 2009).
An important recent development has been the identi-
fication of a subgroup of patients with clinical features of
bvFTD who show little or no progression, often over many
years of follow-up (Davies et al., 2006; Kipps et al., 2007,
2008). Such patients are almost universally men and can
be distinguished on the basis of a number of factors: nor-
mal performance on executive and social cognition tasks
(Hornberger et al., 2008; Kipps et al., 2009b), preserva-
tion of activities of daily living (Mioshi and Hodges 2007;
Mioshi et al., 2007), absence of brain atrophy on magnetic
resonance imaging (MRI) (Davies et al., 2006; Kipps et al.,
2009a) and normal fluorodeoxyglucose-positron emission
tomography (FDG-PET) (Kipps et al., 2009b). The aetiol-
ogy of the so-called bvFTD phenotype syndrome remains
unclear. A small proportion of such patients have the newly
discovered C9orf72 mutation (discussed in Section 66.4)
while others have decompensated personality disorders or
functional psychiatric disorders but much work remains to
be done in this area.
66.3.2 PROGRESSIVE APHASIA AND
SEMANTIC DEMENTIA
The other strand of the story concerns the rediscovery of the
syndrome of progressive aphasia in association with focal
left perisylvian or temporal lobe atrophy. In 1982, Mesulam
reported six patients with a long history of insidiously wors-
ening aphasia in the absence of signs of more generalized
cognitive failure. One of these patients underwent a brain
biopsy, which revealed non-specific histology without spe-
cific markers of either AD or PiD. Following Mesulam’s
seminal paper, approximately 100 patients with progressive
aphasia were reported over the next 15 years (for reviews
see: Mesulam and Weintraub, 1992; Hodges and Patterson,
1996; Snowden et al., 1996; Garrard and Hodges, 1999).
From this literature, it became clear that, although the lan-
guage impairment in patients with progressive aphasia is
heterogeneous, there are two identifiable and distinct apha-
sia syndromes: progressive non-fluent aphasia and progres-
sive fluent aphasia. In the latter syndrome, speech remains
fluent and well-articulated but becomes progressively devoid
of content words. The language and other non-verbal cogni-
tive deficits observed in these patients reflect a breakdown
in semantic memory that has led many authors to apply the
label of ‘semantic dementia’ (Snowden et al., 1989; Hodges
et al., 1992, 1994; Saffran and Schwartz, 1994; Hodges and
Patterson, 1996).
Although, the term ‘semantic dementia’ is recent, the
syndrome has, as discussed above, been recognized under
different labels for many years. Pick (1892) and Warrington
(1975) were the first to clearly delineate the syndrome of
semantic memory impairment in recent times. Drawing on
the work of Tulving (1972, 1983), Warrington recognized
that the progressive anomia in her patients was not sim-
ply a linguistic deficit, but reflected a fundamental loss of
semantic memory (or knowledge) about the items, which
thereby affected naming, word comprehension and object
recognition. Semantic memory is the term applied to the
component of long-term memory that contains the perma-
nent representation of our knowledge about things in the
world and their interrelationship, facts and concepts as well
as words and their meaning (Hodges et al., 1992; Garrard
et al., 1997; Hodges and Patterson, 1997; Hodges et al., 1998).
Cases of semantic dementia have also been recognized for
many years in Japan as cases of ‘gogi (word meaning) apha-
sia’ (Tanabe et al., 1992).
Our original paper reported five cases with progres-
sive loss of semantic memory and focal temporal atrophy
(Hodges et al., 1992). All five presented a fluent aphasia
and all the characteristics of semantic memory loss: empty
speech with word-finding difficulty and occasional seman-
tic paraphasias (mother for father), a severe reduction in
the generation of exemplars on category fluency tests (in
which subjects are asked to produce as many examples as
possible from defined semantic categories, such as animals
or musical instruments, within 1 minute), impaired single
word comprehension on picture-pointing tests, a loss of
fine-grained attribution knowledge about a range of items
with preservation of broad superordinate information on
verbal and pictorial tests of knowledge. By contrast, other
aspects of language competency (phonology and syntax)
were strikingly preserved. In contrast to AD, the patients
762 Dementia
also had good day-to-day (episodic) memory, although
more recently it has been shown that this sparing of auto-
biographical memory applies to fairly recent memories only
(Graham and Hodges, 1997; Hodges and Graham, 1998;
Irish et al., 2011). They also showed no impairment on tests
of immediate (working) memory, visually based problem-
solving or visuoperceptual abilities. Four out of the five
patients showed severe and circumscribed temporal lobe
atrophy on computed tomography (CT) or MRI scanning.
Since 1992, we have studied many such patients further and
have confirmed the association of the temporal lobe with
focal atrophy – involving the temporal pole and inferolateral
neocortex (particularly, the perirhinal cortex and fusiform
gyrus). In many cases, the atrophy is strikingly asymmetric,
involving the left side predominately (Hodges et al., 1998;
Garrard and Hodges, 1999; Mummery et al., 1999; Galton
et al., 2001; Hodges and Patterson 2007).
This raises the following question: what are the
cognitive and/or behavioural signatures of isolated right
temporal atrophy? In 1994, we reported a patient who
suffered from visual hallucination (VH), with progres-
sive prosopagnosia, followed by a specific loss of knowl-
edge about people (Evans et al., 1995). This VH patient
was unable to identify even very famous people from their
face or name, yet had intact general semantic and autobio-
graphical memory (Kitchener and Hodges, 1999). A more
recent study (Thompson et al., 2004) reported a dissocia-
tion of person-specific from general semantic knowledge
in two patients with contrasting patterns of temporal atro-
phy. Subject MA, with predominantly left temporal atro-
phy, showed impairment of general semantics with relative
preservation of knowledge about people, while subject JP,
with predominantly right temporal atrophy, showed the
opposite pattern of impairments with severely impaired
person-specific knowledge in the context of relatively pre-
served knowledge about objects and animals. The group led
by Miller have also drawn attention to the bizarre behav-
iours (including irritability, impulsiveness, alterations in
dress, limited and fixed ideas and decreased facial expres-
sion) exhibited by patients with predominantly right tem-
poral lobe atrophy (Edwards Lee et al., 1997; Miller et al.,
1997). A recent review of 47 patients with semantic demen-
tia identified distinct behavioural and cognitive profiles
associated with the left and right temporal variants of the
disease (Thompson et al., 2003). Social awkwardness, job
loss, lack of insight and difficulty with person identifica-
tion were all more likely to be associated with major right
temporal atrophy, whereas word-finding difficulties and
reduced comprehension were all more likely to be associ-
ated with predominantly left-sided atrophy.
There are a number of compelling reasons to consider
semantic dementia as part of the same disease spectrum as
bvFTD. The first is pathological: the majority of cases with
semantic dementia have deposition of TAR-DNA-binding
protein-43 (TDP-43), which constitutes the pathological
variants of FTLD is also found in a proportion of those with
behavioural presentations of FTD and in motor neurone
disease (MND) (Chare et al., 2014). Second is the evolution
of the pattern of cognitive and behavioural changes over
time: although semantic dementia patients present with pro-
gressive anomia and other linguistic deficits, on follow-up
show emergence of the features that characterize the frontal
form of FTD (Hodges and Patterson, 1996; Edwards Lee et
al., 1997). Indeed, semantic dementia and bvFTD may share
many behavioural features even on presentation (Bozeat et al.,
2000). Third, the fact that modern neuroimaging techniques
demonstrate subtle involvement of the orbitofrontal cortex in
the majority of cases presenting prominent temporal atrophy
and semantic dementia (Mummery et al., 2000; Rosen et al.,
2002a; Williams et al., 2005) needs to be acknowledged.
The status of patients with the non-fluent form of pro-
gressive aphasia within the spectrum of FTD is more com-
plex. Clinically, such cases are clearly separable from cases
of semantic dementia. Speech is faltering and distorted
with frequent phonological substitutions and grammatical
errors in such cases. Other non-language-based aspects of
cognition remain well preserved, as do activities of daily liv-
ing. Changes in behaviour and personality of the type that
typify dementia of frontal type are seen in the later stages
of semantic dementia, but are rare after a number of years
when global cognitive decline occurs (Green et al., 1990;
Hodges and Patterson, 1996). Some patients with progres-
sive non-fluent aphasia have Alzheimer pathology at post-
mortem, albeit with an atypical distribution; that is to say
marked involvement of perisylvian language areas but
sparing of medial temporal structures (Greene et al., 1996;
Galton et al., 2000; Knibb et al., 2006) occurs, while oth-
ers have tau-positive inclusion pathology with classic Pick
bodies or more diffuse neuronal and glial tau inclusions.
(Weintraub et al., 1990; Mesulam and Weintraub, 1992;
Knibb et al., 2006). Recent functional neuroimaging stud-
ies have implicated the anterior insula as the key abnormal
region (Nestor et al., 2003).
A potentially important recent development has been
the separation of non-fluent aphasic patients into two sub-
groups. The first group was characterized by apraxia of
speech and/or agrammatism in association with left interior
frontal lobe and insular atrophy and underlying FTD tau
pathology. The second group had severe anomia, dysfluency
because of word-finding pauses, occasional phonological
errors and markedly impaired sentence repetition that have
been termed logopenic progressive aphasia with emerging
evidence of largely AD pathology at post-mortem or on
amyloid-based PET imaging (Gorno-Tempini et al., 2008;
Mesulam et al., 2008; Leyton et al., 2011).
66.4 FAMILIAL FTD
The story of the chromosome 17 linkage is extraordinary
in a number of ways. Families around the world with what
has become to be known as FTD with parkinsonism linked
to chromosome 17 (FTDP-17) (Spillantini et al., 1998a)
 Pick’s disease: Its relationship to progressive aphasia, semantic dementia and frontotemporal dementia 763
had originally been reported under a range of headings
including: disinhibition–dementia–parkinsonism–amyotro-
phy complex (DDPAC) (Wilhelmsen et al., 1994), rapidly pro-
gressive autosomal dominant parkinsonism and dementia
with pallido-ponto-nigral degeneration (Wszolek et al., 1992),
familial progressive subclinical gliosis (Petersen et al., 1995),
hereditary dysphasic disinhibition dementia (Morris et al.,
1984), hereditary FTD (Heutink et al., 1997), multiple system
tauopathy with presenile dementia (Spillantini et al., 1997),
familial presenile dementia with psychosis (Sumi et al., 1992)
and PiD (Schenk, 1951). In 1996, a meeting of representatives
from all of the groups identifying linkage to chromosome 17
was held in Ann Arbor, MI (Foster et al., 1997). Comparison of
clinical and pathological data revealed a great deal of similar-
ity between the families who all shared the characteristics of
predominately frontotemporal distribution of pathology with
marked behavioural changes. Extrapyramidal dysfunction
was present in most. In some families, psychotic symptoms
were a major feature and a number of them had amyotrophy.
It was recognized at that time that some of the families shared
the common pathology with microtubule-associated protein
(MAP) tau-positive inclusions. Progress in this field then
became rapid. It was soon discovered that, most, if not all,
families had tau inclusions with a distinctive morphological
pattern leading to the coining of the term ‘familial tauopathy’
and the suggestion that the disease might reflect a mutation
in the tau gene known to be located in the 17q21–22 region
(Spillantini et al., 1998a). Within 2 years of the Ann Arbor
meeting, the first mutations were identified (Dumanchin
et al., 1998; Hutton et al., 1998; Poorkaj et al., 1998; Spillantini
et al., 1998b). Subsequent progress has been rapid: more than
50 different tau mutations have been reported in association
with familial FTD, differing according to their positions in
the tau gene, their effects on tau messenger RNA (mRNA)
and protein and the type of tau pathology they cause (Ingram
and Spillantini, 2002).
Not all cases of familial FTD are caused by tau muta-
tions. In one large Danish family with autosomal dominant
FTD, linkage has been established to chromosome 3 (Brown
et al., 1995; Brown, 1998) and, in some families with FTD-
MND, linkage has been established to chromosome 9. In
a series of 22 cases of familial FTD only, 11 (50%) had tau
mutations (Morris et al., 2001).
In 2006, another major breakthrough established muta-
tions of the progranulin gene also on chromosome 17, which
results in dominantly inherited FTD with ubiquitin-posi-
tive tau-negative pathology (Baker et al., 2006). Mutations
of the progranulin gene account for a proportion of familial
cases not caused by tau gene mutations (Gass et al., 2006). In
the same year, mutations of progranulin have been linked
to abnormalities of TDP-43 identified as the pathologi-
cal protein in the majority of those with FTLD with MND
type inclusions but without MND (FTLD-U) and in MND
(Neumann et al., 2006).
The most exciting recent development has been the dis-
covery of the C9orf72 gene mutation. This abnormality,
a pathological hexanucleotide repeat on the non-coding
region of chromosome 9 accounts for approximately a third
of familial FTD and may be a half of familial amyotrophic
lateral sclerosis (ALS) cases (DeJesus-Hermandez et al.,
2011; Renton et al., 2011;Majounie et al., 2012). The major-
ity of FTD cases have the behavioural variant. The clini-
cal course may be very protracted with little in the way of
brain atrophy and a high rate of psychotic phenomena has
been reported in gene carriers (Devenney et al., 2014).
66.5 CORTICOBASAL DEGENERATION,
PROGRESSIVE SUPRANUCLEAR
PALSY AND FTD
In 1967, Rebeiz et al. described three patients with a neuro-
degenerative illness affecting both cortex and basal ganglia
(Rebeiz et al., 1968). Each patient presented with a progres-
sive asymmetrical akinetic-rigid syndrome and apraxia; on
the basis of neuropathology findings. Rebeiz et al. called
the disorder ‘corticodentatonigral degeneration with neu-
ronal achromasia’, later renamed to corticobasal degenera-
tion (CBD). Initially, CBD was conceptualized as a distinct
clinicopathological entity, but in the early 1990s it was
recognized that considerable clinical and pathological het-
erogeneity existed within the disorder. Clinically, cases of
pathologically proven CBD were described presenting the
clinical syndromes of FTD (Mathuranath et al., 2000) or
progressive aphasia (Lippa et al., 1991). Conversely, it was
recognized that other pathologies might underlie the clini-
cal syndrome of CBD; in a review of 32 consecutive cases of
clinically diagnosed CBD (Boeve et al., 1999), the underly-
ing pathological diagnosis was CBD in 18 cases, AD in 3
cases, PiD in 2, progressive supranuclear palsy (PSP) in 6
and dementia lacking specific histology in another 2 of the
total cases. The pathological heterogeneity has been recog-
nized in subsequent studies (Ling et al., 2010). A distinction
has been drawn by some authors between the corticobasal
syndrome (the constellation of clinical features character-
istically) and CBD (the histopathological disorder itself).
There is growing awareness of the overlap between the
clinical syndrome of CBD and progressive non-fluent apha-
sia (PNFA): many patients with PNFA develop apraxia and
parkinsonian features and conversely, many CBD patients
have subtle language production deficits that worsen as the
disease progresses (Graham et al., 2003).
The related disorder, PSP, originally described by Steele,
Richardson and Olszewski in 1964 is classically character-
ized by progressive axial rigidity, bradykinesia, vertical
gaze palsy and dysarthria. Pathologically, tau-positive neu-
rofibrillary tangles and threads are found in the substantia
nigra, the subthalamic nucleus and the dentate nucleus. It
is increasingly recognized that pathological PSP may pres-
ent itself with the clinical features of CBD or even progres-
sive aphasia or a frontal lobe syndrome. Conversely, the
PSP phenotype may result from tau gene mutations (Morris
764 Dementia
et al., 2003; Soliveri et al., 2003). Both CBD and PSP share
an identified genetic risk factor, the H1 extended haplotype
of the tau gene and the tau deposits in both these diseases
consist of the four-repeat isoforms of tau.
66.6 FTD WITH MND
Although, MND has traditionally been regarded as a dis-
order which spares higher cognitive abilities, it has become
clear since early reports from Japan (Mitsuyama and
Takamiya, 1979) that the rate of dementia in MND is sig-
nificantly greater than expected. Indeed, 10% to 20% of
patients with MND show features of FTD (Rakowicz and
Hodges, 1998; Lillo and Hodges, 2009) and a much higher
proportion have more subtle behavioural changes (Lillo
et al., 2011). Neuroimaging in MND cases with cognitive
impairment demonstrates widespread frontal and temporal
atrophy. Conversely, a significant minority of patients with
FTD develop features of MND (Neary et al., 1990; Caselli
et al., 1993; Rakowicz and Hodges, 1998; Bak and Hodges,
1999; Strong et al., 2003; Burrell et al., 2011). Such patients
present cognitive symptoms, either with bvFTD or with
progressive aphasia, which then progresses rapidly, followed
by the emergence of bulbar features and mild limb amyotro-
phy. Such cases have a characteristic pattern of histological
change with TDP-43-positive inclusions in cortical regions
and the dentate gyrus. One interesting observation is that
FTD with MND (FTD-MND) patients almost invariably
have disproportionately greater impairment of verb rather
than noun processing, which affects both production and
comprehension (Bak et al., 2001) and have a high rate of psy-
chotic symptoms (Lillo et al., 2010; Devenney et al., 2014).
The overlap has been consolidated by the discovery of the
C9or72 mutation, which is present in a high proportion of
cases with the overlap syndrome as well as those with famil-
ial FTD and MND.
66.7 CORRELATION BETWEEN
CLINICAL SYNDROMES AND
NEUROPATHOLOGY
The definitive diagnosis of FTD depends upon neuro-
pathological examination. Unlike other dementia syn-
dromes, notably AD, FTD encompasses considerable
pathological heterogeneity. There have been considerable
developments in the past few years. Three broad subdivi-
sions have been recognized depending on the profile of
immunohistochemical staining and the pattern of intra-
cellular inclusions (Mackenzie et al., 2010; Hodges et al.,
2011; Josephs et al. 2011). First of all, patients with tau-
positive pathology, which in turn comprise a number of
subvariants including those with classic argyrophilic,
tau-positive, intraneuronal Pick bodies, those with MAP
tau gene mutations (FTDP-17) and diffuse tau-positive
neuronal and astrocytic immunoreactivity, those charac-
terized by tau-positive astrocytic plaques and ballooned
achromatic neurones (CBD) and those with tau-positive
argyrophilic grain disease (AGD) are included in this cri-
teria. Second, cases with TDP-43-positive inclusions in the
dentate gyrus and brain stem motor nuclei which include
cases with associated MND also include those with pro-
granulin and C9orf72 gene mutations, which have been
subclassified according to the neuropathological appear-
ance. Third, FTD with fused-in sarcoma (FUS)-positive
inclusions which constitutes a very small proportion of
cases is included in this category.
The question as to whether distinct pathological sub-
types map onto distinct clinical syndromes is of great
interest. Relatively few clinicopathological series have
been reported till date (Rascovsky et al., 2002; Rosen et al.,
2002b; Hodges et al., 2003; Josephs et al., 2006; Mesulam
et al., 2008; Chare et al., 2014). To summarize, it appears
that the majority of patients with semantic dementia have
TDP-43-positive pathology with relatively few cases hav-
ing tau-positive inclusions. The converse is true of PNFA,
which is typically associated with tau-positive forms of FTD
while those with the logopenic variant of progressive apha-
sia show Alzheimer pathology. Pathology in bvFTD is least
predictable with approximately a half having tau-positive
FTD and the other half having TDP-43-positive FTD.
66.8 HOW COMMON IS FTD?
Historically, it has long been recognized that FTD is less
common than AD. Until recently, however, most estimates
of the prevalence of FTD were based on reports from spe-
cialist units where FTD tended to be over-represented as a
diagnosis. This has changed with the publication of a num-
ber of community-based studies that give a clearer picture
of the true prevalence of FTD.
Ratnavalli et al. (2002) conducted a prevalence survey
aiming to ascertain all cases of early-onset dementia (age of
onset less than 65 years) in a particular U.K. region with a
total population of 326,000. The overall prevalence for early-
onset dementia was 81 per 100,000 patients aged 45–64
years, with equivalent prevalence of AD and FTD among
15 per 100,000 patients. Of 185 cases seen by the study
group, 23 (12%) fulfilled the Lund– Manchester criteria for
FTD, suggesting that, although FTD is by no means rare, it
still represents only a minority of cases of dementia in the
under-65 age group. (For comparison, AD was diagnosed in
34%, vascular dementia in 18%, alcohol-related dementia in
10% and dementia with Lewy bodies in 7%.)
Similar figures were obtained by Harvey et al. (2003),
who surveyed three London boroughs with a total popula-
tion of 567,500 people and calculated an overall prevalence
for early-onset dementia among 98 per 100,000 patients
aged 45–64 years.
 Pick’s disease: Its relationship to progressive aphasia, semantic dementia and frontotemporal dementia 765
The prevalence of FTD in the over-65-year olds is largely
unknown. Recent prospective investigation of 451 patients
who were 85-year olds in Sweden, found that 86 (19%) ful-
filled the criteria for a frontal lobe syndrome and 14 (3%)
fulfilled the Lund–Manchester criteria for the frontal variant
of frontotemporal dementia (fvFTD) (Gislason et al., 2003).
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The genetics and molecular pathology of
frontotemporal lobar degeneration
DAVID M.A. MANN
67.1 INTRODUCTION
The term frontotemporal lobar degeneration (FTLD) is used
here to describe a clinically and pathologically heteroge-
neous group of non-Alzheimer forms of dementia arising
from degeneration of the frontal and temporal lobes. The
prototypical, and most common, clinical syndrome is fron-
totemporal dementia (FTD), manifesting as behavioural
and personality changes, involving disinhibition, stereotypy,
unsocial acts and language disorder, leading to apathy, mut-
ism and late neurological (frontal release or extrapyramidal)
signs (Neary et al., 1998, 2005, 2007). However, the spectrum
of illness is wider, involving cases where movement disorder,
with relatively mild dementia, is the major disabling feature
(Cordes et al., 1992; Wszolek et al., 1992; Lynch et al., 1994)
or others with the linguistic disorders of semantic dementia
(SD) and progressive non-fluent aphasia (PNFA) (Snowden
et al., 1992; Neary et al., 1998, 2005, 2007). FTD can be
accompanied by clinical motor neurone disease (MND) in
about 10% of cases giving the syndrome of frontotemporal
dementia with motor neurone disease (FTD1MND) (Neary
et al., 1998, 2005, 2007). Onset of illness is usually before
65 years of age, with duration being between 6 and 9 years,
though up to 15 years is not uncommon (Neary et al., 1998;
Rosso et al., 2003; Neary et al., 2005, 2007).
Outward inspection of the brain in FTLD gives few clues
to pathogenesis, but can be a useful index of clinical pre-
sentation. Hence, FTD is associated with bilateral atrophy
of the frontal and anterior temporal lobes and SD is asso-
ciated with bitemporal lobe atrophy, often asymmetric,
but usually favouring the left side. PNFA is associated with
marked asymmetry, most often of the left cerebral hemi-
sphere (Neary et al., 2005, 2007). Routine histology has con-
tributed little to our understanding of the disorder, beyond
67
the early identification of the ‘classic’ inclusion bodies (Pick
bodies) and swollen neurones (Pick cells) (Pick, 1892), and
the characteristic, though non-specific, features of micro-
vacuolation of outer cortical laminae marking the site of the
principal molecular changes (Knopman et al., 1990).
The recognition in about 40% of patients of a previous
family history of a similar disorder consistent with autosomal
dominant inheritance (Stevens et al., 1998; Rosso et al., 2003)
paved the way for the breakthroughs in knowledge and under-
standing of the molecular pathology of the disorder that have
come through the wealth of genetic investigations performed
over the past decade. By 1997, genetic linkage had identified a
locus on the long arm of chromosome 17 (17q21–22) in some
families, and because parkinsonism usually accompanied the
dementia, these cases came to be snappily described as ‘fronto-
temporal dementia and parkinsonism linked to chromosome
17’ (FTDP-17) (Foster et al., 1997). In 1998, mutational events
in the tau gene, MAPT, were identified (Hutton et al., 1998;
Poorkaj et al., 1998; Spillantini et al., 1998). The prevalence of
MAPT mutations within FTLD varies between 6% and 18%
depending on the population studied (Dumanchin et al., 1998;
Rizzu et al., 1999; Houlden et al., 1999a; Kowalska et al., 2001;
Poorkaj et al., 2001; Binetti et al., 2003; Rosso et al., 2003).
Nonetheless, despite exhaustive genetic analyses, there
remained a number of linked families in whom no muta-
tions in MAPT could be found. This paradox was resolved
in 2006 when mutations within the progranulin gene
(PGRN), located just 1.8 cm from MAPT, were identified
(Baker et al., 2006; Cruts et al., 2006). Collectively, MAPT
and PGRN mutations likely account for no more than 20%
of all cases of FTLD and less than 50% of all autosomal-
dominant inherited forms; further causative mutations and
genetic risk factors remain to be defined or confirmed.
Over the past decade, numerous immunohistochemical
studies have identified aggregated or accumulated proteins
771
772 Dementia
within the brain in neurodegenerative diseases not only to
improve diagnostic power and criteria but also to under-
stand better the basic pathology and devise experimental
approaches to enhance knowledge of pathogenesis. About
45% of FTLD cases display insoluble tau proteins in their
brains in the form of intraneuronal neurofibrillary tangles
or Pick bodies; about half are associated with MAPT muta-
tions (Taniguchi et al., 2004; Shi et al., 2005). However, a
tau-negative, but ubiquitin-positive pathology, known as
FTLD-U, accounts for the other 55% of cases (Lipton et al.,
2004; Taniguchi et al., 2004; Mott et al., 2005; Shi et al.,
2005; Forman et al., 2006a); in most, the ubiquitinated tar-
get protein is the transactive response (TAR) DNA-binding
protein, TDP-43.
67.2 THE TAU GENE (MAPT) AND TAU
PATHOLOGY IN FTLD
67.2.1 THE STRUCTURE OF MAPT AND
THE FUNCTION OF TAU PROTEINS
The tau gene (MAPT) has 15 coding regions (exons), and
transcripts are alternatively spliced to produce six different
isoforms ranging from 352 to 441 amino acids in length.
Tau is normally located in axons and regulates microtu-
bule assembly/disassembly and axonal transport of proteins
and organelles. All six isoforms play a role in maintenance
of microtubular structure. If one or more fails, or if there is a
stoichiometric imbalance in the different variants, microtu-
bule formation will become more difficult or the stability of
microtubules formed will become compromised. Any excess
of tau (of any isoform composition) can be bundled into
indigestible residues (neurofibrillary tangles or Pick bodies)
that choke the cell, but may also induce neurotoxicity.
67.2.2 MAPT MUTATIONS IN FTLD
To date, about 44 MAPT mutations in around 131 families
have been identified (see Alzheimer’s disease [AD] and FTD
mutation database: wwww.molgen.ua.ac.be/FTDmutations).
Typically, patients with MAPT mutations display FTD with
early signs of disinhibition, loss of initiative, stereotypic
behaviours and linguistic changes of a semantic nature
(Pickering-Brown et al., 2002), although other patients dis-
play a phenotype resembling progressive supranuclear palsy
(PSP) or corticobasal degeneration (CBD) (Bugiani et al.,
1999; Wszolek et al., 2001).
67.2.3 PATHOLOGY AND BIOCHEMISTRY
All cases with MAPT mutations are characterized by the
deposition of insoluble, aggregated tau proteins within neu-
rones and glial cells in the cerebral cortex and other brain
regions. Nevertheless, there are two histological patterns:
those mutations in and around the stem loop structure
produce an excess of 4R tau, and hence, the insoluble tau
aggregates are composed predominantly of 4R tau isoforms
(Clark et al., 1998; Hong et al., 1998; Hasegawa et al., 1999;
Pickering-Brown et al., 2002; De Silva et al., 2006), appear-
ing as neurofibrillary tangle-like structures within large
and smaller pyramidal cells of cortical layers III and V and
prominent within glial cells in the deep white matter, globus
pallidus and internal capsule (Pickering-Brown et al., 2002).
Neurones within subcortical structures, such as corpus stri-
atum, medial thalamus, nucleus basalis of Meynert, dorsal
raphe, pontine and dentate nuclei, locus caeruleus and sub-
stantia nigra can likewise be affected, but less severely so
(Pickering-Brown et al., 2002).
67.3 
PGRN AND TDP-43 PATHOLOGY
67.3.1 PGRN MUTATIONS IN FTLD
MAPT mutations account for only 10% of FTLD cases at
most (Rizzu et al., 1999; Houlden et al., 1999a; Poorkaj et al.,
2001; Rosso et al., 2003), although the frequency may reach
20% when only cases consistent with autosomal dominance
are considered (Rizzu et al., 1999). Indeed, following the
identification of MAPT mutations, there remained at least
five chromosome 17-linked families for which no mutational
event in MAPT could be determined. Moreover, no insoluble
aggregates of tau were seen biochemically or histopatho-
logically (Foster et al., 1997; Rosso et al., 2001; Rademakers
et al., 2002; Froelich Fabre et al., 2003), although ubiquitin-
positive inclusions were variably present (Rosso et al., 2001;
Rademakers et al., 2002; Froelich Fabre et al., 2003). Such
cases became known as FTLD-ubiquitinated (FTLD-U). In
2006, causative mutations in these families were identified
(Baker et al., 2006; Cruts et al., 2006). Many subsequent stud-
ies identified mutations in PGRN, with 66 different muta-
tions within 199 families recorded to date (see AD and FTD
mutation database: wwww.molgen.ua.ac.be/FTDmutations).
PGRN mutations in FTLD include missense mutations
generating premature stop codons, insertion or deletion
mutations resulting in frameshifts, or changes within ini-
tiation codons precluding transcription (Baker et al., 2006;
Cruts et al., 2006). Some are located within or close to splice
donor sites, resulting in splicing out of particular exons
(Baker et al., 2006; Cruts et al., 2006; Masellis et al., 2006;
Le Ber et al., 2007). Missense mutations in exon 0 lead to
nuclear degradation, and mutations that affect the Kozak
sequence prevent translation (Cruts et al., 2006; Le Ber et al.,
2007). One particular mutation, Ala9Asp, affects the hydro-
phobic core of the signal peptide sequence disrupting the
normal insertion of the protein into the endoplasmic reticu-
lum leading to a trapping of the (transcribed and translated)
mutated protein within the Golgi apparatus (Mukherjee
et al., 2006). Whole deletions of PGRN occur, but only
rarely (Gijselinck et al., 2008; Rovelet-Lecrux et al., 2008).
Nonetheless, all mutations, irrespective of type, ultimately
 The genetics and molecular pathology of frontotemporal lobar degeneration 773
generate the same functional effect – a null allele – with at
least 50% loss of translated protein giving haploinsufficiency.
Most transcripts are immediately destroyed through non-
sense-mediated decay, and it is unlikely that any, or perhaps
only a small proportion, are translated into mutated proteins,
thereby explaining the lack of mutated PGRN protein within
the ubiquitinated lesions (Baker et al., 2006). The biological
effects would, therefore, seem to be ones of a ‘loss of function
effect’, although the brain accumulation of abnormal ubiqui-
tinated proteins may also confer a neurotoxic ‘gain of func-
tion’, or some combination of the two is possible.
In contrast to MAPT, PGRN mutations may not be fully
penetrant. In one family (DR8), several unaffected car-
riers have been reported to live well beyond the obligate
onset age for the mutation, one as late as 81 years (Cruts
et al., 2006). In R493X mutation, there is delayed onset age
in patients carrying the rare rs9897528 on the wild-type
PGRN allele (Rademakers et al., 2007), suggesting genetic
variability on the wild-type allele might influence the age-
related disease penetrance of PGRN mutations. Bruni et al.
(2007) also reported a potential influence of the wild-type
allele upon age-associated disease penetrance. Common
polymorphisms on the normal allele may impact on disease
expression through (further) lowering of PGRN protein.
Conversely, MAPT haplotype or apolipoprotein E (ApoE)
genotype does not influence either age at onset or disease
penetrance (Cruts et al., 2006; Gass et al., 2006; Bruni et al.,
2007; Rademakers et al., 2007).
67.3.2 THE STRUCTURE AND FUNCTION
OF PROGRANULIN
PGRN contains 13 exons and encodes a full-length protein
(predicted molecular weight of 68 kDa) secreted as a glyco-
sylated 85-kDa precursor that can be cleaved by elastase-
like activity into a series of 6-kDa cysteine-rich fragments
called granulins (GRNs) (Zhu et al., 2002; He et al., 2003).
Both PGRN and the GRNs are biologically active with roles
in tissue remodelling processes (Ahmed et al., 2007; van
Swieten and Heutink, 2008). In peripheral tissues, PGRN
plays a role in development, wound repair and inflamma-
tion, by activating signalling cascades that control cell cycle
progression and cell motility (He and Bateman, 2003). In
the brain, PGRN is expressed in both neurones and microg-
lia. Reduced levels of this secreted mitogenic factor induce
neurodegeneration in FTLD, indicating an important role
in neuronal survival. As with VCP and CHMP2B mutations,
loss of PGRN may be associated with defects in protein deg-
radation through cytoplasmic organelles (Ahmed et al.,
2007). Suppression of PGRN expression results in caspase-
dependent cleavage of TDP-43, with cellular accumulation
of C-terminal fragments (Zhang et al., 2007).
67.3.3 PATHOLOGY OF PGRN MUTATIONS
Consistent with observations that PGRN mutations do not
result in the translation of mutated proteins, pathological
changes in FTLD are not reflected by changes in biochem-
istry or structure of PGRN, but are witnessed as brain
accumulations of ubiquitinated protein devoid of PGRN,
principally in the cerebral cortex and hippocampus, as
neuronal cytoplasmic inclusion (NCI) bodies or dystro-
phic neurites (DNs) (Baker et al., 2006; Cruts et al., 2006).
Neuronal intranuclear inclusions (NIIs) of a ‘cat’s eye’ or
‘lentiform’ appearance have been described (Baker et al.,
2006; Cruts et al., 2006; Pickering-Brown et al., 2006;
Snowden et al., 2006; Mackenzie et al., 2006b; Snowden
et al., 2007; Pickering-Brown et al., 2008), although these
occur in FTLD-U cases where no PGRN mutation has been
determined (Davidson et al., 2007). The ubiquitinated NCI
and DN contain TDP-43 (Arai et al., 2006; Neumann et al.,
2006). TDP-43 is a 43-kDa nuclear protein, 414 amino
acids long, first identified as a binding partner to the TAR
DNA element of the human immunodeficiency virus. The
TDP-43 gene (TARDBP), located on chromosome 1p36.2,
contains six exons and is ubiquitously expressed. It has
two highly conserved RNA recognition motifs (RRM1 and
RRM2) and a C-terminal, glycine-rich tail, which medi-
ates protein–protein interactions, including interactions
with other heterogeneous ribonuclear protein (hnRNP)
family members. Under physiological conditions, TDP-43
is mostly present within the nucleus although low levels
occur within the cytoplasm (Ayala et al., 2008; Buratti
and Baralle, 2008; Thorpe et al., 2008; Turner et al., 2008;
Winton et al., 2008). It is believed that TDP-43 shuttles
continuously between nucleus and cytoplasm, a process
regulated by nuclear localization and nuclear export signal
motifs. Ultrastructural studies show TDP-43 is enriched
within euchromatin domains, specifically within peri-
chromatin fibrils (Casafont et al., 2009), which are nuclear
sites of transcription and transcriptional splicing. TDP-43
may, therefore, function as a transcription repressor or as
an initiator of exon skipping in the alternative splicing of
messenger RNA (mRNA) (Wang et al., 2004; Buratti and
Baralle, 2008).
Most cases of FTLD-U, however, are not associated
with PGRN mutations, although the majority of these still
display TDP-43 pathological changes. There are qualita-
tive differences in the relative burdens of TDP-43 immu-
noreactive NCI, DN and NII across the FTLD-U cases,
and four major histological types have been indepen-
dently described (Sampathu et al., 2006; Mackenzie et al.,
2006a), now unified under a single classification (Cairns
et al., 2007a; Mackenzie et al., 2009). In this, type 1 histol-
ogy describes cases with a preponderance of DN within
neocortical regions with rounded, solid (Pick body-like)
NCI within the hippocampus dentate gyrus (DG) gran-
ule cells. Type 2 histology describes cases with a pre-
ponderance of neuronal NCI and few, if any, DN within
the neocortex, with more granular NCI within the hip-
pocampus. In type 3 histology, numerous NCI and DN
are present within the neocortex, and in many cases len-
tiform NII are seen. Granular NCI are again seen within
the hippocampus.
774 Dementia
These histological variations are not without clinical
significance. Type 1 histology is common in SD, whereas
type 2 histology describes FTD1MND. Type 3 histology is
present in PGRN mutation, but not exclusively so, and can
describe either a ‘straightforward’ FTD presentation or
often, PNFA (Mackenzie et al., 2006b; Davidson et al., 2007;
Josephs et al., 2009). In addition to these diagnostically
characteristic changes in cerebral cortex and hippocampus,
similar changes are widespread throughout other neocorti-
cal regions, including insular and anterior parietal cortex
and cingulate gyrus; posterior parietal and occipital cortex
are rarely affected. Non-cortical regions, such as amygdala
and corpus striatum are frequently and severely affected,
although thalamus, substantia nigra and inferior olives are
variably and mildly involved (Brandmeir et al., 2008; Geser
et al., 2008a; Davidson et al., 2009; Josephs et al., 2009).
Because of the regional variations in distribution of TDP-43
pathological changes throughout the neuraxis, these histo-
logical subtypes might represent distinct clinicopathological
entities with separate pathogenesis (Josephs et al., 2009).
When TDP-43 NCI are present in the cell, TDP-43
immunostaining is absent from the nucleus, possibly hav-
ing been sequestered into NCI. Perturbation of trafficking
of TDP-43 between nucleus and cytoplasm may be a func-
tional consequence of its incorporation into these cyto-
plasmic aggregates (Winton et al., 2008), although it is still
unclear whether disease is due to a toxic gain of function
relating to these pathological aggregates, or from loss of
normal nuclear functions, or some combination of the two.
67.4 OTHER TAU AND TDP-43
NEGATIVE FTLD CASES
67.4.1 PATHOLOGY
Although about 95% of FTLD cases can be accounted by
tauopathy or TDP-43 proteinopathy, there still remains a
small proportion of cases where alternative target proteins
are involved or remain undetermined.
In some of these, ubiquitinated, Pick body-like inclu-
sions are present in neurones of frontal and temporal cor-
tex, and basal ganglia. These are negative for tau, TDP-43
and α-synuclein but (variably) immunoreactive for all
class IV intermediate filaments (IFs), light, medium and
heavy neurofilament subunits (Bigio et al., 2003; Cairns
et al., 2003; Josephs et al., 2003; Cairns et al., 2004a) and
α-internexin (Cairns et al., 2004b). Consequently, the dis-
order became known as neuronal intermediate filament
inclusion disease (NIFID) and was classed as FTLD-IF
(Mackenzie et al., 2009).
67.4.2 FUSOPATHIES
Very recent work (Munoz et al., 2009; Neumann et al.,
2009a, 2009b) has shown that in the majority of these
tau-negative, TDP-43-negative FTLD cases, the ubiquiti-
nated inclusion bodies are immunoreactive to a protein
called fused-in sarcoma (FUS) (also known as translocation
in liposarcoma [TLS]), and may be part of a newly identified
‘family’ of proteinopathies, termed ‘FUSopathies’ (Munoz
et al., 2009; Neumann et al., 2009a, 2009b). In the context
of FTLD, these should be known as FTLD-FUS (Mackenzie
et al., 2009).
67.4.3 PATHOGENETIC CONSIDERATIONS
TDP-43 and FUS are both transcription factors involved
in the transport of mRNA to dendritic spines for local
­translation in relation to synaptic activity. This process
requires the involvement of several types of RNA-containing
­granules – ribonuclear protein particles (RNP), process-
ing bodies (PBs) and stress granules (SGs) (Bramham and
Wells, 2007). However, while TDP-43 appears to be associ-
ated with PB, FUS relates to SG (Bramham and Wells, 2007;
Wang et al., 2008). PB are associated with mRNA decay
processes, and decapping enzyme 1 protein – a marker
for PB – is absent from NCI in basophilic inclusion body
disease (BIBD) (Fujita et al., 2008), explaining the lack of
TDP-43 in such inclusions. In contrast, NCI in BIBD con-
tain mRNA-binding proteins poly(A) binding protein 1 and
T-cell intracellular antigen 1, indicating their association
with SG rather than RNP or PB (Fujita et al., 2008). Hence,
TDP-43 and FUS play different, although complementary,
roles in the processing of RNA.
While for purposes of classification it is logical to clump
aFTLD-U, NIFID and BIBD into the broad-brush category of
FTLD-FUS, this might hide mechanistic differences. The dis-
orders clearly differ in neuropathology – the NCI in NIFID
and aFTLD-U do not contain RNA, vermiform NII are com-
monplace in NIFID and aFTLD-U but rare or absent in
BIBD, loss of lower motor neurones, giving MND phenotype,
is frequent in BIBD but less common in aFTLD-U (Munoz
et al., 2009) – all features pointing to distinctions in patho-
genesis. The challenge will be to understand how changes in
the metabolism of TDP-43 and FUS dictate patterns of neu-
rodegeneration and clinical expression of disease.
67.5 OTHER TDP-43 PROTEINOPATHIES
TDP-43 pathological changes colocalize within the ubiqui-
tinated NCI in various other neurodegenerative disorders.
Such changes occur in 20%–30% patients with AD
(Amador-Ortiz et al., 2007; Hu et al., 2008; Uryu et al.,
2008) or dementia with Lewy bodies (DLB) (Nakashima-
Yasuda et al., 2007; Arai et al., 2009), in some cases of CBD
(Uryu et al., 2008), PSP and in others with Parkinson’s dis-
ease (Uryu et al., 2008) and parkinsonism–dementia com-
plex of Guam (Guam PDC) (Hasegawa et al., 2007; Geser
et al., 2008b), in argyrophilic grain disease, Perry syndrome
(Farrer et al., 2009) and in familial British dementia (FBI)
 The genetics and molecular pathology of frontotemporal lobar degeneration 775
(Schwab et al., 2009). TDP-43 protein has not been (consis-
tently) found in tangles in AD (Amador-Ortiz et al., 2007;
Uryu et al., 2008), in Pick bodies (Davidson et al., 2007;
Uryu et al., 2008, but see Arai et al., 2006; Freeman et al.,
2008) or in the ubiquitinated inclusions of FTD-3 (Holm
et al., 2007). Elsewhere, TDP-43 pathological changes
occur in Rosenthal fibres and granular eosinophilic bod-
ies in l­ow-grade tumours and reactive brain tissue (but not
in anoxic or ischaemic lesions) (Lee et al., 2008), indicat-
ing pathological alterations in the structure or function of
TDP-43 may occur across a wide range of neurodegenera-
tive diseases and other disorders, and might result from a
variety of mechanistic disturbances.
67.6 OTHER GENETIC CHANGES
67.6.1 CHROMOSOME 9
Linkage to chromosome 9p in several families clinically
sharing an FTD and MND phenotype has been claimed
(Hosler et al., 2000; Morita et al., 2006; Vance et al., 2006),
but not confirmed (Ostojic et al., 2003). A sequence varia-
tion in the intraflagellar transport 74 gene (IFT74) was
reported to segregate with disease in one family, but similar
variations were not found in other linked families (Momeni
et al., 2006; Xiao et al., 2007). Nonetheless, the pathology
in such cases that have been reported is that of FTLD-TDP,
type 2 (Cairns et al., 2007b), consistent with expectations
given the clinical phenotype.
UBAP1 encodes a protein of 502 residues, predicted to
have a molecular weight of 55 kDa and originally cloned
from a tumour suppressor locus (Qian et al., 2001). While
little is known of the actual function of the protein, the gene
is a likely member of the ubiquitin-activated enzymes fam-
ily, which includes proteins with connections to ubiquitin
and the ubiquitination pathway, suggesting a link between
the ubiquitin proteasome system (UPS) and this condition.
67.6.2 CHROMOSOME 3
Linkage to chromosome 3p11–12 has been reported in a
Danish family (Brown et al., 1995) showing FTD with fron-
totemporal atrophy, neuronal loss and gliosis (Gydesen
et al., 2002). The gene responsible for disease in this pedigree
(Skibinski et al., 2005), and in three smaller families with
FTD1MND (Parkinson et al., 2006), has been identified as
CHMP2B, which encodes the endosomal sorting complex
required for transport III (ESCRTIII complex subunit).
CHMP2B is part of the chromatin-modifying protein/
charged multivesicular body protein family and is involved
in the degradation of surface receptor proteins and the for-
mation of endocytotic multivesicular bodies, and forms
a component of the UPS. The neuropathology is that of
FTLD-U. The ubiquitinated inclusions contain p62 pro-
tein, but not TDP-43 or FUS, occurring mostly as granular
NCI within the hippocampal DG granule cells (Holm et al.,
2007). Such cases are thus presently classified as FTLD-
UPS (Mackenzie et al., 2009). In some family members, a
few tau tangles are seen, without senile (amyloid) plaques
(Yancopoulou et al., 2003), but less commonly than is usual
for cases of FTLD with MAPT mutations. To date, only four
families have been identified with this particular muta-
tion (see AD and FTD mutation database: www.molgen.
ua.ac.be/FTDmutations) and the significance of this par-
ticular genetic change to the broader pathogenesis of FTLD
remains unknown.
67.6.3 OTHER GENETIC RISK FACTORS
FOR FTLD
Although it is well established that ApoE e4 allele is a risk
factor for late-onset sporadic and familial AD (Corder et al.,
1993), whether this plays a role in FTLD is still unclear.
There have been many claims that ApoE e4 allele frequency
is elevated in FTLD (Czech et al., 1994; Frisoni et al., 1994;
Farrer et al., 1995; Schneider et al., 1995; Stevens et al., 1997;
Fabre et al., 2001), although other (usually larger) studies
generally have not substantiated this in either Caucasian
(Minthon et al., 1997; Geschwind et al., 1998; Pickering-
Brown et al., 2001; Riemenschneider et al., 2002; Short
et al., 2002; Verpillat et al., 2002; Binetti et al., 2003) or
non-Caucasian (Kowalska et al., 2001) populations. Indeed,
a meta-analysis involving most of these studies (Verpillat
et al., 2002) found no overall association between ApoE
e4 allele frequency and FTLD (but see Srinivasan et al.,
2006). In patients with MAPT mutations, ApoE e4 allele fre-
quency is not different from controls (Houlden et al., 1999b;
Pickering-Brown et al., 2002). Nonetheless, Srinivasan et al.
(2006) reported that ApoE e4 allele frequency might be
selectively increased in males with FTLD, thereby doubling
their chances of developing disease. It is also possible that
clinical subgroups under FTLD umbrella might be differ-
entially affected. Short et al. (2002) reported ApoE e4 allele
frequency to be increased in SD, compared to FTD and PA,
although Pickering-Brown et al. (2001) found this to be
normal in FTD and SD, but tended to be increased in PA.
However, in both studies the number of patients with PA
and SD was relatively small and the present variability in
findings could be a reflection of this.
In contrast to AD, possession of ApoE e4 allele does not
appear to affect age at onset of disease (or duration of ill-
ness) in sporadic FTLD (Pickering-Brown et al., 2001; Short
et al., 2002; Srinivasan et al., 2006) or in cases with MAPT
mutations (Houlden et al., 1999b; Pickering-Brown et al.,
2002; Riemenschneider et al., 2002). Hence it seems unlikely
that ApoE e4 allele acts as a risk factor or disease modifier
in FTLD generally, but could play a role in other clinical
subtypes, such as SD or PA.
Results from small series of FTLD patients suggest ApoE
e2 allele could act as a risk factor (Lehmann et al., 2000;
Verpillat et al., 2002), but again this remains to be substan-
tiated (Kowalska et al., 2001; Pickering-Brown et al., 2001;
776 Dementia
Riemenschneider et al., 2002; Binetti et al., 2003). Meta-
analysis, nevertheless, suggested increased ApoE e2 allele
frequency.
67.7 FOUNDER EFFECTS
67.7.1 MAPT
P301L is the most common MAPT mutation found to date,
being present in many families worldwide (Clark et al.,
1998; Dumanchin et al., 1998; Hutton et al., 1998; Mirra
et al., 1999; Rizzu et al., 1999; Houlden et al., 1999a; Binetti
et al., 2003; Rosso et al., 2003). Four of five families with
P301L mutation shared the less common H2 haplotype on
the disease gene (Houlden et al. 1999a). These four families
were of Dutch origin (Rizzu et al., 1999) and might, there-
fore, stem from a founder within this population (Rosso
et al., 2003). Two other families with P301L mutation on
the same H2 haplotype background (Sobrido et al., 2003)
indicate this same founder probably underlies other North
American/French Canadian families with French/Dutch
ancestry (Bird et al., 1999). However, P301L mutation has
been reported in other North American families with no
known Dutch/French or French Canadian ancestry (Mirra
et al., 1999) raising the possibility of a separate founder.
Japanese families with P301L mutation do not share the
same extended H2 haplotype, again implying separate
founders. However, despite sharing H1 haplotype, several
other MAPT polymorphisms, unique to Japanese individu-
als, differed between two Japanese subjects with P301L
mutation suggesting separate founders.
Haplotype analysis (Pickering-Brown et al., 2004) has
shown a likely founder effect for British (Pickering-
Brown et al., 2002), North American (Yamaoka et al., 1996;
Hulette et al., 1999) and Australian families (Dark, 1997;
Hutton et al., 1998) with 116 splice site mutation. Subsequent
analysis (Colombo et al., 2009) dates this particular muta-
tion back to around 1300 ad within North Wales, a rural and
relatively remote region, some 23 generations ago. It is likely
that the founder lived in this part of the United Kingdom
with ‘spread’ of the mutation into more industrialized regions
during the Industrial Revolution, further spreading to other
parts of the world, particularly the Commonwealth countries
through emigration in the eighteenth to twentieth centuries.
The identification of this large extended pedigree may be use-
ful for identifying d
­ isease-modifying loci.
All other MAPT mutations appear to exist within sin-
gle families, or single family members, and may represent
mutational events that have remained ‘private’ to that fam-
ily or to have ‘spread’ less extensively to other countries.
67.7.2 PGRN
R493X is the most commonly reported PGRN mutation to
date, explaining the disease in 2.2% of FTLD cases, and
ascertained in 13 genealogically unrelated FTLD families
(Gass et al., 2006; Huey et al., 2006; Pickering-Brown et al.,
2006; Spina et al., 2007). Patients have a wide onset age
range (44–69 years) and variable clinical diagnoses includ-
ing FTD, PNFA, CBD and AD (Rademakers et al., 2007).
Haplotype analysis has suggested two separate founding
events. A single common founder, most likely originating
in the United Kingdom approximately 300 years ago, impli-
cated 27 present day families. As with MAPT 116 mutation,
patients with R493X founder haplotype have been observed
in countries of British migration, including the United
States and Australia. Significantly, neither the PGRN R493X
nor the MAPT 116 mutations have been identified in FTLD
series from continental Europe (including the Netherlands,
Belgium, Poland, France, Italy and Spain) consistent with
the view that the likely founders were from the United
Kingdom, the appearance of patients in other countries fol-
lowing patterns of British migration. Founder effects have
also been suggested for Gln415X (Pickering-Brown et al.,
2008) and Cys31LeufsX35 (Mackenzie et al., 2006b) muta-
tions, both again relating to British stock.
67.8 BIOMARKERS FOR FTLD
Although clinicopathological correlations have sug-
gested that certain clinical FTLD subtypes are strongly
associated with one particular kind of histology, or even
histological subtype, these associations are not perfect,
particularly for FTD that can be associated with all known
histological forms of FTLD (including FUS pathology),
and for PNFA where tauopathy (Pick histology) can some-
times be present. While the determination of genotype
(i.e. identification of MAPT/PGRN/ CHMP2B/VCP muta-
tions) can unequivocally point towards the relevant histol-
ogy, such cases are still relatively few and the full range of
genetic involvement is unclear. Conversely, although par-
ticular clinical phenotypes are frequently associated with
particular mutational events (for example certain MAPT
mutations usually present with FTD, often with linguistic
changes [Pickering-Brown et al., 2008], and PGRN muta-
tions with FTD or PNFA phenotype [Snowden et al., 2006;
Snowden et al., 2007; Pickering-Brown et al., 2008]), the
mutation present in familial autosomal dominantly inher-
ited FTLD cannot be precisely inferred without gene anal-
ysis. Hence, a straightforward laboratory test, based on
easily accessible body fluids or tissues, that would identify
patients with FTLD from other neurodegenerative disor-
ders, or perhaps more importantly discriminate cases with
underlying FTLD-tau from those with FTLD-TDP without
the requirement of complex genetic investigations, would
be a major adjunct to diagnostic precision. It could also act
as a predictive test, having great practical value in direct-
ing therapeutic strategies aimed at preventing or remov-
ing tau or TDP-43 pathological changes from the brain
in FTLD and other TDP-43 proteinopathies. The recent
 The genetics and molecular pathology of frontotemporal lobar degeneration 777
identification of key molecular changes in the pathogen-
esis of FTLD (and MND) should open the way to progress
in these respects.
67.9 CONCLUSIONS
The past 3 years has seen a sea change in appreciation of
the genetics and molecular pathology of FTLD. The twin
discoveries of the presence of gene mutations in progranu-
lin as a cause of FTLD, and the identification of the ubiq-
uitinated proteins, TDP-43 and FUS in the pathological
lesions of non-tauopathy forms of FTLD, has opened new
vistas into the causes and effects of those tissue changes
that are the pathological markers of disease, even if they
may not be the actual damaging agents. However, what
we have seen so far, and what meagre clues have gained, is
likely to be only the tip of the iceberg. There is still a whole
world of basic neurobiology relating to PGRN, TDP-43 and
FUS waiting to be discovered, and with that it will become
increasingly clear as to the roles these molecules play not
only in FTLD, or even in other neurodegenerative disor-
ders such as AD, but perhaps most importantly in terms
of how they might maintain a watchful surveillance over
the health and well-being of the nervous system ensuring
proper brain function. These data will not be won easily.
It has been nearly two decades since the discovery of the
amyloid precursor protein (APP), yet a definitive role for
this protein in the brain is still elusive. Likewise, the prion
protein has long been known, yet its precise brain func-
tion remains unclear. PGRN, like APP and prion protein,
may subserve a variety of roles concerned with regulating
the fundamental health, environment and infrastructure
of the brain. Although AD and prion disease are patho-
logically characterized by accumulations of aggregated
proteins, with presumed neurotoxic effects, it may be loss
of the parent protein that is vital. The loss of function effect
of PGRN mutations in FTLD is instructive in this latter
context.
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Semantic dementia
JULIE S. SNOWDEN AND MATTHEW JONES
68.1 INTRODUCTION
Semantic dementia (SD) is a disorder of conceptual knowl-
edge resulting from degeneration of the anterior temporal
lobes. It is one of the canonical clinical syndromes, along
with the behavioural variant of frontotemporal demen-
tia (bvFTD) disorder and expressive language disorder of
progressive non-fluent aphasia (PNFA), associated with a
non-Alzheimer, frontotemporal lobar degeneration (FTLD)
pathology (Neary et al., 1998; Josephs et al., 2011). People
with SD lose the ability to name and understand words, to
recognize faces and to understand the significance of objects.
Although relatively rare, recognition of this disorder is
important because of its distinct implications for manage-
ment. Moreover, in recent years it has attracted considerable
academic interest because of its potential to shed light on the
organization and neural basis of semantic memory. From a
neurobiological perspective, a central interest is the relation-
ship between SD and other clinical presentations of FTLD.
68.2 BACKGROUND
The term ‘semantic dementia’ was introduced in 1989
(Snowden et al., 1989) to encapsulate the multimodal loss
of knowledge that typifies this syndrome. Prior to this, there
were seminal reports in the literature of patients with cir-
cumscribed impairments of semantic memory associated
with neurodegenerative disease, who would nowadays be
classified as having SD (Warrington, 1975; Schwartz et al.,
1979). Moreover, in the classical neurological and psychi-
atric literature, there are patient descriptions (Pick, 1892;
Rosenfeld, 1909) that appear prototypical of SD (Snowden,
2001). It is clear that SD has long existed.
SD is sometimes described within the context of primary
progressive aphasia (PPA) (see Chapter 69). Since the earli-
est descriptions (Mesulam, 1982), PPA has been recognized
68
to be heterogeneous (Mesulam, 1982; Tyrrell et al., 1990a;
Snowden, et al., 1992). While some people present a non-
fluent, effortful and agrammatic form, others exhibit a flu-
ent aphasia, characterized by impaired naming and word
comprehension. The label ‘semantic variant of PPA’ or
‘svPPA’ (Gorno-Tempini et al., 2011) has been applied to this
latter form. Close examination of such patients frequently
reveals that the semantic disorder extends beyond the ver-
bal domain (Adlam et al., 2006) in keeping with SD. The
aphasia classification reflects the prominence of the lan-
guage symptoms. The terms SD and svPPA are sometimes
used interchangeably (e.g. Libon et al., 2013).
Cases of progressive prosopagnosia (Tyrrell et al., 1990b;
Evans et al., 1995) are likely to represent right hemisphere
presentations of SD (Josephs et al., 2008).
68.3 DIAGNOSTIC CRITERIA
Clinical diagnostic criteria for SD developed in 1998 (Neary
et al., 1998) are shown in Table 68.1. Table 68.2 shows cri-
teria defined under the label svPPA (Gorno-Tempini et al.,
2011). The SD criteria recognizes that face and object rec-
ognition difficulties may be prominent early symptoms,
whereas the svPPA criteria, being part of more general cri-
teria for PPA, require that language difficulties are the most
prominent deficit. The SD criteria incorporate behavioural
features as supportive diagnostic features, whereas the
svPPA criteria do not. The SD criteria distinguish between
core and supportive features, whereas the svPPA criteria
specify the number of features required to make a diagnosis
and distinguish different levels of diagnostic certainty (clin-
ical only, imaging-supported, pathologically confirmed).
Perhaps, the most fundamental difference, however, relates
to the underlying intention of the criteria. The SD criteria
are intended to predict an FTLD pathology, hence the inclu-
sion of features such as behavioural characteristics and the
783
784 Dementia

Table 68.1 Clinical diagnostic features of semantic dementia

I. Core diagnostic features
a. Insidious onset and gradual progression
b. Language disorder characterized by the following:
i. Progressive, fluent, empty spontaneous speech
ii. Loss of word meaning, manifested by impaired naming and comprehension
iii. Semantic paraphasias
c. Perceptual disorder characterized by the following:
i. Prosopagnosia: impaired recognition of identity of familiar faces
ii. Associative agnosia: impaired recognition of object identity
d. Preserved perceptual matching and drawing reproduction
e. Preserved single word repetition
f. Preserved ability to read aloud and write orthographically-regular words to dictation
II. Supportive diagnostic features
a. Speech and language
i. Press of speech
ii. Idiosyncratic word usage
iii. Absence of phonemic paraphasias
iv. Surface dyslexia and dysgraphia
v. Preserved calculation
b. Behaviour
i. Loss of sympathy and empathy
ii. Narrowed preoccupations
iii. Parsimony
c. Physical signs
i. Absent or late primitive reflexes
ii. Akinesia, rigidity and tremor
d. Neuropsychological testing
i. Profound semantic loss manifests in failure of word comprehension and naming and/or face and object
recognition
ii. Preserved phonology and syntax, elementary perceptual processing, spatial skills and day-to-day memorizing
e. Electrophysiology
i. Normal
f. Brain imaging (structural and/or functional)
i. Predominant anterior temporal abnormality (symmetric or asymmetric)
Source: Neary, D. et al., Neurology, 51, 1546–1554, 1998. Reproduced with permission from Wolters Kluwer Health Publishers.

preservation of calculation skills known to be helpful in
distinguishing FTLD from AD. The svPPA criteria by con-
trast are designed to identify a specific language phenotype
associated with neurodegenerative disease, but make no
assumptions or predictions regarding the precise nature of
that neurodegenerative pathology.
socio-economic factors which affect incidence. Accurate
incidence and prevalence data are scarce. In an analy-
sis of patient referrals to a specialist dementia clinic in
Manchester, patients with prototypical, ‘pure’ SD accounted
for approximately 10% of cases of FTLD, which in turn
accounted for about 25% of cases of primary degenerative
dementia presenting itself before the age of 65.

68.4 DEMOGRAPHIC FEATURES
SD affects men and women equally. The mean age at onset is
around 60 years (Hodges et al., 2010), ranging from 40 to 80
years. The median survival has been estimated at 12.8 years
(Hodges et al., 2010), although there is wide variation with
durations as short as 3 years and as long as 16 years. Most
cases are sporadic, a positive family history being less com-
mon than in other forms of FTLD (Goldman et al., 2005;
Hodges et al., 2010). There are no known geographical or
68.5 PRESENTING COMPLAINTS
The presenting complaint is typically of a difficulty ‘with
words’ or ‘remembering things’. Careful history-taking
reveals that the problem in ‘remembering’ is not one of
memory loss in the traditional sense. Patients are able to
remember day-to-day events, keep track of time, remem-
ber appointments, find their way around without being lost
and retain a degree of functional independence that would
 Semantic dementia 785

Table 68.2 Clinical diagnosis of semantic variant PPA

I.
a. Both of the following core features must be present in the patient:
i. Impaired confrontation naming
ii. Impaired single-word comprehension
b. At least three of the following other diagnostic features must also be present:
i. Impaired object knowledge, particularly for low frequency or low-familiarity items
ii. Surface dyslexia or dysgraphia
iii. Spared repetition
iv. Spared speech production (grammar and motor speech)
II. Imaging-supported semantic variant PPA diagnosis
a. Both of the following criteria must be present in the patient:
i. Clinical diagnosis of semantic variant PPA
ii. Imaging must show one or more of the following results:
A. Predominant anterior temporal lobe atrophy
B. Predominant anterior temporal hypoperfusion or hypometabolism on SPECT or PET
III. Semantic variant PPA with definite pathology
a. Clinical diagnosis (criterion 1 below) and either criterion 2 or 3 must be present as well:
i. Clinical diagnosis of semantic variant PPA
ii. Histopathologic evidence of a specific neurodegenerative pathology (e.g. FTLD-tau, FTLD-TDP, AD, others)
iii. Presence of a known pathogenic mutation
Source: Gorno-Tempini, M.L. et al., Neurology, 76, 1006–1014, 2011. Reproduced with permission from Wolters Kluwer Health publishers.
Notes: To meet svPPA criteria, patients must first meet overarching criteria for PPA. These specify that language difficulties should be the
most prominent problem. Prominent behavioural disturbance is a basis for exclusion.
Abbreviations: PPA, primary progressive aphasia; SPECT, single photon emission computed tomography; PET, positron emission topogra-
phy; FTLD-tau, frontotemporal lobar degeneration-tau; FTLD-TDP, FTLD variant with TAR-DNA-binding protein 43 (TDP-43); AD,
Alzheimer’s disease.

be incompatible with a classical amnesia. The problem lies
in remembering what words mean, who people are and what
objects are for. The presenting symptoms are most often in
the verbal domain, manifested by patients’ difficulty in the
understanding and use of words, but occasionally they are
in the visual realm, manifested by a difficulty in recognizing
faces. Relatives may also report a failure of object recogni-
tion: for example, an inability to recognize fruits and veg-
etables in the supermarket. Medical referral is sometimes
precipitated by an accompanying behavioural alteration.
68.6 BEHAVIOURAL CHANGES
precisely the same time each day. They may have a prefer-
ence for order and align objects, straighten out folds in the
curtains and plump up the cushions as soon as a person
rises from an armchair.
People with SD may show hypersensitivity to sensory
stimuli (Snowden et al., 2001; Mahoney et al., 2011) and
overact to light touch or to ostensibly innocuous environ-
mental sounds. They may be oblivious to danger, probably
linked to their loss of conceptual understanding of the
world. They commonly show narrowed food preferences
and favour sweet flavour in foods.
Although many of these ‘temporal’ behaviours overlap
with those found in the predominantly ‘frontal’ disorder
bvFTD, there are qualitative differences (Snowden et al.,
2001). These are summarized in Table 68.3.

Patients become self-centred, lacking in empathy and

inflexible. Their behavioural repertoire becomes narrowed
and they frequently become preoccupied with one or two
activities (e.g. painting, solving jigsaw puzzles or sudoku
puzzles), which they pursue relentlessly and at which they
are adept (Green and Patterson, 2009). They may become
mentally preoccupied by particular themes (e.g. the with-
drawal of their driving licence), which they repeat inces-
santly to the exasperation of family members. Behaviour
acquires a stereotypical quality. Patients may adopt a fixed
routine, clock-watch and carry out specific activities at
68.6.1 INSIGHT
Patients are aware of difficulties, yet frequently provide
trivial explanations for them, such as being ‘out of prac-
tice with talking’ by virtue of being alone all day. Signs
of frustration are rare. A likely reason is the absence of
an internal model of prior conceptual knowledge: patients
have no comparator by which to judge the magnitude of
what they have lost.
786 Dementia
Table 68.3 Behavioural characteristics of semantic dementia and bvFTD
Characteristics Semantic dementia
Affect Warm
Social behaviour Exaggerated sociability
Interest and motivation Narrowed interests
Task performance Productive and goal-directed
Attention Focused, good persistence
Wandering and pacing Uncommon
Repetitive behaviours Complex routines
Clockwatches
Compulsive quality
Eating Food fads, more selective
Response to sensory stimuli Exaggerated
Abbreviation: bvFTD, behavioural variant of frontotemporal dementia.
68.7 NEUROLOGICAL SIGNS
Patients are generally free from neurological signs until
late in the disease. Akinesia and rigidity and frontal release
phenomena may emerge in advanced disease. Very rarely
SD may be accompanied by motor neurone disease (Kim
et al., 2009; Ostberg and Bogdanovic, 2011). Myoclonus is
absent.
68.8 COGNITIVE CHARACTERISTICS
68.8.1 LANGUAGE
Patients speak fluently and effortlessly, with normal artic-
ulation and grammar and without phonological (sound-
based) errors, giving the superficial impression of normal
language. Indeed, patients are often garrulous (Table 68.4).
Nevertheless, there is typically a reduction in content words.
Specific terms may be used over inclusively: e.g. ‘container’
to refer to objects that have no capacity to ‘contain’; ‘twist-
ing’ used to refer to actions, where no twisting motion is
involved.
The semantic impairment, which may be scarcely appar-
ent at clinical interview, becomes strikingly evident on for-
mal testing of naming and word comprehension. Patients
often score close to floor level on standard picture naming
tasks and derive no benefit from phonemic cues. Semantic
errors (e.g. ‘dog’ for tiger) may occur, reflecting loss of con-
ceptual discrimination between related concepts. Word
comprehension is also affected. Expressions of lack of under-
standing of words patients were previously familiar with (e.g.
‘Tiger, tiger, what’s a tiger? I don’t know what that is’) are a
revealing demonstration of the loss of word meaning. There
are known influences on naming performance. Common
words are more likely to be named than low frequency terms
(Lambon Ralph et al., 1998) and items typical of a category
better than atypical items (Woollams et al., 2008). There is
bvFTD
Blunted
Reduced sociability
General loss of interest
Unproductive, no goal-direction
Inattentive, poor persistence
Common
Simple motor stereotypes
Unconcerned by time
No compulsive quality
Gluttony, more indiscrimination
Diminished
a tendency for vocabulary relating to patients’ daily life to
be better preserved than non-personally relevant vocabu-
lary (Snowden et al., 1994, 1995). Word comprehension and
naming assessment should, therefore, probe vocabulary that
does not relate directly to the patient’s daily routine. Loss
of knowledge about a word’s meaning may not be absolute.
The patient may, for example, know that a lemon is a food
rather than an animal, but not know how it differs from a
banana. Assessment needs to probe knowledge of attributes
as well as broad category knowledge. Potential methods of
assessing knowledge are shown in Figure 68.1.
Language comprehension problems arise principally at
the single word level. Comprehension of syntax is relatively
well preserved. Reading and writing is similarly preserved
for words with regular spellings. However, patients read
phonetically rather than meaningfully, so produce ‘regular-
ization’ errors (e.g. ‘glove’ pronounced to rhyme with ‘rove’
and ‘stove’; ‘pint’ to rhyme with ‘mint’), consistent with sur-
face dyslexia (Patterson et al., 1985). Parallel errors occur in
writing (e.g. ‘caught’ written as ‘cort’).
With progression of the disease, speech content is
increasingly empty and stereotypical. Conversational rep-
ertoire becomes progressively reduced until only a few ste-
reotypical words or phrases remain.
68.8.2 FACE AND OBJECT RECOGNITION
Problems in recognizing familiar faces occur early in the
course of disease. Difficulties are most profound for imper-
sonal faces, such as those of celebrities and least marked for
family and friends with whom the patient maintains daily
contact. Perceptual discrimination of faces (i.e. whether two
faces are the same or different) is preserved.
Object recognition difficulties invariably emerge with
disease progression. Like words, loss of understanding is
not all or none. Patients may recognize a lemon as edible
but not know whether it tastes sweet or sour, or if it needs
to be cooked. Moreover, they may recognize and use appro-
priately their own belongings while failing to recognize
 Semantic dementia 787

Table 68.4 Characteristics of language disorder in semantic dementia

Spontaneous speech Fluent, effortless, often garrulous
Empty content, reduced nominal terms
Semantic paraphasias
Substitution of generic terms
Verbal stereotypes
Preserved use of syntax
Preserved phonology
Normal articulation and prosody
Comprehension Impaired word understanding
Good understanding of syntax
Repetition Relatively preserved
Naming Profound anomia
Semantic errors present (e.g. ‘dog’ for elephant)
No benefit from phonemic cues
Reading Fluent reading aloud
Accurate reading of regular words
Regularization of irregular words (surface dyslexia)
Impaired comprehension of written material
Writing Fluent, effortless execution
Regularization of irregular words
(e.g. ‘cort’ for caught) (surface dysgraphia)

Word-picture match

Which is the lion?

Knowledge of habitat Hot country or cold country?

Where would you find this? In the farmland or in the wild?

In Africa or in America?

Knowledge of attributes Friendly/tame or

Lion
unfriendly/dangerous?
How does this behave?

What noise does it make? Roars or barks?

Figure 68.1 Methods of assessing semantic knowledge.

other examples of those same objects or pictures of those
objects (Snowden et al., 1994; Bozeat et al., 2002) belong-
ing to others. This latter feature helps to explain the clinical
observation that patients function reasonably well within
the narrow confines of their familiar environment and rep-
ertoire of daily activities at a time when abstract semantic
knowledge is profoundly impaired. Eventually, even highly
familiar objects may no longer be recognized.
Non-semantic aspects of object perception are well pre-
served. Patients have no difficulty carrying out perceptual
discrimination and matching tasks that are not dependent
upon recognition of object meaning. They may draw nor-
mally, sometimes to a strikingly proficient level (Figure 68.2).
68.8.3 RECOGNITION FROM TOUCH,
TASTE, SMELL AND SOUND
Primary sensory abilities are well preserved, so patients
have no difficulty detecting the presence of tactile, gusta-
tory, olfactory and auditory stimuli and discriminating
788 Dementia
Figure 68.2 Painting by semantic dementia patient.
whether two stimuli are the same or different. However,
the disorder of meaning extends to all sensory modali-
ties (Snowden et al., 1996; Bozeat et al., 2000; Hodges and
Patterson, 2007; Luzzi et al., 2007; Piwnica-Worms et al.,
2010). Patients may have difficulty recognizing the identity
of textures, tastes, smells and non-verbal sounds such as the
ringing of a telephone or the sound of thunder despite per-
ceiving those stimuli normally.
68.8.4 NUMERACY
Understanding of number concepts and the ability to
carry out arithmetical procedures often appear remarkably
well preserved (Cappelletti et al., 2001, 2002; Crutch and
Warrington, 2002), perhaps explaining why SD patients com-
monly enjoy number puzzles such as sudoku and television
quiz shows involving numbers. Nevertheless, number con-
cepts are not entirely normal (Julien et al., 2008). Eventually,
arithmetical skills become compromised and patients cease
to understand the meaning of spoken and written numerals.
68.8.5 SPATIAL SKILLS
Spatial and navigational skills are generally excellent.
Patients are able to find their way without becoming lost and
may use spatial cues to compensate for object recognition
difficulties (for example, by recalling the spatial location of
food items on a supermarket shelf). On neuropsychologi-
cal testing, patients typically perform well on traditional
spatial tests such as line orientation (Benton et al., 1978),
dot counting, position discrimination and cube estima-
tion (Warrington and James, 1991), although in late stage
disease performance may be compromised secondarily by
their semantic disorder (e.g. failure to recall the names of
numbers). Even in advanced stage of the disease, patients
negotiate their environment skilfully, may recall the loca-
tion of their chair or bed on a hospital ward, localize and
manipulate objects in the environment with ease and spa-
tially align objects perfectly. By contrast to the essential
preservation of spatial skills, patients may exhibit a ‘topo-
graphical agnosia’ reflecting a failure to recognize buildings
and other locations.
68.8.6 MEMORY
A feature that is striking on clinical grounds and that helps to
distinguish SD from other forms of dementia is the apparent
preservation of patients’ current autobiographical memory
(Warrington, 1975; Snowden et al., 1996). Patients remember
appointments and personally relevant events and keep track of
time. They negotiate the environment without being lost. If they
moved to a new home, they have no difficulty learning their
new surroundings. In contrast, they show gross breakdown in
impersonal, factual (semantic) knowledge, including knowl-
edge about public figures and important world events. The
preservation of autobiographical memory is not easily ­captured
by standard memory tests, which typically involves lists of
words, faces or line drawings that may have little ­meaning for
the patient. Moreover, routine bedside questions, designed to
probe orientation, such as ‘What town are we in?’ demand nam-
ing skills and thus may be compromised in SD. Time orienta-
tion scores are typically superior to those of place o
­ rientation,
reflecting better preservation of number-related vocabulary.
Testing of memory needs to include test m ­ aterials that are
meaningful to the patients and questions regarding the patient’s
daily life. Episodic memory, assessed in a ­naturalistic setting,
has been shown to be well preserved (Adlam et al., 2009).
68.8.7 EXECUTIVE SKILLS
Executive skills, such as rule abstraction, mental set-
shifting, response inhibition and problem solving, that are
heavily dependent on frontal lobe function, can be remark-
ably well preserved in SD. Nevertheless, semantic break-
down inevitably impacts task performance when stimuli
have no meaning for the patient.
68.9 BRAIN IMAGING
Magnetic resonance imaging (MRI) shows cerebral atrophy,
particularly marked in the anterior temporal lobes, and affect-
ing inferior more than superior temporal gyri (Hodges et al.,

1992; Mummery et al., 2000; Chan et al., 2001; Rohrer et al.,
2008, 2009). Although bilateral, the temporal lobe atrophy is
often asymmetric (see Figure 68.3), the left or right predomi-
nance being associated with clinical presentations emphasiz-
ing word meaning or face recognition disorder, respectively.
With the progression of the disease, atrophy spreads within
both hemispheres (Rohrer et al., 2008; Brambati et al., 2009),
although asymmetries may manifest even at end stage.
Parallel hypometabolic changes in the temporal lobes are
found on positron emission tomography (PET) imaging
(Diehl et al., 2004; Desgranges et al., 2007).
Studies of white matter connectivity have shown extensive
loss of connectivity of ventral pathways, including uncinate
and inferior longitudinal fasciculus, with relative sparing of
frontoparietal pathways (Agosta et al., 2010; Acosta-Cabronero
et al., 2011), suggesting breakdown of a wider semantic net-
work extending beyond the anterior temporal lobes.
68.10 NEUROPATHOLOGY
The striking feature on macroscopic examination is atrophy
of the temporal lobes. Atrophy is bilateral, but often asym-
metrical and affects particularly anterior and inferior parts
of the temporal lobes. Frontal cortex is affected to a lesser
degree. There is relative sparing of superior temporal gyrus,
parietal and occipital cortex.
In FTLD, the histopathological changes are not uniform
(see Chapter 67). A primary distinction is made between
tau- and TAR DNA-binding protein 43 (TDP-43) patholo-
gies (Mackenzie et al., 2010), the latter being distinguished
into three subtypes based on the relative preponderance of
neuronal cytoplasmic and intranuclear inclusions and dys-
trophic neurites (Mackenzie et al., 2011). Pure SD cases are
strongly associated with TDP-43, type C pathology (Josephs
et al., 2009, 2011; Snowden et al., 2011) characterized by a
preponderance of dystrophic neurites within cerebral cor-
tex. Occasionally, an association with tau pathology has
been reported (Hodges et al., 2010), although it might be
(a)
Figure 68.3 Magnetic resonance imaging (MRI) scans of two patients with semantic dementia showing severe temporal
lobe atrophy. In one case (a) atrophy is more marked on the left side and in the other case (b) on the right.
Semantic dementia 789
speculated that such cases have a less pure semantic disor-
der. Tau pathology has been linked (Pickering-Brown et al.,
2002) to a mixed clinical picture in which bvFTD is com-
bined with semantic breakdown.
In some series (Hodges et al., 2010), a minority of
patients have been reported to show Alzheimer pathology.
Such findings exemplify the fact that semantic impairment
may be a prominent feature in some Alzheimer patients and
so can be mistaken for SD. Such patients typically exhibit a
classical amnesia and early calculation problems, in addi-
tion to their semantic impairment.
68.11 MOLECULAR GENETICS
Genetic mutations in the MAPT, GRN and C9orf72 genes
that are associated with bvFTD and PNFA (see Chapter
67) are typically absent in pure SD, in keeping with the
low familial incidence. A mixed syndrome of semantic loss
combined with bvFTD is a feature of +16 tau mutations
(Pickering-Brown et al., 2002). Semantic loss may occa-
sionally be a prominent symptom of C9orf72 mutations
(Galimberti et al., 2013; Abbate et al., 2014).
68.12 RELATIONSHIP TO BVFTD AND
PNFA
The established association between SD, bvFTD and
PNFA, comes from several sources: (1) the existence of
mixed/overlapping clinical syndromes, (2) the poten-
tial association of each syndrome with motor neurone
disease (Neary et al., 1990; Caselli et al., 1993; Kim et al.,
2009), and (3) shared pathologies. The latter point requires
elaboration. Until recently, the assumption was that syn-
dromic differences reflected differences in the anatomi-
cal distribution within the anterior hemispheres of a
common underlying pathology. Nevertheless, refinement of
(b)
790 Dementia

histopathological characterization points to distinct patho-
logical as well as clinical phenotypes and a closer mapping
between clinical phenotype and underlying histopathology
than previously thought (Josephs et al., 2009; Snowden et al.,
2011). SD appears uniquely associated with TDP-43 type C
pathology, whereas PNFA is strongly linked to TDP-43 type
A or tau pathology and FTD with motor neurone disease to
TDP-43 type B. Such findings suggest fundamental differ-
ences in the neurobiology of SD and other forms of FTLD.
68.13 DIFFERENTIAL DIAGNOSIS
SD is poorly recognized for understandable reasons (see
Table 68.5). It is most likely to be confused with Alzheimer’s
disease (AD), reflecting the fact that presenting symp-
toms in both are commonly of ‘memory’ problems and
patients’ fluent, effortless conversational speech might, at a
clinical interview, mask the underlying semantic disorder.
Nevertheless, the ‘typical’ clinical profiles of SD and AD are
very different (see Table 68.6) as outlined below:
●● In SD, ‘memory loss’ refers to loss of impersonal, con-
ceptual knowledge about the world, whereas personal,
autobiographical memories remain relatively well pre-
served. In AD the converse is true.
●● In SD speech production is fluent and effortless. In AD,
it is typically hesitant, suggesting a difficulty in retriev-
ing words and sentences may be unfinished reflecting
loss of train of thought. There may be phonologi-
cal errors and in later stages a stuttering quality that
accompanies speech is usually evident.
●● In SD, comprehension is most impaired for words and
better preserved for syntax, whereas in AD, the reverse
is typically the case.
●● Numerical skills are well preserved in SD, whereas cal-
culation problems are affected early in AD disease.
●● Spatial abilities are well preserved in SD, whereas AD
patients commonly show difficulty orientating clothing
when dressing and topographical disorientation within
a familiar environment.
●● Patients with both SD and AD may have object recog-
nition problems. In SD, the difficulty lies in assigning
meaning to objects that are perceived normally (associa-
tive visual agnosia). They can copy drawings of objects
that they cannot recognize. In AD, perceptual break-
down lies at the level of achieving an integrated percept
(apperceptive agnosia). Patients may interpret elements
of a figure instead of the overall outline (e.g. a pair of
scissors identified as a bowl on the basis of the circular
handle). They have difficulty copying line drawings,
their copies often being fragmented with loss of the
spatial relationships between elements of the figure.

Table 68.5 Factors affecting poor recognition of semantic dementia

• Rare disorder
• Historical reports of ‘memory’ disorder
• Semantic disorder may not be evident during clinical interview
• Semantic impairments may be misinterpreted as classical amnesia
• Need explicit tests of word comprehension and naming, face and object recognition

Table 68.6 Clinical differences between semantic dementia and Alzheimer’s disease

Features Semantic dementia Alzheimer’s disease

Age of onset Most common in middle age Most common among elderly
Language Selective semantic disorder No selective semantic disorder
Impaired single word comprehension Impaired sentence comprehension
Perception Associative agnosia Apperceptive agnosia
Calculation Preserved early in course Impaired early in course
Spatial orientation Preserved Impaired early in course
Constructional skills Preserved Impaired early in course
Memory Autobiographical memory preserved Autobiographical memory impaired
Neurological signs Myoclonus absent Myoclonus may be present
Electroencephalography Normal Slowing of wave forms
Structural brain imaging Focal anterior-inferior temporal lobe atrophy Focal anterior temporal atrophy rare
typical
Hippocampi relatively preserved Hippocampi atrophic
Marked hemispheric asymmetry common Marked asymmetry rare
Functional brain imaging Anterior hemisphere abnormalities Posterior hemisphere abnormalities
Marked hemispheric asymmetry common Marked asymmetry rare

Notwithstanding these distinct profiles, differentia-
tion is not invariably clear-cut. Semantic impairment may
be present in AD (Hodges and Patterson, 1995; Rogers
and Friedman, 2008; Libon et al., 2013) and in some AD
patients it is a prominent feature (Alladi et al., 2007).
Diagnostic differentiation in such cases is likely to lie
in the degree of accompanying amnesia and pattern of
behavioural change.
68.14 TREATMENT AND
MANAGEMENT
Pharmacological therapies for AD do not have a rational
role in SD, because there is no evidence of abnormalities in
the cholinergic system (Francis et al., 1993). In patients with
problematic behavioural changes, symptomatic treatment
may be warranted. There is anecdotal evidence that repeti-
tive, stereotypical behaviours may respond to selective sero-
tonin reuptake inhibitors (SSRIs).
With regard to practical management, it is of relevance
that concepts (of words, object meaning etc.), relevant to
the patient’s daily life appear to be better retained than
those which have no personal relevance (Snowden et al.,
1994, 1995; Westmacott et al., 2003). It has been argued
that this feature results from patients’ preserved auto-
biographical memory: concepts, which would otherwise
be lost in their abstract sense, have some meaning to
the patient if they are framed within the context of the
patient’s ongoing daily experience. A word, in isolation,
may have no meaning to the patient, yet meaning may be
conveyed by the context of a complete sentence. An object
might not be recognized out of context, yet recognized
within the context of its usual location. By implication,
input from speech therapists is more likely to be beneficial
if this takes place in the patient’s own surroundings using
as referents patients’ own belongings, than in the abstract
setting of a clinical consultation room using standard
pictorial materials. Moreover, the findings highlight the
importance of maintaining a familiar routine in patient
management.
There is clinical evidence in SD that some learning is pos-
sible. Patients may, for example, effectively learn the names
of new acquaintances or of prescribed medicines. They may
also succeed in relearning lost vocabulary (Snowden and
Neary, 2002; Henry et al., 2008; Jokel and Anderson, 2012;
Savage et al., 2013; Hoffman et al., 2015). However, reten-
tion depends on continued rehearsal and is more robust
when words are linked to patients’ ongoing daily experi-
ences (Snowden and Neary, 2002). An alternative therapeu-
tic approach involves the use of compensatory strategies
of enactment to bypass verbal communication difficulties
(Kindell et al., 2013). These findings demonstrate the poten-
tial value of speech and language therapy intervention in the
management of SD.
Semantic dementia 791
68.15 THEORETICAL ISSUES
SD attracts considerable theoretical interest from neuropsy-
chologists. Its circumscribed nature means that the disor-
der represents a natural model for understanding semantic
memory. It is now widely accepted that concepts depend
on a distributed brain network, modality-specific concep-
tual features being represented by distinct sensory and
motor brain regions (Pulvermüller et al., 2009; Kiefer and
Pulvermüller, 2012). Nevertheless, the profound and per-
vasive nature of conceptual loss in SD provides compelling
grounds for the view that the anterior temporal lobes have
a special role to play. The precise nature of that privileged
role remains contentious. For some, the anterior temporal
lobes constitute a supramodal or amodal hub where infor-
mation is distilled and represented in a non-modal form
(Patterson et al., 2007; Hoffman et al., 2012). A challenge
to this ‘amodal’ position is the fact that understanding of
names (verbal information) and faces (visual information)
may be affected differentially in SD, depending on whether
the left or right temporal lobe is most affected (Snowden
et al., 2004, 2012). Such findings, it is argued (Snowden
et al., 2012), would favour the notion of the anterior tem-
poral lobes as modality-specific convergence zones rather
than a unitary amodal hub. Other authors (Mion et al.,
2010) have accommodated hemispheric differences within
the ‘amodal’ framework by attributing those differences
to differential strength of connectivity of the amodal hub
to modality specific brain regions within the two hemi-
spheres. Such debate exemplifies the importance of SD in
informing, understanding and constraining theories of the
neural basis of conceptual knowledge.
68.16 CONCLUSIONS
SD is a striking disorder, clinically distinct from AD and
other forms of dementia. Patients exhibit unique pat-
terns of cognitive and behavioural symptomatology, which
demand novel approaches to treatment and management.
Neuropsychological studies are likely to improve under-
standing of the cognitive characteristics of this disorder.
Meanwhile, basic scientific advances ought to shed light on
the underlying aetiology of this and other clinical manifesta-
tions of FTLD.
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Primary progressive aphasia and posterior
cortical atrophy
JONATHAN D. ROHRER, SEBASTIAN J. CRUTCH AND JASON D. WARREN
This chapter consists of two sections covering the focal
dementia syndromes of primary progressive aphasia (PPA)
(Section 69.1) and posterior cortical atrophy (PCA) (Section
69.2). Though uncommon, these heterogeneous clinico-
pathological entities have a disproportionate importance
due to the insights they provide into regional brain mecha-
nisms of neurodegeneration and the particular challenges
they pose for clinical diagnosis and management.
69.1 NONFLUENT AND LOGOPENIC
VARIANTS OF PRIMARY
PROGRESSIVE APHASIA
69.1.1 INTRODUCTION AND NOSOLOGY
PPA is a term that has been used to encompass all patients
with progressive language impairment as the initial fea-
ture of a degenerative disorder (Mesulam, 1982; Mesulam,
2001; Mesulam, 2003). There is overlap with the frontotem-
poral dementia (FTD) spectrum both pathologically and
genetically (Neary et al., 1998; Mackenzie and Rademakers,
2007). Although some research groups have previously
classified all language disorders under this one term of PPA
(Mesulam 2001; Mesulam et al., 2003), it is clear that a num-
ber of subtypes can be identified (see reviews by Grossman
et al., 2004; Amici et al., 2006; Hodges and Patterson, 2007;
Mesulam et al., 2007; Rohrer et al., 2008a; Grossman, 2012;
Mesulam et al., 2014). The fluency of speech output forms
the basis for a basic clinical descriptive subclassification
of PPA; however, fluency is often problematic to opera-
tionalize; it has been used to refer to reduced, effortful or
sparse speech, however these may map onto distinct syn-
dromes within the PPA syndrome. Semantic dementia
(SD) or semantic variant PPA (svPPA) is a homogeneous
69
clinico-pathological entity with characteristic clinical, neu-
ropsychological and radiological findings (see Chapter 68).
SvPPA presents usually with a ‘fluent’ aphasia (and there-
fore has previously been called fluent PPA: Adlam et al.,
2006), however two other major PPA syndromes are associ-
ated with ‘nonfluent’ language output: these nonfluent dis-
orders, progressive nonfluent aphasia (PNFA) or nonfluent
variant PPA (nfvPPA) and logopenic aphasia (LPA) or logo-
penic variant PPA (lvPPA), are discussed in detail in this
chapter. It remains unclear if these are the only subtypes
of PPA and how this heterogeneous group of conditions
maps onto the underlying genetic and pathological causes.
While early nfvPPA can resemble Broca’s aphasia and early
lvPPA may resemble conduction aphasia (Hachisuka et al.,
1999; reviewed in Rohrer et al., 2008a), the PPA subtypes do
not correspond closely with the acute aphasia syndromes
of stroke, due both to differing neuroanatomical patterns
of involvement and the progressive nature of the disease.
Initial consensus criteria for PNFA and SD (Neary et al.,
1998) and other criteria for PPA as a unitary syndrome
(Mesulam, 2001, 2003) have recently been updated, defin-
ing criteria for the semantic, nonfluent and logopenic vari-
ants of PPA (Gorno-Tempini et al., 2011).
69.1.2 SYNONYMS
●● Nonfluent variant of PPA (nfvPPA), progressive non-
fluent aphasia (PNFA), nonfluent progressive aphasia
(NFPA), progressive apraxia of speech (AOS), agram-
matic variant of PPA.
●● Logopenic variant of PPA (lvPPA), logopenic/phonologi-
cal aphasia (LPA), logopenic aphasia (LPA), progressive
logopenic aphasia (PLA).
●● Semantic variant of PPA (svPPA), semantic dementia
(SD), fluent variant of PPA, ‘Gogi aphasia.’
795
796 Dementia
69.1.3 EPIDEMIOLOGY
The PPA variants are collectively uncommon although there
are no large epidemiological studies of PPA. There are no
clearly associated non-genetic risk factors for PPA although
one study has shown an increased frequency of learning dis-
ability in patients with PPA and their first-degree relatives
(Rogalski et al., 2008a, 2013).
69.1.4 GENETICS
PPA is usually sporadic but can rarely be familial (Krefft
et al., 2003; Goldman et al., 2005) with one study showing
that nfvPPA was associated with an autosomal dominant
family history of PPA or FTLD in 6.9% of cases (Goldman
et al., 2005). Many familial PPA patients have been found to
have mutations in the progranulin (GRN) gene (Snowden
et al., 2006, 2007a, 2007b, 2007c; Mesulam et al., 2007; Beck
et al, 2008), and more recently a few familial PPA patients
have been found to have mutations in the C9orf72 gene
(Rohrer et al., 2015). In contrast, lvPPA and svPPA are only
very rarely familial. Beyond Mendelian genetics, there have
been inconsistent results from studies investigating apoli-
poprotein E (ApoE) and prion protein (PRNP) codon 129
genotypes as well as microtubule-associated protein tau
(MAPT) haplotype in PPA, and no clear genetic risk factors
have emerged (Mesulam et al., 1997; Sobrido et al., 2003;
Gorno-Tempini et al., 2004a, 2004b; Li et al., 2005; Acciarri
et al., 2006; Rohrer et al., 2006; Daniele et al., 2009).
69.1.5 PATHOLOGY
The main pathological causes of PPA fall into three categories:
the two major frontotemporal lobar degeneration (FTLD)
pathologies known as FTLD-tau and FTLD-TDP (where
TDP is the TAR DNA binding protein) and Alzheimer’s dis-
ease (AD) pathology. SvPPA is typically a FTLD-TDP type C
disorder but can rarely be caused by FTLD-tau Pick’s disease
or globular glial tauopathy, or less commonly Alzheimer’s
pathology (Knibb et al., 2006; Snowden et al., 2007a, 2007b,
2007c; Pereira et al., 2009; Clark et al., 2015). In contrast,
nfvPPA can be caused by all three pathologies, although
patients with a prominent motor speech impairment are
associated particularly with the FTLD-tau pathologies, corti-
cobasal degeneration (CBD), progressive supranuclear palsy
(PSP) and Pick’s disease (Josephs et al., 2006a) rather than
FTLD-TDP. However, a single case of progressive motor
speech impairment and Alzheimer pathology is reported
(Gerstner et al., 2007). LvPPA appears to be most commonly
associated with AD pathology although some cases have
been reported with FTLD-TDP inclusions (Mesulam et al.,
2008): In a parallel theme in the literature and prior to the
detailed description of lvPPA, a number of research groups
described an atypical language variant of AD, many cases of
which might now be characterized as lvPPA (Greene et al.,
1996; Galton et al., 2000; Alladi et al., 2007; Josephs et al.,
2008). Those PPA cases associated with GRN and C9orf72
mutations fall within the FTLD-TDP spectrum pathologi-
cally. See Figure 69.1 for a schematic diagram of the clinico-
pathological associations of PPA.
69.1.6 CLINICAL AND
NEUROPSYCHOLOGICAL FEATURES
Table 69.1 summarizes the clinical and neuropsychological
features of the PPA syndromes; svPPA is also included for
the purposes of comparison.
69.1.7 NONFLUENT VARIANT OF PPA
69.1.7.1 Spontaneous speech
The characteristic features of nfvPPA are the presence of
agrammatism and hesitant, effortful speech secondary to
a motor speech impairment that is usually characterised as
an AOS (Weintraub et al., 1990; Tyrrell et al., 1991; Turner
et al., 1996; Westbury and Bub, 1997; Neary et al., 1998;
Gorno-Tempini et al., 2004a, 2004b; Ogar et al., 2007).
Either of these features may dominate at presentation
though there is some controversy as to which is the core
deficit and how they are related to each other. Cases of pure
progressive AOS have been described; however, most cases
with longitudinal follow-up appear to develop agramma-
tism/aphasia. Similarly, there are patients who have pure
agrammatism initially. Both of these symptoms are neuro-
anatomically related to left inferior frontal/insular atrophy
and it is therefore unsurprising that they commonly occur
together. Nonetheless, there are still some authorities who
exclude pure motor speech impairment in the absence of
other speech and language deficits from the PPA spectrum
(Mesulam et al., 2007). One other ongoing difficulty has
been in defining AOS (a problem of planning articulation)
so that it is uniformly applied by different centres (Ogar
et al., 2005): the key features are difficulty initiating speech
and trial and error groping towards the correct word lead-
ing to dysprosodic, hesitant and effortful speech output.
Errors in patients with AOS are sound distortions (often
additions) and are termed apraxic or phonetic errors. In
practice, these can be difficult to distinguish from phone-
mic errors (i.e. errors due to the incorrectly selected sound)
although it is likely that both phonetic and phonemic errors
occur in nfvPPA. The importance of defining patients as
nfvPPA with or without motor speech impairment is the
association with a particular pathological substrate: AOS
is likely to predict tau-positive histopathology (Josephs
et al., 2006a). In imaging studies, AOS has been associated
with premotor and supplementary motor areas (Josephs
et al, 2006a) as well as the insula and basal ganglia (Ogar
et al., 2007). Most patients will eventually become mute
although non-speech vocalizations such as laughter may be
present even when there is no speech (Rohrer et al., 2009c).
Early mutism in nfvPPA has been associated with left pars
opercularis and basal ganglia atrophy (Gorno-Tempini
­
et al., 2006).
 Primary progressive aphasia and posterior cortical atrophy 797

Primary progressive aphasia (PPA)

Sporadic PPA Familial PPA

GRN-associated C9orf72-associated
svPPA nfvPPA IvPPA
aphasia aphasia

Pathological subtypes

FTLD-TDP FTLD-TDP FTLD-TDP FTLD-tau FTLD-tau FTLD-tau Alzheimer

Type A Type B Type C CBD/PSP Pick’s GGT pathology

Figure 69.1 (See colour insert.) Clinico-pathological and clinico-genetic associations in primary progressive aphasia (PPA).
PPA as a syndrome has heterogeneous genetic and pathological associations. However, the importance of subtyping PPA
is indicated by the third row of boxes, which show in a schematic manner the pathological associations with semantic vari-
ant PPA (svPPA), nonfluent variant PPA (nfvPPA), logopenic PPA (lvPPA) and with the familial progranulin (GRN)-associated
or C9orf72-associated form of PPA, where one pathological subtype tends to dominate. Each of the pathological subtypes
are indicated by a separate coloured box: frontotemporal lobar degeneration – TAR DNA binding protein (FTLD-TDP)
types A to C, FTLD-tau (CBD, corticobasal degeneration; PSP, progressive supranuclear palsy; GGT, globular glial tauopa-
thy; and Pick’s disease) and Alzheimer pathology.

69.1.7.2 Naming and single-word
comprehension
Other features include anomia that is initially mild with a sug-
gestion that verb naming may be affected more than nouns
(broadly, the reverse pattern to that seen in svPPA: Hillis et al.,
2002, 2004). The underlying cognitive deficit causing anomia
has not been fully established in nfvPPA and although there
is some evidence to implicate a primary word retrieval deficit,
this may not be the only or even the primary domain (Rogalski
et al., 2008b). Indeed, imaging studies have implicated a net-
work of brain areas in association with anomia in nfvPPA,
particularly inferior frontal, lateral temporal and anterior pari-
etal lobes (Grossman et al., 2004; McMillan et al, 2004; Amici
et al, 2007). Single-word comprehension is essentially normal
early in the disease but becomes affected a number of years
into the illness (Blair et al., 2007). The cause of single-word
comprehension impairment in nfvPPA as the disease develops
is unclear though this may partly reflect a more generalized
auditory agnosia associated with posterior perisylvian damage
(Uttner et al., 2006; Goll et al., 2010).
comprehension deficit. This has been studied in great-
est detail in a series of studies by Grossman et al. (Cooke
et al., 2003; Grossman and Moore, 2005; Peelle et al., 2007).
Patients perform poorly on complex sentences but relatively
normally with simple sentence structures. One small func-
tional magnetic resonance imaging (fMRI) study showed
decreased activation in left ventral inferior frontal lobe
areas known to be associated with grammatical processing
(Cooke et al., 2003).
69.1.7.4 Repetition
Patients with nfvPPA have early difficulty with repetition
of polysyllabic words and sentences. This progresses such
that later in the disease even monosyllabic word repetition
becomes difficult. Impaired polysyllabic word repetition
with intact single-word comprehension has been proposed
as a simple bedside measure for distinguishing the nonflu-
ent aphasias from svPPA, e.g. by asking the patient to repeat
‘hippopotamus’ and then to identify a picture of a hippo-
potamus (Hodges et al., 2008).

69.1.7.3 Grammar and sentence 69.1.7.5 Literacy

comprehension
Patients with nfvPPA often have phonological dyslexia.
Like the expressive agrammatism seen in nfvPPA, Writing may be agrammatic with phonological errors,
patients also have receptive agrammatism and a sentence although tends to be affected later than speech.
798 Dementia

Table 69.1 Summary of language, neuropsychological and imaging features in PPA

svPPA nfvPPA lvPPA

Speech rate/pauses Normal Slow with hesitancy, Slow with word-finding
effortfulness secondary to pauses
motor speech disorder
and/or agrammatism
Speech errors Semantic Phonetic/apraxic errors Occasional phonemic errors,
Phonemic errors rare semantic errors
Apraxia of speech None Present None
Dysarthria None Can be present as the None
disease progresses
Naming Anomia Initially can be normal but Anomia
anomic as disease
progresses
Single-word comprehension Impaired secondary to Initially intact but in late Initially relatively intact but
verbal semantic disease becomes affected becomes affected as
impairment disease progresses
Sentence comprehension Normal initially but Impaired for complex Impaired for simple and
becomes impaired as sentences complex sentences
single-word
comprehension
deteriorates
Single-word repetition Normal Impaired with phonetic/ Impaired with occasional
apraxic errors phonemic errors
Sentence repetition Often normal initially but Can be impaired Very impaired
can make transposition
errors
Reading Surface dyslexia Phonological dyslexia Phonological dyslexia
Other cognitive domains Non-verbal semantic Can later develop dominant Verbal short-term
involved impairment can develop parietal impairment (phonological) memory
object agnosia/ (dyscalculia, limb apraxia) and other dominant
prosopagnosia particularly if associated parietal functions –
with CBS dyscalculia, limb apraxia
Behaviour Disinhibition, appetite Depression, apathy Apathy, anxiety
change
Additional neurological Usually none Can be associated with Usually none
abnormalities CBS, hemiparkinsonism,
PSP syndrome
Neuroanatomy Asymmetrical anteroinferior Asymmetrical L > R inferior Asymmetrical L > R posterior
temporal lobes frontal lobe/insula temporal–inferior parietal
lobes
Abbreviations: PPA, primary progressive aphasia; svPPA, semantic variant; nfvPPA, nonfluent variant PPA; lvPPA, logopenic PPA; CBS, corti-
cobasal syndrome; PSP, progressive supranuclear palsy; L, left hemisphere; R, right hemisphere.

69.1.7.6 Other cognitive domains
Other domains including calculation and limb praxis may
also be affected (Joshi et al., 2003). Episodic memory, visuo-
spatial and visuoperceptual skills generally remain rela-
tively intact in patients with nfvPPA.
features similar to the behavioural variant of FTD as the
disease progresses. Early on there may be a co-existing
depression (Medina and Weintraub, 2007) with subsequent
emergence of apathy, anxiety, and in particular, irritabil-
ity (Marczinski et al., 2004; Rosen et al., 2006; Banks and
Weintraub, 2008).

69.1.7.7 Behavioural features 69.1.7.8 Additional neurological features

Although language impairment is the dominant feature, Recent work has emphasized that the presence of a motor
early on in the disease patients do develop behavioural speech disorder, in particular AOS, predicts the pathological

diagnosis of a tauopathy, either CBD or PSP (Josephs et al.,
2008, 2012, 2013). Similarly, during life a corticobasal
syndrome or PSP syndrome often accompanies nfvPPA
(Kertesz et al., 1999; Mochizuki et al., 2003; Gorno-Tempini
et al., 2004b; McMonagle et al., 2006a; Josephs et al., 2008).
Dysphagia can occur as a late feature in nfvPPA (Fuh et al.,
1994).
Rarely, nfvPPA can be associated with motor neurone
­disease (MND)/amyotrophic lateral sclerosis (ALS) (Caselli
et al., 1993; Tsuchiya et al., 2000; Bak et al., 2001; Catani et al.,
2004; da Rocha et al., 2007) although there are currently no
systematic studies of MND/ALS in PPA. Limited evidence
suggests that selective impairment of verb processing may be
an aphasic hallmark of PPA/MND (Bak et al., 2001).
69.1.8 LOGOPENIC VARIANT OF PPA
69.1.8.1 Spontaneous speech
The spontaneous speech of patients with lvPPA is slow with
long word-finding pauses but without agrammatism or
motor speech impairment. When the patient does actually
produce speech, output is relatively ‘fluent’ (non-effortful):
an important bedside distinction from nfvPPA.
69.1.8.2 Naming and single-word
comprehension
Naming is affected to a greater extent than in nfvPPA (but
less prominently than with svPPa). Similarly, single-word
comprehension is relatively intact initially but may become
affected as the disease progresses.
69.1.8.3 Grammar and sentence
comprehension
Patients with lvPPA have difficulty with both simple and
complex sentence comprehension. This is thought to be
secondary to a verbal short-term (phonological) memory
deficit rather than a primary grammatical deficit (Gorno-
Tempini et al., 2008).
69.1.8.4 Repetition
Sentence repetition is particularly affected in patients with
lvPPA with single-word repetition relatively intact at least
early in the disease (Gorno-Tempini et al., 2008; Gorno-
Tempini et al., 2011).
69.1.8.5 Literacy
A study of reading in lvPPA suggested that patients have
greater difficulty reading nonsense or pseudowords that
they characterized as phonological dyslexia, associated
neuroanatomically with left temporo-parietal atrophy
(Brambati et al., 2009a, 2009b).
Primary progressive aphasia and posterior cortical atrophy 799
69.1.8.6 Other cognitive domains
Verbal or phonological short-term memory appears to be a
key cognitive domain affected in lvPPA. This is reflected in
the poor forwards digit span exhibited by these patients and
may underpin linguistic deficits such as impaired sentence
repetition and sentence comprehension that help to define
the syndrome (Gorno-Tempini et al., 2008). Consistent
with underlying Alzheimer’s pathology in a high pro-
portion of cases, episodic memory appears frequently to
become affected later in the disease (Gorno-Tempini et al.,
2004b) though less prominently than in typical amnestic
AD (tAD). However, few studies have addressed the lan-
guage features of typical AD in comparison with lvPPA
(Westbury et al., 2002; Mendez et al., 2003; Taler and
Phillips, 2008).
69.1.8.7 Behavioural features
As in nfvPPA, behavioural features are generally not salient
early in lvPPA but may emerge later in the course. One study
identified depression, anxiety and apathy as behavioural
features of lvPPA (Rosen et al., 2006).
69.1.8.8 Additional neurological features
There are usually no additional neurological features in
lvPPA, and in particular (in contrast to nfvPPA) associated
parkinsonism or MND appear to be rare.
69.1.9 GENETIC PPA
There have been few detailed studies of the aphasia associ-
ated with mutations in the GRN or C9orf72 genes. Initial
reports of GRN-associated aphasia suggested a nonfluent
aphasia, but more detailed studies have reported cases
with a prominent early anomia, no motor speech impair-
ment and a relatively early single-word comprehension
deficit (Snowden et al., 2006, 2007a, 2007b, 2007c; Rohrer
et al., 2008b). Further detailed studies of patients with
GRN-and C9orf72-associated PPA will be required to
understand where such patients fall within the nonfluent
PPA spectrum and their relationship to sporadic nfvPPA
and lvPPA.
69.1.10 OTHER FOCAL SPEECH AND
LANGUAGE SYNDROMES
A number of other speech and language syndromes have
been described that do not clearly fit into the current
scheme of the progressive aphasias. As these presently lack
defined pathological or genetic associations, it remains
unclear exactly how they are related to svPPA, nfvPPA and
lvPPA. Progressive articulatory disorders associated with
cortical disease have been described as ‘progressive dysar-
thria’ (Soliveri et al., 2003), ‘slowly progressive anarthria’
(Broussolle et al., 1996; Lucchelli and Papagno, 2005), or
800 Dementia
‘pure progressive aphemia’ (Cohen et al., 1993). Although it
is clear that dysarthria commonly occurs as an accompani-
ment to AOS and aphasia in nfvPPA (Gorno-Tempini et al.,
2004a; Ogar et al., 2007), it remains unclear whether iso-
lated ‘cortical dysarthrias’ eventually evolve into the same
syndrome or whether they may remain isolated. Similarly,
progressive impairment of prosody has been described as a
selective deficit (Ghacibeh and Heilman, 2003; Luzzi et al.,
2008), but probably occurs more frequently as part of a PPA
syndrome (Tsao et al., 2004). So-called ‘dynamic aphasia’,
a selective disorder of verbal planning, may manifest as a
progressive disorder independent of a widespread apathy or
abulia (Warren et al., 2003; Perez et al., 2013).
69.1.11 NEUROIMAGING
There have been a number of imaging studies investigat-
ing the neuroanatomical patterns of atrophy or hypo-
metabolism in nfvPPA and lvPPA (Nestor et al., 2003;
Gorno-Tempini et al., 2004a; Grossman et al., 2004; Clark
et al., 2005; Zahn et al., 2005; Josephs et al., 2006b; Nestor
et al., 2007; Ogar et al., 2007; Schroeter et al., 2007; Gorno-
Tempini et al., 2008; Lindberg et al., 2009; Rohrer et al.,
2009a; Galantucci et al., 2011; Mahoney et al., 2013; Caso
et al., 2014; Rogalski et al., 2014). As with the clinical and
neuropsychological findings discussed above, neuroim-
aging findings in PPA have been relatively heterogeneous
indicating involvement mainly of the left hemisphere
fronto-temporo-parietal language network (Sonty et al.,
2003; Vandenbulcke et al., 2005; Sonty et al., 2007). This is
largely attributable to a scarcity of well-defined, uniform
clinico-pathological cohorts: most studies have been per-
formed in clinically defined cohorts that (at least in older
studies) are likely to contain patients with heterogeneous
tissue pathologies. Nonetheless, in most studies of nfvPPA,
the most significantly affected areas are in the left infe-
rior frontal lobe and anterior insula (Nestor et al., 2003;
Gorno-Tempini et al., 2004a; Ogar et al., 2007; Rohrer
et al., 2009a), with the left middle and superior frontal
and superior temporal lobes also commonly affected as
the disease evolves (Gorno-Tempini et al., 2004b; Ogar
et al., 2007; Rohrer et al., 2009b). Anterior parietal lobe
involvement is less commonly reported but may occur
particularly with disease progression and when there is
an accompanying corticobasal syndrome (Gorno-Tempini
et al., 2004b; Rohrer et al., 2009b). Pathologically con-
firmed studies of nfvPPA have usually been based on
mixed pathological groups (e.g. tau-positive but a mix-
ture of PSP, CBD and/or Pick’s disease) but have also
shown broadly similar involvement of anterior insula and
inferior frontal lobe (Josephs et al., 2006b; Rohrer et al.,
2009b). Metabolic (positron emission tomography/single-
photon emission computed tomography [PET/SPECT])
brain imaging may be helpful in distinguishing nonflu-
ent patients with Alzheimer pathology from others with
FTLD pathology (Nestor et al., 2007). There are few lon-
gitudinal studies of nfvPPA (Gorno-Tempini et al., 2004b;
Knopman et al., 2009): with disease progression, there is
spread from the left inferior frontal and insular cortex to
involve superior temporal, middle and superior frontal
and anterior parietal lobes (Gorno-Tempini et al., 2004b;
Rohrer et al., 2009b), and whole brain atrophy rates are
similar to other neurodegenerative diseases (1.6% per
year) (Knopman et al., 2009).
LvPPA has been less widely studied than nfvPPA (Gorno-
Tempini et al., 2004a, 2008; Wilson et al., 2009); however,
most studies have shown most significant involvement of
the left posterior superior temporal and inferior parietal
lobes with spread to the posterior cingulate and middle/
inferior temporal lobe as the disease unfolds. Consistent
with the hypothesis that most patients with lvPPA have
Alzheimer pathology, multiple studies have now shown that
the majority of lvPPA cases have positive amyloid PET scans
(Rabinovici et al., 2008; Leyton et al., 2011).
There are few neuroimaging studies of GRN-associated
PPA (Borroni et al., 2008; Cruchaga et al., 2008; Rohrer
et al., 2008b). There tends to be asymmetrical left greater
than right hemisphere atrophy affecting frontal, temporal
and (to a lesser extent) parietal lobes with somewhat more
prominent posterior atrophy than usually occurs in nfvPPA
and more anterior temporal lobe atrophy than occurs
in lvPPA.
Little information is available for nfvPPA associated with
MND/ALS, but in single cases, bilateral (often more severe
on the left) frontal or frontotemporal atrophy/hypometabo-
lism has been reported (Bak et al, 2001; Catani et al., 2004;
da Rocha et al., 2007).
69.1.12 MANAGEMENT
There are currently no symptomatic or curative phar-
macological therapies for PPA. Small trials have yielded
inconclusive results (bromocriptine: Reed et al., 2004;
galantamine: Kertesz et al., 2008) and there are a number
of unsubstantiated single case reports of the use of a vari-
ety of drugs (Decker and Heilman, 2008; Tobinick, 2008).
Although there is no clear evidence base, many patients find
speech and language therapy helpful to provide communi-
cation strategies: the use of Augmentative and Alternative
Communication (AAC) methods are little studied but low-
technology input such as communication notebooks are
generally favoured over more high-technology devices such
as handheld computers (Rogers et al., 2000; Beukelman
et al., 2007). Genetic counselling is important in those with
a family history and/or a known GRN or C9orf72 mutation.
69.1.13 CONCLUSIONS
The progressive aphasias have provided uniquely valuable
neurobiological perspectives on the processes of focal neuro-
degeneration, yet there is continuing controversy within the
field. How many subtypes of nonfluent PPA are there?; how
can motor speech disorders/AOS best be operationalized?;
is the first symptom of agrammatism compared to a motor

speech disorder significant?; what are the clinico-patholog-
ical correlates of the different subtypes?; how do patterns of
brain atrophy change over time? Only studies with larger
cohorts of patients followed over a longer period of time will
resolve these key issues. None of the PPA syndromes has so
far achieved consensus criteria for diagnosis, and although
new criteria are currently in development, it seems likely that
only future research studies with detailed anatomical, patho-
logical and genetic correlation will yield sufficiently robust
criteria. The arrival of disease-modifying therapy is likely to
accelerate this process: together with molecular biomark-
ers, criteria that allow pathological diagnosis to be predicted
with accuracy in life will ultimately be required for the ratio-
nal application of effective treatments.
69.2 POSTERIOR CORTICAL ATROPHY
69.2.1 INTRODUCTION AND NOSOLOGY
PCA is a clinico-radiologic syndrome characterized by
­progressive decline in visual processing skills, relatively
intact memory and language in the early stages and atro-
phy of posterior brain regions (Benson et al., 1988; Mendez
et al., 2002; Tang-Wai et al., 2004; see Crutch et al., 2012
for a review). Histopathological studies have identified amy-
loid plaques and neurofibrillary tangles as the most com-
mon underlying pathology, and PCA is now recognized
as a common form of atypical AD (McKhann et al., 2011;
Dubois et al., 2014). However, the occurrence of PCA associ-
ated with alternative aetiologies has led to renewed calls for
PCA to be considered as a distinct nosological entity with
its own diagnostic criteria (Tang-Wai and Mapstone, 2006;
Crutch et al., 2013a).
Many questions remain over whether PCA should be
considered a unitary clinico-anatomical syndrome or as
a collection of related but distinct syndromic subtypes.
Extrapolating from basic neuroscience evidence of distinct
cortical streams which process different kinds of visual
information (Ungerleider and Mishkin, 1982; Goodale and
Milner, 1992), it has been suggested that separate parietal
(dorsal), occipitotemporal (ventral) and primary visual
(posterior) forms of PCA exist (Galton et al., 2000). One
difficulty is that such claims are based upon the obser-
vation of patterns of impairment in single cases, and the
existence of an occipitotemporal variant has not been sup-
ported by larger group studies (McMonagle et al., 2006b).
These anterior-posterior and superior-inferior distinctions
also fail to capture the pronounced asymmetry apparent
in the neuropsychological and neuroimaging profiles of
many individuals with PCA (e.g. Freedman et al., 1991;
Snowden et al., 2007a, 2007b, 2007c). At a more general
level, it is noteworthy that with a relative preservation
of episodic memory, individuals with PCA do not meet
all established criteria for dementia (e.g. Diagnostic and
Primary progressive aphasia and posterior cortical atrophy 801
Statistical Manual of Mental Disorders, Fourth Edition
[DSM-IV]).
69.2.2 SYNONYMS
Posterior cortical atrophy, Benson’s syndrome, progressive
posterior cortical dysfunction, biparietal AD, visual variant
of AD.
69.2.3 EPIDEMIOLOGY
The exact prevalence and incidence of PCA are not known
and any figure is likely to be an underestimate because
of poor general knowledge of the syndrome’s existence.
However, in a study of 523 patients with AD at a single
specialist centre, a visual presentation (also labelled PCA)
was reported in 5% of the cohort (Snowden et al., 2007a,
2007b, 2007c). Studies comparing PCA and amnestic AD
suggest few epidemiological differences apart from age of
disease onset, which tends to be earlier in PCA around the
mid-50s and early 60s (e.g. Mendez et al., 2002; McMonagle
et al., 2006b) although some studies report a wide distri-
bution (40–86 years) (Tang-Wai et al., 2004). Group studies
and reviews have indicated either no difference in preva-
lence among the genders (e.g. Mendez et al., 2002, Renner
et al., 2004; McMonagle et al., 2006b) or over-representation
among women (e.g. Tang-Wai et al., 2004; Snowden et al.,
2007a, 2007b, 2007c).
69.2.4 GENETICS
The proportion of individuals with PCA with a positive
family history of dementia is not significantly different to
individuals with typical AD (Mendez et al., 2002; Tang-Wai
et al., 2004). It is of note that there have been no convinc-
ing reports of an autosomal-dominant inheritance pattern
in PCA, and indeed of the 11 PCA patients (27.5%) in the
Tang-Wai et al. (2004) study who had a family history of
a dementing illness, none of those family members had
a posterior cortical syndrome. These studies also report
no difference in the ApoE status of PCA relative to typi-
cal AD. However, a difference between the ApoE status of
individuals with posterior cortical presentations of AD and
amnestic AD has been suggested (Schott et al., 2006; van
der Flier, 2006; Snowden et al., 2007a, 2007b, 2007c). Schott
et al. (2006) reported that fewer patients with biparietal AD
than typical AD have one or more ε4 alleles (20% and 86%,
respectively). In a larger study examining the relationship
between cognitive profile and ApoE status in 302 patients
with typical or atypical AD (Snowden et al., 2007a, 2007b,
2007c), the percentage of patients with a visual presenta-
tion possessing at least one ε4 allele was significantly lower
than patients with an amnestic presentation (30% and 82%,
respectively; typical AD: 55%) and not different to a popula-
tion of 756 healthy individuals from the same region (27%;
Payton et al., 2003). This evidence suggests that risk factors
802 Dementia
other than ApoE underpin posterior cortical syndromes in
AD. A recent collaborative study with 302 patients has con-
firmed that ApoE alters PCA risk, but with a smaller effect
than for typical AD, and has identified three candidate loci
(near CNTNAP5, FAM46A and SEMA3C) that, if repli-
cated, may provide insights into selective vulnerability and
phenotypic diversity in AD (Schott et al., 2016).
69.2.5 PATHOLOGY
Histopathological studies have revealed that AD is the
most common underlying cause of PCA (Hof et al., 1989,
1990; Ross et al., 1996; Galton et al., 2000; Renner et al.,
2004; Tang-Wai et al., 2004; Alladi et al., 2007; Snowden
et al., 2007a, 2007b, 2007c). The distinction between PCA
and typical AD lies in the distribution of this pathology.
Compared to individuals with typical AD, patients with
PCA show a much greater density of senile plaques and
neurofibrillary tangles in occipital cortex and regions of
posterior parietal cortex and temporo-occipital junction,
while showing fewer pathological changes in more anterior
areas such as prefrontal c­ ortex (e.g. Levine et al., 1993; Ross
et al., 1996; Hof et al., 1997). However, AD is not the only
aetiology responsible for the syndrome, with a small num-
ber of cases attributable to CBD (Tang-Wai et al., 2003a;
Renner et al., 2004), ­dementia with Lewy bodies (Tang-Wai
et al., 2003b; Renner et al., 2004), prion disease (Renner
et al., 2004; Victoroff et al., 1994) and so-called subcortical
gliosis (Victoroff et al., 1994).
69.2.6 CLINICAL AND
NEUROPSYCHOLOGICAL
FEATURES
69.2.6.1 Proposed diagnostic features
Two broadly comparable sets of diagnostic criteria have
been proposed (Mendez et al., 2002; Tang-Wai et al.,
2004). Suggested core features include: (1) insidious onset
and gradual progression; (2) presentation with visual
complaints in the absence of ocular disease; (3) relatively
preserved episodic memory, verbal fluency and personal
insight; (4) presence of symptoms including visual agno-
sia, simultanagnosia, optic ataxia, ocular apraxia, dys-
praxia and environmental disorientation; (5) absence
of stroke or tumour. Supportive features include alexia,
ideomotor apraxia, agraphia, acalculia, onset before the
age of 65 years and neuroimaging evidence of PCA or
hypoperfusion.
69.2.6.2 Additional neurological features
Neurological signs have been inconsistently reported in
group studies of PCA, and estimates of symptom frequency
are dependent upon the composition of the study popula-
tion. However, among 24 PCA patients with probable AD,
the frequency of extrapyramidal signs (41%), myoclonus
(24%) and grasp reflex (26%) was found to be compara-
ble to individuals with typical AD (Snowden et al., 2007a,
2007b, 2007c). Approximately 30% of PCA patients exhibit
asymmetrical left upper limb rigidity in addition to their
visual dysfunction (Ryan et al., 2014). A recent systematic
evaluation of oculomotor function using tests of fixation,
saccade and smooth pursuit has also shown that eye move-
ment abnormalities are near-ubiquitous in PCA (80% PCA,
17% tAD, 5% controls) (Shakespeare et al., 2015a). Up to
25% of PCA patients may also experience visual halluci-
nations (Tang-Wai et al., 2004; McMonagle et al., 2006b).
In a series of 59 patients with PCA, visual hallucinations
were observed in 13 individuals (22%) and were associated
with parkinsonism, rapid eye movement sleep behaviour
disorder, myoclonic jerks and not only atrophy of occipito-­
parietal regions but also disruption of thalamocortical cir-
cuits (Josephs et al., 2006b).
69.2.6.3 Neuropsychological profiles
The most frequently cited neuropsychological deficits
in PCA are visuospatial and visuoperceptual deficits,
including some or all of the features of Balint’s syndrome
(simultanagnosia, oculomotor apraxia, optic ataxia, envi-
ronmental agnosia), Gerstmann’s syndrome (acalculia,
agraphia, finger agnosia, left/right disorientation), alexia,
agraphia, acalculia and apraxia (Mendez et al., 2002;
Renner et al., 2004; Tang-Wai et al., 2004; Charles and
Hillis, 2005; McMonagle et al., 2006a; Whitwell et al.,
2007; Yong et al., 2014a). Neuropsychological studies of
PCA suggest that of these symptoms, alexia, agraphia,
simultanagnosia and optic ataxia are the most consistently
identified features (e.g. McMonagle et al., 2006b; Kas et al.,
2011). Additional features reported in a proportion of
patients include agnosia for objects, faces and colours. In
addition to higher order visual processing deficits of object
and space perception, impairments of more basic visual
functions (e.g. edge detection, form and motion coher-
ence) also affect the majority of PCA patients (Lehmann
et al., 2011b). Excessive crowding has recently been shown
to particularly limit object perception in the central vision
of PCA patients (Yong et al., 2014b). Overall, the plethora
of associated posterior cognitive deficits have predict-
able consequences for the performance of PCA patients
on more general neuropsychological tests such as perfor-
mance intelligence quotient (IQ) (often up to 30–40 points
lower than verbal IQ scores) and constructional tasks (e.g.
Rey figure copy, clock drawing). Longitudinal studies have
demonstrated that anterograde memory functions, linguis-
tic skills and frontal lobe functions, which are sometimes
strikingly preserved in the earlier stages of the condition,
do gradually deteriorate as individuals progress to a more
global dementia state (e.g. Levine et al., 1993; McMonagle
et al., 2006a). The aphasic difficulties are characterized
by progressive anomia and phonological impairment and
increasingly resemble the lvPPA syndrome described above
(Crutch et al., 2012).

69.2.6.4 Unusual symptoms
Although individuals with PCA experience the loss of many
visual functions, many also describe unusual new experi-
ences or ‘positive perceptual phenomena’. These phenomena
have not been widely recognized, but include abnormally
prolonged colour afterimages (Chan et al., 2001), reverse size
phenomena (e.g. Stark et al., 1997; Yong et al., 2014a), the
perception of movement among static stimuli, and in one
case even the 180° upside-down reversal of vision (Crutch
et al., 2010). Anecdotally, individuals with PCA also report a
range of localized sensory and pain phenomena, and distur-
bances of balance and bodily orientation potentially linked
to deranged visuo–vestibular interactions. Detailed inves-
tigation of these positive symptoms could potentially yield
important new insights about the pathophysiology as well as
the phenomenology of PCA.
69.2.7 OTHER FOCAL POSTERIOR
CORTICAL SYNDROMES
The proposed diagnostic criteria for PCA (Mendez et al.,
2002; Tang-Wai et al., 2004) both consider ‘presentation
with visual complaints’ as a core feature of the syndrome.
However, some patients with AD present initially with focal
deterioration in other cognitive domains such as praxis or
spelling (e.g. De Renzi, 1986; Green et al., 1995; Aharon-
Peretz et al., 1999; Snowden et al., 2007a, 2007b, 2007c)
with relative early sparing of visual function. Often these
individuals then progress to a more general posterior corti-
cal syndrome with memory relatively spared until later in
the disease course and consequently could be considered
to fall within the spectrum of PCA phenotypes. Given the
increasing awareness of non-AD pathologies underpinning
PCA and the move towards considering PCA as a distinct
nosologic entity in its own right, it may be that the available
diagnostic criteria for PCA will require some expansion to
include posterior cortical presentations, which are not pri-
marily visual in nature (Crutch et al., 2012, 2013b).
69.2.8 NEUROIMAGING
As the term PCA suggests, the syndrome is associated with
tissue loss primarily of the occipital, parietal and temporo-
occipital cortices. This pattern of atrophy is often evident from
visual inspection of structural magnetic resonance (MR) or
computed tomography (CT) images, but less specific radiolog-
ical findings such as generalized atrophy or normal volume for
age are also common (e.g. Sala et al., 1996; Galton et al., 2000;
Mendez et al., 2002). Systematic evaluations of brain struc-
ture in PCA using automated methods have been conducted,
with voxel-based morphometry revealing greater right pari-
etal and less left medial temporal and hippocampal atrophy in
PCA patients compared with those with typical AD (Whitwell
et al., 2007; Lehmann et al., 2011a). In addition, direct cortical
thickness comparisons between PCA and typical AD revealed
greater cortical thinning in the right superior parietal lobe and
Primary progressive aphasia and posterior cortical atrophy 803
less thinning in the left entorhinal cortex among PCA patients
(Lehmann et al., 2011a) (see Figure 69.2).
Consistent with these structural findings of atrophic
changes, functional imaging techniques such as SPECT
and PET imaging often reveal hypoperfusion and indicate
hypometabolism in dorsal occipito-parietal more than
ventral occipito-temporal regions (e.g. Pietrini et al., 1996;
Aharon-Peretz et al., 1999; Goethals and Santens, 2001; Kas
et al., 2011; Lehmann et al., 2013; Ossenkoppele et al., 2015).
In addition to posterior regions, fludeoxyglucose-positron
emission tomography (FDG-PET) has revealed specific areas
of hypometabolism in the frontal eye fields bilaterally, which
may occur secondary to loss of input from occipito-parietal
regions and underpin ocular apraxia in PCA (Nestor et al.,
2003). Pathophysiological studies using fMRI are lacking in
PCA and may be especially pertinent in PCA as the positive
perceptual phenomena described by these patients suggest
not merely loss of activity but aberrant activity in affected
cortical areas. Diffusion tensor imaging (DTI) has revealed
extensive degeneration of the major anterior–posterior con-
necting fibre bundles and of commissural frontal lobe tracts
(Cerami et al., 2015). Molecular imaging indicates that in
individuals with PCA attributable to AD, the focal poste-
rior pattern of cortical dysfunction involvement is evident
with tau imaging but less clear-cut with amyloid imaging
where results indicate with focal tangle distribution rather
than a more global pattern of amyloid deposition, which
is global (Lehmann et al., 2013; Ossenkoppele et al., 2015).
These findings suggest that tau is more closely linked to
PCA symptomatology than amyloid.
69.2.9 MANAGEMENT
There are currently no published studies examining the
­effectiveness of acetyl cholinesterase therapy specifically in
PCA. However, anecdotal and limited single case reports
suggest that donepezil, rivastigmine and galantamine
are associated in symptomatic benefit in a proportion of
the population (e.g. Kim et al., 2005), most likely those
­individuals with an underlying pathological diagnosis of
AD or dementia with Lewy bodies. There is also insuffi-
cient understanding of the psychological impact of PCA;
­preliminary studies suggest comparable levels of anxiety
and low mood but lower levels of apathy in PCA compared
with typical AD ( Shakespeare et al., 2015b) but a formal
study of the neuropsychiatric profile of PCA is yet to be
conducted.
A lack of understanding of PCA in the wider community
limits patients’ access to relevant services, and the care and
advice which is provided is often inappropriate, catering
to problems that are not significant (e.g. memory deficits)
while failing to cater to functionally critical perceptual defi-
cits (e.g. many activities in day centres and nursing homes
are visually mediated). Owing to the relative preservation of
memory, language and personal insight particularly in the
mild and moderate stages of the condition, individuals with
PCA are well-disposed to take advantage of peer support
804 Dementia

Figure 69.2 (See colour insert.) Regional percentage differences in cortical thickness in posterior cortical atrophy (PCA)
(N = 48) compared with typical amnestic Alzheimer’s disease (tAD; N = 30) for the left and right hemispheres. The colour
scale represents magnitude of cortical thickness difference. Red and yellow (positive values) represent lower cortical
­thickness in PCA subjects compared with tAD, whereas dark to light blue (negative values) represents greater cortical
thickness. (From Lehmann, M., et al., Cerebral Cortex, 21, 2122–2132, 2011a.)

meetings and group, couple and individual psychological
therapies where the need exists. Peer support meetings, in
particular, provide an important opportunity for reducing
social isolation, for sharing the experience of what is often
a particularly long and difficult route to diagnosis and for
exchanging practical tips and advice for managing problems
associated with the condition. Individuals with PCA often
benefit from resources designed primarily for the blind and
partially sighted, such as talking watches, mobile phones
with simplified displays, voice recognition software, talking
books, culinary aids and lamps to increase ambient light
levels in the home. Referral to an ophthalmologist may also
be required for an individual to register as partially sighted
under statutory invalidity schemes, which can enable access
to financial and social benefits and services.
69.2.10 CONCLUSIONS
PCA is a debilitating and under-recognized focal degener-
ative condition, which is associated with a range of differ-
ent disease pathologies. Analogies can be drawn between
the key focal dementia syndromes of PCA and PPA: like
PPA, PCA at once provides a crucial window on the neu-
robiology of neurodegeneration and raises substantial
nosological difficulties. The PCA syndrome justifies an
independent nosological status, but with AD as the most
common underlying cause, a lack of consistency between
studies regarding the classification of PCA at the disease
or syndrome level is likely to continue until more detailed
diagnostic criteria and terminology are available. Better
understanding and awareness of the syndrome among the
medical and lay communities is necessary to improve the
support services and information provided to individu-
als with PCA and their families. Dedicated clinical trials
assessing the effectiveness of pharmacological and non-
pharmacological interventions are also required in this
small but significant population of patients with degenera-
tive conditions.
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The cerebellum and cognitive impairment
ELSDON STOREY AND EVELYN A. LINDSAY
70.1 INTRODUCTION
The motor features of the cerebellar syndrome were crystal-
lized by the great English neurologist Sir Gordon Holmes
soon after the World War I. He did not ascribe any cognitive
function to the cerebellum and, until the last decade or two,
this view held a general sway. However, a confluence of evi-
dence from new anatomical tracing techniques, functional
neuroimaging experiments and careful clinical studies now
points strongly to a significant role that the cerebellum plays
in cognition, although the exact process(es) underlying this
contribution have not been fully elucidated. This chapter
aims to distil some of the important studies supporting a
non-motor role for the cerebellum. The reader interested
in a detailed exposition is referred to The Cerebellum and
Cognition, edited by Jeremy Schmahmann (1997), while
several shorter reviews have also been published (Timmann
and Daum, 2007; Baillieux et al., 2008; Strick et al., 2009;
O’Halloran et al., 2012; Koziol et al., 2014) on this topic for
scholarly reference.
70.2 THE NEUROANATOMICAL BASIS
OF CEREBELLAR COGNITIVE
FUNCTION
The cerebellum, which contains 80% of the neurones in the
whole brain in 10% of its total mass (Azevedo et al., 2009),
has a regular and relatively simple modular structure. The
‘corticonuclear microcomplex’ is essentially a positive loop
through the deep cerebellar nuclei, modulated by a vari-
able negative side loop through the cerebellar cortex (Ito,
1993). The degree of inhibitory influence of the cerebel-
lar cortical Purkinje cells on the deep cerebellar nuclei is
governed by the development of long-term depression
(LTD) at the excitatory parallel fibre-Purkinje cell dendrite
812
70
synapses (Ito, 1993). LTD itself develops in response to
near-simultaneous Purkinje cell activation by parallel fibres
and by climbing fibres from the inferior olive. It may thus
be considered to be analogous to associative long-term
potentiation in the hippocampus. In the influential Marr–
Albus–Ito model of cerebellar function, the climbing fibres
are regarded as carrying the ‘error signals’ responsible for
adaptive motor learning.
While there is no universally accepted model whereby
LTD in the corticonuclear microcomplex might result in
motor learning at the animal level (Massaquoi and Topka,
2002), it has been assumed from its stereotyped modu-
lar structure that the cerebellum performs the same type
of basic computation on whatever inputs it receives and
informs all its various efferent targets of the results of such
computation, similarly. If different areas of the cerebellum
differ in function, they do so by virtue of their differing
inputs and outputs.
With this in mind, the evidence for cerebellar input from
and output to non-motor areas can be considered. Such evi-
dence is both indirect and direct. The former consists of the
observation that, in primate phylogeny and especially in
hominids, the prefrontal portion of the frontal lobes and the
lateral neocerebellum with its associated ventral macrogyric
region of the dentate nucleus have undergone massive parallel
selective enlargement out of proportion to other brain areas
(Matano, 2001; Macleod et al., 2003). More direct evidence
has awaited the development of anterograde and retrograde
trans-synaptic (viral) tracers (Middleton and Strick, 1997).
Such tracers are necessary because cerebral cortical input to
the cerebellum proceeds via cortico-pontine fibres synapsing
in the pontine nuclei, which in turn project to the deep cer-
ebellar nuclei and cerebellar cortex, while cerebellar output
to the cortex proceeds via synaptic relays in the thalamus
(Schmahmann and Pandya, 1997). Studies utilizing such trac-
ers in primates have shown that a series of anatomically dis-
crete parallel cortico-ponto-cerebello-thalamo-cortical loops
exist, with pre-frontal input predominantly to the ventral,

macrogyric portion of the dentate nucleus and associated lat-
eral neocerebellar cortex and output via the ventrolateral and
medial dorsal thalamic nuclei (Middleton and Strick, 2000,
2001). Motor and premotor cortices, in contrast, are recipro-
cally connected to the phylogenetically older dorsolateral,
microgyric portion of the dentate nucleus (Middleton and
Strick, 2001). The analogy with separate, parallel corticobasal
ganglionic circuits subservient to motor and non-motor func-
tions, as conceptualized by Alexander et al. (1986) is readily
drawn (Middleton and Strick, 2000). This circuitry has now
been imaged in humans, using diffusion tensor imaging
(DTI) to identify prefrontal-pontine white matter projections
in the cortico-ponto-cerebellar system (Ramnani et al., 2006)
and functional connectivity magnetic resonance imaging
(MRI) to map cortico-cerebellar loops associated with higher
cognitive functions (Allen et al., 2005; Habas et al., 2009;
O’Reilly et al., 2009; Buckner et al., 2011; see Buckner, 2013
for a review).
70.3 FUNCTIONAL NEUROIMAGING
STUDIES
A large number of functional neuroimaging studies over
the last 25 years have reported cerebellar activation during
tests of various cognitive domains, utilizing positron emis-
sion tomography (PET) and functional magnetic resonance
imaging (fMRI) (Cabeza and Nyberg, 2000; Stoodley, 2012).
The typical design compares patterns of cerebellar activa-
tion on a cognitive task with that on what is thought to be
a relevant control ‘motor’ and/or perceptual task. Recent
meta-analyses identified consistent cerebellar involvement
in the domains of language, executive function and work-
ing memory (Stoodley and Schmahmann, 2009; Keren-
Happuch et al., 2014). This section includes a broadly
representative sample of such studies across these cognitive
domains, as well as memory and attention.
The phylogenetic development of the neocerebellum
in humans and evidence of reciprocal pathways between
the cerebellum and language-dominant frontal regions
prompted interest in a cerebellar contribution to language
(see Murdoch, 2010; Mariën et al., 2014, for reviews). For
example, Fullbright et al. (1999) asked subjects to read
silently. Their fMRI study showed that semantic compari-
son and judgement of non-word rhyming activated pos-
terolateral (and especially right posterolateral) cerebellar
cortex, compared with the control conditions of line ori-
entation judgement, upper versus lower case print judge-
ment or judgement of real word rhyming. Xiang et al. (2003)
confirmed the role of the right posterolateral cerebellum in
semantic discrimination divorced from articulation. Such
studies have led to the concept of the ‘lateralized linguistic
cerebellum’, reviewed by Mariën et al. (2001). Thürling et al.
(2011) used 7T MRI with a matrix block design to demon-
strate that motor speech (reading aloud) activated paraver-
mal areas of lobule VI and dorsorostral parts of the dentate
The cerebellum and cognitive impairment 813
nuclei bilaterally, whereas a more lateral region of the cer-
ebellar right hemisphere, lobule VI bordering on Crus I and
ventrocaudal parts of the dentate were activated by silent
verb generation. Their results confirmed that, as identified
in anatomical studies of monkeys, segregated regions of the
human cerebellar cortex and corresponding areas of the
dentate nuclei are allocated separately to motor and non-
motor functional domains. Operationalizing a contextual
semantic priming task, a study by Moberget et al. (2014)
showed an increased fMRI response in the right cerebel-
lum during target word predictability conditions, suggest-
ing that the cerebellum is involved in predictive language
processing, analogous to its hypothesized role in the motor
domain to predict and control actions.
The cerebellum also appears to be involved in executive
functioning and working memory. Cognitive processing dur-
ing attempted solution of a pegboard puzzle task compared
with simple peg movement was studied using fMRI estima-
tion of dentate activation by Kim et al. (1994). The cogni-
tively demanding task produced increased dentate activation
­bilaterally, compared with the activation seen with simple peg
movement. In as much as this task tapped visuospatial work-
ing memory, it is conceptually similar to the verbal working
memory fMRI study of Desmond et al. (1997), who found
that delayed matching of letter strings, but not the control
task, activated the right inferolateral cerebellar hemisphere.
Meta-analyses have confirmed different activation patterns
depending upon the type of working memory task, with ver-
bal working memory located more prominently in the right
hemisphere and spatial working memory in the left hemi-
sphere (Stoodley and Schmahmann, 2009; Keren-Happuch
et al., 2014). For instance, a study by Marvel and Desmond
(2010) showed separate clusters of cerebellar activity in dif-
ferent regions of the dentate nucleus during encoding and
retrieval and an increase in cerebro-cerebellar activity as a
result of cognitive load. The Wisconsin Card Sorting Test
(WCST), a complex task often used to assess aspects of execu-
tive functioning, has also been found to activate the lateral
cerebellum (Nagahama et al., 1996). In a study examining
whether the cerebellum is engaged only by prefrontal infor-
mation that requires action, Balsters et al. (2013) demon-
strated that lateral hemispheric regions of the cerebellum
receiving prefrontal projections were activated while pro-
cessing both rules specifying action and higher order rules
independent of action.
The role of the cerebellum in learning and memory has
been evidenced mainly in studies of procedural memory
and associative learning (O’Halloran et al., 2012). An aspect
of episodic memory was addressed by Andreasen et al.
(1999) in a ‘pure thought’ PET experiment. Subjects were
asked to recall a personal memory silently. The right lateral
cerebellum was activated in addition to several relevant
supratentorial areas. Fliessbach et al. (2007) found that
words remembered in a subsequent memory test following
incidental encoding evoked stronger fMRI responses in the
superior posterior region of the right cerebellum than words
that had been forgotten.
814 Dementia
A further area of recent active study has been the role(s)
of the cerebellum in attention. Allen et al. (1997) showed an
anatomical double dissociation in cerebellar regional acti-
vation; a visual attention task activated the lateral cerebel-
lum, while the motor task activated more medial regions.
Attention is, however, a multifaceted concept, placing a
variety of different demands on the subject. Le et al. (1998)
showed that shifting attention between stimulus dimen-
sions (colour/shape) activated the right lateral cerebellum,
while sustained attention did not. However, Bischoff-Grethe
et al. (2002) have demonstrated that the lateral cerebellum’s
role in this paradigm may actually be a reassignment of a
given motor response to the new stimulus dimension rather
than in shifting attention per se, a view supported more
recently by Haarmeier and Thier (2007).
Theory-of-mind (TOM) refers to inferential thinking
about the mental and emotional states of others (Premack
and Woodruff, 1978) and involves the ability to recognize
and identify emotions, understand implicit language and
interpret social situations. Functional imaging has impli-
cated the cerebellum in prefrontal and limbic cortical net-
works involved in TOM (or the broader concept of social
cognition) (Calarge et al., 2003; Van Overwalle et al., 2014).
It is clear that the weight of evidence from functional
neuroimaging studies in favour of lateral cerebellar contri-
butions to cognition is strong, as illustrated by the selected
studies cited above. However, it is also clear that the exact
role(s) of the lateral cerebellum in complex aspects of cogni-
tion, such as language and attentional shifting, still requires
considerable clarification.
70.4 DIFFICULTIES IN STUDYING
COGNITIVE FUNCTION IN
SUBJECTS WITH CEREBELLAR
DYSFUNCTION
The results of functional neuroimaging studies in normal
adults notwithstanding, the practising clinician is primarily
concerned with the potential impact of cerebellar disease or
dysfunction on cognition. Unfortunately, several confound-
ing factors must be borne in mind when interpreting such
studies. The first problem is that performance on the neu-
ropsychological tests utilized may be adversely affected by
requirements for rapid verbal output, motor accuracy and
speed or by dependence on rapid visual scanning. A corre-
lation between test results and ataxia severity will not nec-
essarily indicate that such requirements are confounding
the results; however, motor and cognitive function would
be expected to decline in diffuse cerebellar degeneration in
parallel, whether the observed cognitive dysfunction was
secondary to the cerebellar disorder or was merely second-
ary to the resultant motor impairment.
Several types of neuropsychological tasks would be
expected a priori to limit the potential for confounding of
results. Some tests are untimed and do not require motoric
or visual speed or accuracy. In the executive domain, these
include the WCST, Raven’s Progressive Matrices (RPM) and
the Zoo Map subtest (of planning) from the Behavioural
Assessment of the Dysexecutive Syndrome (BADS) battery.
Most measures of verbal anterograde episodic memory also
fall into this category, provided that dysarthria is not so
severe as to compromise intelligibility. Other tests include
a timed internal control condition involving similar scan-
ning and output to the test condition. The effects of visual,
verbal and motor dysfunction can therefore be subtracted
out. Such tests within the executive function cognitive
domain would include Trails B (versus A) and the Stroop
test. Some other tests requiring verbal output are timed, but
empirical observation suggests that the speed of articula-
tion is not the time-limiting factor. The Controlled Oral
Word Association test, first called the Verbal Associative
Fluency Test (COWAT, FAS) appears to fall into this cat-
egory (Storey et al., 1999).
An indirect way of exploring the possibility that motor
dysfunction might secondarily affect performance on
cognitive tests is to study patients with Friedreich’s ataxia
(FA), whose motoric deficit is partly consequent upon
disruption of afferent cerebellar input rather than direct
disruption of the cerebellar microcorticonuclear units,
although the deep cerebellar nuclei are also affected
(Koeppen, 2002). While FA patients display impairments
in a number of domains (Wollmann et al., 2002), they have
been shown to be less impaired on verbal working mem-
ory and visuospatial reasoning tasks than patients with
assorted other cerebellar degenerations (Botez-Marquard
and Botez, 1997). Indeed, White et al. (2000) demon-
strated slowed processing speed and decreased cognitive
inhibition on the Stroop test but preserved planning, ver-
bal fluency and WCST performance.
The potential confounding factor of motor deficit has
recently been explicitly addressed by Timmann et al.
(2002), who correctly pointed out that even ataxic patients
who cope well with the motor demands of a test may do so
at the cost of attentional resources not required by control
patients. These authors reported that subjects with pure
cerebellar cortical atrophies (including spinocerebellar
ataxia type 6 [SCA6], spinocerebellar ataxia type 8 [SCA8]
and idiopathic cerebellar cortical atrophy) demonstrated
impairments of visual association learning independent of
the separately manipulated motor output requirements of
the task.
The second problem affecting patient studies is that of
choice of the patient type. The ideal patient group for such
a study would have widespread/diffuse involvement of cer-
ebellar corticonuclear microcomplex units with complete
sparing of all other central nervous system (CNS) struc-
tures. Unfortunately, such patients probably do not exist,
at least to the extent of satisfying those sceptical of the idea
of cerebellar contributions to cognition. Even relatively
‘pure’ cerebellar ataxias, such a SCA6 and SCA8 often
have mild non-cerebellar features (e.g. pyramidal signs).

Other degenerative cerebellar diseases studied in this
context, such as spinocerebellar ataxias (SCAs) 1, 2 and
3, are even more problematic, as they are known to mani-
fest extracerebellar involvement of structures potentially
or actually contributing to cognition, such as the cere-
bral cortex, the striatum and substantia nigra (Koeppen,
2002). On the other hand, focal cerebellar lesions, such as
infarcts and resected tumours, may be ‘pure’ but there is
no guarantee that cerebellar region(s) potentially impor-
tant for cognition will be involved, unless a range of
lesions in different locations is studied. Pooled results may
then conceal regional differences in cognitive contribu-
tion unless sufficient subjects are available in each group
for comparison. A further potential limitation, of which
to be aware, concerns functional changes due to neural
plasticity in patients with chronic focal lesions (Timmann
et al., 2009). While controlling these potential confounds
is difficult, such studies do perhaps provide the most con-
vincing clinical evidence, as outlined below.
70.5 ALTERED COGNITION IN ADULTS
WITH FOCAL CEREBELLAR
LESIONS
In a seminal report, Schmahmann and Sherman (1998)
described the features of an entity they named the ‘cer-
ebellar cognitive affective syndrome’ in 20 adults with
isolated cerebellar lesions: strokes, resected tumours
not treated with radiotherapy and post-viral cerebellitis.
Posterior (and roughly equivalent to lateral neocerebellar)
lobe lesions produced executive dysfunction with impair-
ment in planning, set shifting, verbal fluency by semantic
category and abstract reasoning. There was also impair-
ment of spatial cognition including visual organization
and visual memory. Lesions of the posterior vermis tended
to produce personality change with blunting and disinhi-
bition, while anterior lobe lesions resulted only in motor
deficit. Similar findings were reported by Malm et al.
(1998) in 24 consecutive young adult patients with cere-
bellar infarcts who were compared with 14 age-matched
controls. These patients performed less on working mem-
ory and cognitive flexibility tasks, while intelligence (The
Wechsler Adult Intelligence Scale – Revised [WAIS-R]
scores) and episodic memory were seen to be unaffected.
Interestingly, while most made a good motor recovery,
only half of them returned to work. The broad conclu-
sions of these studies have since been confirmed by Neau
et al. (2000), who reported the neuropsychological profile
of 15 consecutive patients with recent, isolated cerebellar
infarcts compared with 15 demographically matched con-
trols. A further assessment was undertaken 1 year after
the infarcts. These authors demonstrated impairments
on a range of tasks tapping aspects of executive function-
ing, such as verbal fluency, working memory on the Paced
The cerebellum and cognitive impairment 815
Auditory Serial Addition Test (PASAT) and the Stroop
colour–word interference test. These abnormalities were
not accompanied by a clinically apparent ‘frontal’ neuro-
psychiatric syndrome. Block design was also affected, the
deficit of which the authors likened to a mild parietal syn-
drome, although problems with block design can also be
a feature of executive dysfunction. Interestingly, infarcts
in any of the three cerebellar arterial territories produced
similar deficits, although the numbers in each group were
small. This is in contrast to the findings of Schmahmann
and Sherman (1998) and Exner et al. (2004), the latter
reporting that posterior inferior, but not superior, cerebel-
lar artery infarcts resulted in cognitive deficits. As might
be expected with infarcts, the deficits reported by Neau
et al. (2000) tended to have improved at the 1 year assess-
ment. The authors plausibly suggest that this improve-
ment may have been partly responsible for the failure of
Beldarrain et al. (1997) to demonstrate consistent defi-
cits in a patient population including subjects with old
cerebellar infarcts, a finding since confirmed by Richter
et al. (2007a). Hokkanen et al. (2006) reported 26 Finnish
subjects with cerebellar lesions, assessed acutely before
and after 3 months. Those with left cerebellar lesions were
slow on a visuospatial task, whereas those with right-sided
damage showed impairments of verbal episodic and work-
ing memory. These deficits improved over the course of
time, such that all but one patient eventually returned to
work and 77 % had done so after 3 months. The reasons for
this discrepancy in long-term outcome from the Swedish
study of Malm et al. (1998) are unclear.
Using the lesion-symptom correlation method with 39
patients, following an acute/subacute cerebellar infarct, a
recent study demonstrated that a focal but quite large lesion
to the cerebellum is neither necessary nor sufficient condi-
tion for motor impairment and provided clinical support
for the notion that there are cerebellar regions devoted to
non-motor function (Schmahmann et al., 2009). Following
assessment with a modified International Cooperative
Ataxia Rating Scale (MICARS), patients whose stroke
avoided the anterior lobes (lobules I–V) and was confined
to parts of lobules VII–X (in particular lobule VII), demon-
strated no signs of the cerebellar motor syndrome (i.e. gait
ataxia, appendicular ataxia or dysarthria). Minimal motor
impairment was identified if lobule VI was involved. These
findings were consistent with a later review of functional
imaging and clinical data, which concluded that cogni-
tive impairment may occur with lesions impacting lobules
VI, VII (principally Crus I, Crus II) and lobule VIIIB and
suggesting disruption of ‘cognitive’ cerebro-cerebellar
connectivity with the association cortices (Stoodley and
Schmahmann, 2010).
The specific role of the right lateral cerebellum in lan-
guage, outlined in the section on functional neuroimag-
ing above, was studied in control subjects and subjects
with left lateral or right lateral cerebellar infarcts (Gebhart
et al., 2002). Those with right lateral cerebellar damage
were impaired only on antonym generation and not on
816 Dementia
semantic (category) noun fluency or verb selection. This
argues in favour of a cerebellar role in producing word asso-
ciations and not just in ‘imaging’ verb action to a noun cue.
Helmuth et al. (1997) also failed to demonstrate impaired
noun-triggered verb generation in subjects with right cer-
ebellar lesions, opposing the findings from earlier func-
tional neuroimaging studies. In contrast, verbal fluency was
the only impaired function in subjects with chronic focal
cerebellar lesions, being most evident in those with right-
sided lesions (Richter et al., 2007b). Exploring the role of
the cerebellum in verbal fluency further, Schweizer et al.
(2010) compared the performance of patients with chronic
unilateral cerebellar lesions (right versus left) and healthy
controls on phonemic (letter) and semantic (category) flu-
ency tasks. Performance on the phonemic fluency task was
more impaired for the right cerebellar lesion group than for
either the left cerebellar lesion group or controls and was
characterized by executive and attention deficits normally
expected with left prefrontal lesions. Semantic fluency per-
formance was worse relative only to controls for the right
cerebellar lesion group.
The potential role of the cerebellum in more complex
rather than simpler tasks has recently been extended to
reading: Ben-Yehudah and Fiez (2008) showed that focal
cerebellar damage impaired a visual rhyme judgement task
for irregularly spelt words, but not for phonetically regular
words, and impaired working memory only for non-words
rather than for real words. Reading fluency and comprehen-
sion were unaffected.
Verbal working memory – the ability to manipulate
phonological data in consciousness (e.g. reversing digit
strings) – is one aspect of executive function often found
to be mildly affected in subjects with cerebellar lesions
(Bellebaum and Daum, 2007). A parsimonious explanation
would be that the cerebellum has a role in subvocal articu-
latory rehearsal. However, Ravizza et al. (2006) provide
evidence that the cerebellum’s role is actually in initial pho-
nological encoding and/or in strengthening memory traces.
Episodic memory has generally been reported as relatively
preserved with focal cerebellar lesions, but a relatively
recent study of patients after removal of cerebellar tumours
revealed episodic memory deficits in most, although there
was no clear correlation of modality with lesion laterality
(de Ribaupierre et al., 2008).
Various attentional processes have also been studied
in subjects with cerebellar lesions with varying results.
Orienting visuospatial attention has been found to be
markedly delayed in such subjects, independent of motor
responses (Townsend et al., 1999), while the speed of visual
attention is also slowed, independent of eye movements
(Schweizer et al., 2007). Gottwald et al. (2003) compared
16 subjects with cerebellar tumours or haematomas to 11
matched control subjects and to demographically adjusted
results from normative studies and detected deficits in
divided attention and working memory, but not in sus-
tained directed attention. However, Helmuth et al. (1997)
did not demonstrate deficits in spatial attention shifting or
in intra- or inter-dimensional non-spatial attentional shift-
ing, again failing to confirm earlier functional neuroim-
aging studies in a clinical population. Moreover, Ravizza
and Ivry (2001) found that, while patient groups with
Parkinson’s disease (PD) and with cerebellar lesions each
showed impairment of attentional shifting, reducing the
motor demands of the task, improved the performance of
only the cerebellar patients. Neglect may be regarded as a
disorder of lateralized spatial attention. Conflicting results
have been obtained in line bisection tasks in subjects with
lateralized cerebellar lesions (Daini et al., 2008; Kim et al.,
2008) with the minority in whom neglect was demonstrable
not always showing this ipsilateral to the lesion, as might
be expected a priori (Kim et al., 2008). The question of a
cerebellar contribution to various forms of attention has
generated conflicting results and, while this remains to be
settled conclusively, the evidence so far is not convincing
when potential oculomotor/motor confounds are removed
(Haarmeier and Thier, 2007).
The role of the cerebellum in sequencing – an aspect of
executive functioning – has also been highlighted (Leggio
et al., 2008). Analogous with its role in sensory and motor
sequence detection and production, cerebellar damage also
disturbs verbal (sentence) and spatial sequencing (Leggio
et al., 2008). Furthermore, there is an effect of lesion lateral-
ity with right-sided lesions impairing verbal and left-sided
lesions impairing spatial sequencing.
The ecological validity of executive function impairment
identified on neuropsychological tests following cerebellar
lesions was addressed by Manes et al. (2009). Eleven patients
with focal cerebellar vascular lesions variously affecting pos-
terior inferior cerebellar artery, superior cerebellar artery
and mixed territories were assessed with a neuropsycholog-
ical test battery, with significant differences from controls
found on tests sensitive to frontal lobe function (including
the WCST and the flexibility scale of The Test of Attentional
Performance). Ecological validity – the degree to which neu-
ropsychological performance corresponds with real world
behaviour – was measured using the Multiple Errands Test
Hospital Version (MET-HV) with scores reflecting difficul-
ties with timing, task planning and organization in the cer-
ebellar infarct patients. Roldan Gerschcovich et al. (2011),
presenting a case study of a patient with extensive, bilateral
cerebellar infarction without supratentorial involvement,
noted mild deficits in verbal fluency (particularly to phone-
mic cues) and working memory, moderate deficits in story
recall, conceptualization, executive function and cogni-
tive flexibility and impairment on tests of decision making
(e.g. ABCD Iowa Gambling Task [IGT], Game of Dice Task
[GDT], Stimulus Reward Learning, Reversal and Extinction
Task [SRLRET]). This patient also demonstrated significant
difficulties on TOM tasks. A later report of the study con-
ducted by Manes et al. (2009) commented that, in contrast
to Roldan Gerschcovich et al. (2011), their 11 patients with
focal cerebellar vascular lesions performed no differently to
controls on a TOM test of their ability to detect social faux
pas (Roca et al. 2013).

Studies in children with resected cerebellar tumours
have produced similar results to those in adults (Levisohn
et al., 2000).
70.6 EVIDENCE FOR COGNITIVE
IMPAIRMENT IN DEGENERATIVE
CEREBELLAR DISEASE
Evidence for cognitive impairment in degenerative cerebel-
lar disease comes from both neurophysiological and clinical
neuropsychological studies. The best known neurophysi-
ological method of studying cognition involves measuring
the latency of the P300 event-related cerebral potential. This
occurs with conscious registration of an unusual stimulus,
such as an occasional (oddball) high-pitched tone inserted
into a series of usual stimuli, such as many low-pitched
tones. It may be regarded as a neurophysiological measure
of selective attention and processing speed and is delayed
in various forms of dementia (Goodin, 2003). Tachibana
et al. (1999) measured the P300 during a visual discrimi-
nation task and found it to be delayed in 15 subjects with
idiopathic late-onset cerebellar ataxia, when compared with
10 controls. Single-photon emission computed tomogra-
phy (SPECT) scanning in the ataxic subjects showed corre-
lated cerebellar/frontal cortex hypoperfusion. Tanaka et al.
(2003) did not find any differences in P300 timing or scalp
distribution to the classical auditory ‘oddball’ paradigm in
13 subjects with cerebellar cortical atrophy when compared
to 13 demographically matched controls. However, P300
latency was prolonged and its peak attenuated frontally, in
the ‘No-Go’ condition of the ‘Go/No-Go’ paradigm. The
authors suggested that the cerebellum contributes to the
frontal inhibitory system.
The neuropsychological consequences of degenerative
cerebellar disease have been studied extensively. In an
early study, Grafman et al. (1992) compared nine patients
with ‘pure cortical cerebellar atrophy’ with 12 controls.
There were no differences on paired associate learning,
verbal fluency or procedural (skill) learning. However, the
ataxic subjects performed significantly worse on the Tower
of Hanoi planning task (ToH), which is conceptually simi-
lar to the Tower of London (TOL) test. Botez-Marquard
and Botez (1997) showed that cerebellar degenerations
resulted in impaired executive functioning, visuospatial
organization, working memory and spontaneous retrieval
of episodic memories. Cerebellar strokes produced simi-
lar patterns of impairment, but these cognitive deficits
resolved in 2–5 months. In both types of subjects, SPECT
scanning showed reverse cerebellar/frontoparietal dias-
chisis. Drepper et al. (1999) studied nine subjects with
‘isolated’ cerebellar degeneration and 10 controls. The
ataxic subjects showed a significant impairment in novel
associative learning (colours with numbers) that did not
correlate with either simple reaction time or visual scan-
ning time.
The cerebellum and cognitive impairment 817
Kish et al. (1994) studied the performance of 43 sub-
jects with undefined dominant cerebellar degenerations of
varying ataxia severity on a number of neuropsychological
measures. Impaired performance on the WCST correlated
with ataxia severity; none of those with mild ataxia showed
deficits while all those with severe ataxia were impaired.
Some of the latter subjects also showed evidence of mild
generalized cognitive deficit. The authors concluded that
the dominant ataxias are not homogeneous with respect to
cognitive involvement and indeed the topography of extra-
cerebral neuropathological involvement does vary consid-
erably between these disorders (Rüb et al., 2013). Trojano
et al. (1998) also studied a mixed population of subjects
with dominant ataxias of varying severity, although 15 out
of their 22 subjects had SCA2. They attempted to avoid con-
founding effects of motor impairment on performance by
restricting their investigation to tests with untimed verbal
response modes. The domains examined were predomi-
nantly verbal memory and non-verbal reasoning (Raven’s
Progressive Matrices). None of the four genetically con-
firmed but asymptomatic subjects performed poorly on any
of the tests, while most of the symptomatic subjects showed
impairment on at least one measure, most commonly, the
progressive matrices. Some showed widespread deficits on
a large scale but there was no correlation with ataxia sever-
ity. This might have reflected the small sample size and the
contaminating effects of inclusion of several SCA subtypes.
Several studies have assessed subjects with different SCA
types, singe or placed separately from other types, thereby
avoiding this particular confounding factor. Maruff et al.
(1996) compared six patients with SCA3 (Machado–Joseph
disease [MJD]) to 15 matched controls using a touchscreen
testing system: the Cambridge Neuropsychological Test
Automated Battery (CANTAB). Learning and visual mem-
ory were unaffected, but SCA3 subjects displayed impaired
visual information processing speed on high-demand tasks
and impaired attentional switching between visual stimu-
lus dimensions. Executive dysfunction in SCA3 was con-
firmed by Zawacki et al. (2002). Braga-Neto et al. (2012)
compared 38 molecularly and clinically proven patients
with SCA3 to 31 controls on measures of neuropsychologi-
cal function, ataxia rating scales, depression and anxiety.
Patients with SCA3 reported significantly more symptoms
of depression and anxiety than controls, but performances
on tests of visuospatial abilities and executive function were
significantly impaired independent of psychiatric scores
and demographic factors. Results failed to confirm a visual
memory deficit in this patient group. In a SCA3 sample
group of 32 patients, Lopes et al. (2013) found mild impair-
ments in episodic and working memory and executive func-
tion relative to demographically matched controls, deficits
that were not associated with CAG expansion size, disease
duration or ataxia severity. Neuroimaging with 3T MRI and
DTI revealed reduced grey matter volume in the temporal,
parietal and frontal lobes as well as the cerebellum, which
was associated with episodic memory impairment and
executive dysfunction in the patient group. There was also
818 Dementia
a positive correlation between fractional anisotropy values
in the brain stem and forwards digit span. Progressive cog-
nitive dysfunction, notably in verbal and figural memory,
was also observed over 3½ years by Roescke et al. (2013) in
a small group of SCA3 patients with a range of CAG repeat
expansion sizes. While motor deterioration was observed,
the memory tests were independent of motor impairment
and cognitive changes could not be attributed to progressive
cerebellar ataxia.
SCA2 may be associated with cortical atrophy and clini-
cally with obvious dementia in some pedigrees (Dürr et al.,
1995; Geschwind et al., 1997). Although it is not ideal for the
purpose it has been studied by several groups. Gambardella
et al. (1998) and Storey et al. (1999) demonstrated impair-
ments of executive function on the WCST and the Stroop
test. Bürk et al. (1999) found that 25% of their subjects were
demented, while the others showed impairments of execu-
tive function and verbal memory that were independent of
the severity of motor impairment. In contrast, Le Pira et al.
(2002) reported that the impairments of executive function,
attention and verbal memory in their SCA2 patients were
partly related to ataxia severity.
The pattern of neuropsychological impairment in SCA1
patients compared to matched controls was reported by
Bürk et al. (2001). Evidence of executive and verbal memory
dysfunction was found, while visuospatial memory and
attention were unaffected. The deficits did not correlate with
CAG repeat length or with disease duration, which may be
regarded as surrogate markers of disease severity in differ-
ent dimensions.
While the studies on SCAs 1, 2 and 3 cited above paint a
fairly consistent picture of executive dysfunction and verbal
memory impairment, the effects of differences in the pattern
and extent of extracerebellar neuropathological involve-
ment, if any, can only be addressed adequately by direct
comparison. This was undertaken by Bürk et al. (2003),
who found that executive dysfunction was more marked
in SCA1 than in SCAs 2 or 3, while mild verbal memory
impairment was present in all of them. On the basis of these
findings, the authors suggested that the cognitive deficits
were likely to result from disruption of cerebro-cerebellar
circuitry at the pontine rather than at the cerebellar level.
Given that SCA2 causes more severe pontine atrophy than
SCA1, the reason for this conclusion is unclear. A prob-
lem with this study is the lack of control for ataxia sever-
ity. Klinke et al. (2010) also found poorer performances by
SCA1 patients on cognitive tests when compared to SCA2
and 3, with attentional and executive dysfunction predomi-
nantly present in these three types. Semantic and episodic
memory were essentially preserved. Cognitive domains of
deficit were partly correlated with ataxia severity and fine
motor coordination. Fancellu et al. (2013) examined the
progression of cognitive, psychiatric, motor and functional
abilities of patients with SCA1(9) and SCA2(11). Baseline
cognitive measures showed mild deficits in both groups
in attention and executive function, with the most notable
psychiatric feature being apathy rather than depression,
anxiety or positive symptoms. The SCA2 group of patients
performed worse on cognitive tests than the SCA1 group.
Memory was not impaired and only three patients out of
a total of 42 at baseline scored below 24/30 on the Mini-
Mental State Examination (MMSE), suggesting dementia
was not a feature of these SCA types in the moderate stage
of the disease. A 2-year follow-up assessment of small sub-
sets of both patient groups (9 SCA1 and 11 SCA2) was car-
ried out and revealed that only performances on attentional
matrices in the SCA2 group had deteriorated significantly.
There was a significant increase in motor impairment and
a trend towards worsening of functional abilities in this
group, compared to the SCA1 group. Although findings
were limited to small sample groups for follow-up and the
short follow-up duration was to be taken into account, the
researchers proposed their study as supporting dissociation
between cognitive and motor impairment in SCA2.
Social cognition was investigated by Sokolovsky et al.
(2010) in common types of SCA, which included SCAs 1, 2
and 7 and compared with previously investigated cognitive
and social cognitive characteristics in the SCA3 and SCA6,
using an identical assessment battery (Garrard et al., 2008).
SCA2 patients demonstrated the most cognitive impairment,
notably in attention, non-verbal intellectual abilities and
executive function and at a degree similar to SCA3 patient
group. SCA1 patients had relatively intact cognitive profiles
and the SCA7 group patients had selective mild deficits in
executive function. On social cognition tests, SCA2 and
SCA7 patients demonstrated impairment on a test of social
attribution (providing a one-word description of a character’s
feeling in an emotional situation, e.g. happiness, sadness,
disgust, fear, anger, embarrassment). Only one patient with
SCA1 was impaired on a TOM test, a deficit which had been
previously observed in SCA3 and SCA6 patients (Garrard
et al., 2008). The results of these studies again bring into focus
the need to consider the wide range of non-motor deficits
that may afflict patients with cerebellar disease and the addi-
tional impact beyond motor disability on daily functioning.
Perhaps the best way of clarifying the relative contribu-
tions of cerebellar and extracerebellar pathology to cog-
nitive dysfunction in the SCAs is to study those disorders
characterized by relatively pure cerebellar involvement, such
as SCA6 and to a lesser extent, SCA8. Although McMurtray
et al. (2006) found that SCA6 patients, in contrast to those
with other SCA types, tended not to show memory deficits,
Suenaga et al. (2008) reported significant impairments of
verbal fluency and immediate visual memory in SCA6, inde-
pendent of motor dysfunction. In a group of 27 patients with
genetically confirmed SCA6, Cooper et al. (2010) reported
an absence of memory decline and identified significant
impairment in executive function on tests of cognitive flex-
ibility, response inhibition, verbal reasoning and abstrac-
tion. A later study by this research group (Cooper et al.,
2012) used high resolution structural MRI to demonstrate
a relationship between verbal working memory based on
phonological storage and retrieval and grey matter density
in bilateral lobules VI and Crus I as well as in the inferior

lobe (bilateral lobules VIIIA and VIIIB and right lobule IX)
of 15 patients with SCA6. Two groups have reported a dysex-
ecutive syndrome (DES) in SCA8 (Lilja et al., 2005; Torrens
et al., 2008) with the first group also demonstrating deficits
in attention and information processing.
70.7 CONCLUSIONS
There is converging evidence from neuroanatomical, neu-
roimaging, neurophysiological and neuropsychological
patient studies that the lateral cerebellum is involved in
network(s) subservient to a range of cognitive functions,
including aspects of language and executive functioning.
The exact nature of the cerebellar contributions to cogni-
tion and especially to attention, are still being debated
and ­elucidated. Nevertheless, the broad picture is suffi-
ciently well established that clinicians should consider the
possibility of cognitive dysfunction in patients with overt
cerebellar disorders. In this context, executive dysfunction
is both the most likely to be overlooked in the structured
clinical setting and potentially, the most disruptive to the
patients’ ability to compensate for impaired motor func-
tioning. Clinicians should also bear in mind that obvious
cognitive dysfunction may result from cerebellar disease, at
the least from degenerative disorders and acute focal lesions,
and such dysfunction does not necessarily signify that a sec-
ond supratentorial disorder has been overlooked.
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Delirium: A clinical overview
ANDREW TEODORCZUK AND DANIEL DAVIS
71.1 INTRODUCTION
Despite delirium being described in the Greek literature as
far back as 400 bc, current levels of knowledge and practice,
in comparison to other medical conditions, lag considerably
behind. However, over the past 20 years, there has been sig-
nificant progress in the way that we understand, conceptu-
alize and manage delirium (Maclullich et al., 2013).
This chapter provides an overview of the clinical pre-
sentation and current diagnostic criteria (Diagnostic and
Statistical Manual of Mental Disorders, Fifth Edition [DSM-
5]), epidemiology and prevalence of delirium. In addition,
clinical principles are described in relation to assessment,
management (non-pharmacological and pharmacological)
and prevention of delirium. An up-to-date understanding of
the pathophysiology of delirium and aetiology of delirium is
outlined. The chapter concludes with current thoughts on
the association between dementia and delirium, challenges
for researchers and possible future directions.
71.2 CLINICAL FEATURES, CONCEPTS
AND DIAGNOSTIC CRITERIA OF
DELIRIUM
Delirium is a clinical syndrome characterized by the
cardinal symptoms of inability to focus, shift or sustain
attention, acute change in mental state, fluctuations and
altered level of consciousness (Inouye et al., 2014). Other
supportive symptoms include disorganized thinking,
disturbance of the sleep–wake cycle, hallucinations and
delusions. The core features of delirium of inattention
and distractibility can be considered pragmatically as the
ability to focus (for example, on a conversation) and is
71
akin to be a ‘first rank symptom’ without which a diagno-
sis cannot be made.
71.2.1 DIAGNOSTIC CRITERIA
In 2013, new DSM-5 criteria for delirium were developed
(American Psychiatric Association, 2013). These criteria
are outlined in Box 71.1. In comparison to Diagnostic and
Statistical Manual of Mental Disorders, Fourth Edition
(DSM-IV), which had been adopted widely within clinical
practice, DSM-5 is less inclusive and more phenomenologi-
cally precise. Though DSM-5 elevates attention as a feature
of delirium, if the criteria are precisely applied there will be
cases of people who had DSM-IV criteria delirium and who
would no longer qualify for delirium by DSM-5 standards.
This is because it specifies the need for both disturbances
in awareness and attention when pragmatically it may
not be possible to undertake tests of awareness in patients
who may have a low level of arousal (Meagher et al., 2014).
Hence, in clinical practice, a relaxed approach to diagnosis
is advocated.
71.2.2 CLINICAL EXPERIENCE
Delirium is a highly distressing disorder for patients, rela-
tives and indeed care staff (Partridge et al., 2013). To appre-
ciate just how distressing it can be, readers are directed to a
patient experience video available in the European Delirium
Association website (Teodorczuk, 2012). Furthermore, it is
not uncommon for patients to suffer post-delirium depres-
sive symptoms in this context.
71.2.3 CLINICAL CONCEPTS
Previously, delirium was considered to be the manifestation
of a medical precipitant not requiring specific management
823
824 Dementia
BOX 71.1: DSM-5 criteria for delirium
(American Psychiatric Association, 2013).
1. A disturbance in attention (i.e. reduced abil-
ity to direct, focus, sustain and shift attention)
AND awareness (reduced orientation to the
environment).
2. The disturbance develops over a short period of
time (usually hours to a few days), represents a
change from baseline attention and awareness
AND tends to fluctuate in severity during the
course of the day.
3. An additional disturbance in cognition (e.g. mem-
ory deficit, disorientation, language, visuospatial
ability or perception).
4. The disturbances in criteria 1 and 3 are not better
explained by a pre-existing established or evolving
neurocognitive disorder and do not occur in the
context of a severely reduced level of arousal, such
as coma.
5. There is evidence from history, physical examina-
tion or laboratory findings that the disturbance
is a direct physiological consequence of another
medical condition, substance intoxication or
withdrawal.
beyond treatment of the underlying cause. However, delir-
ium is now best considered as a diagnostic treatment tar-
geted in its own right (MacLullich and Hall, 2011; Meagher
et al., 2013). It can be conceptualized as acute brain failure
in contrast to dementia (chronic brain failure). Expanding
on this concept further, delirium can be viewed as a marker
of brain vulnerability (the opposite of cognitive reserve)
(Davis et al., 2012).
Importantly, it should be recognized that delirium is the
harbinger of an acute medical problem, and hence an emer-
gency. It is a sensitive (but highly non-specific) marker of
illness in older persons and so can represent any number of
occult presentation symptoms.
Diagnosis is made clinically and rests firmly on iden-
tifying the characteristic features as outlined above.
Electroencephalography (EEG) changes, such as diffuse
slowing in activity and increased theta and delta activity
can support the diagnosis in some cases (Kooi et al., 2012).
However, EEG is not routinely used in practice.
Increasingly, it is recognized that delirium is both treat-
able and preventable; however, the body of evidence in sup-
port of strategies to prevent delirium is considerably weaker
than that concerning treatment (MacLullich and Hall, 2011).
It has been reported by Inouye et al. (1999) that as many
as 30% of cases of delirium could be prevented by means
of a multicomponent tailored intervention. Though in the
real world setting this figure may not be an easy target,
the fact that delirium is preventable is particularly impor-
tant, as delirium carries a negative impact in both terms of
morbidity, mortality and healthcare costs. Prevention of
delirium therefore, can be a particularly high-yield strategy
(Akunne et al., 2012).
Lastly, delirium is under-recognized in clinical set-
tings (Collins et al., 2010). This potentially is as a conse-
quence of the fact that staff lack knowledge and expertise
and the absence of reliable collateral history. Common
diagnostic mistakes include misattributing delirium
to depression or behavioural psychological symptoms
of dementia (BPSD). Moreover, there is an element of
therapeutic nihilism when it comes to treating delirium
(Teodorczuk et al., 2012). Furthermore, though there
are many different assessment tools in practice, none
are widely used and arguably, delirium screening should
form a core part of nursing assessments of the older con-
fused patients. Commonly used tools in practice include
the Confusion Assessment Method (CAM), Confusion
Assessment Method for the Intensive Care Unit (CAM-
ITU), Delirium Observation Screening Scale (DOSS),
evaluating the performance of the 4 ‘A’s Test (4AT),
Nursing delirium screening scale (NuDESC) and The
Neelon and Champagne Confusion Scale (NEECHAM)
(Wong et al., 2010).
71.3 AETIOLOGY
As described above, delirium is considered conceptually as
decompensation of the brain acutely. This is important in
order to understand the settings where prevalence would
be expected to be high, such as in areas of high frailty (e.g.
nursing homes) and/or high acute illness burden (e.g. criti-
cal care). The Stress Vulnerability Model has been proposed
and is widely accepted (Figure 71.1). In essence, any patient
may become delirious if sufficiently insulted. Reciprocally,
the extent of vulnerability factors may allow delirium to
result from a relatively trivial precipitant.
Therefore, it follows that patients with dementia, who
are in a high vulnerability state due to their pre-existing
cognitive impairment, will require a less severe insult
than patients without dementia. Other important risk
factors that increase vulnerability include age, frailty,
sensory impairment, polypharmacy and co-morbidity
(Table 71.1). Similarly, in settings such as ITU or surgery,
where a patient has had a severer insult, they are more
likely to be delirious. Important noxious insults include
pain, constipation, medication, dehydration, nutritional
deficiencies.
A fundamental consideration that arises from the Stress
Vulnerability Model is that in patients with high vulner-
ability there are multiple causes for delirium. Therefore,
treatment should be broadened to identify multiple causes
or insults. Too often a failure of non-pharmacological inter-
ventions is a consequence of inadequate understanding of
the causal factors and at risk vulnerability state.

Precipitating factors
Acute medical or surgical conditions
caused by drugs, toxics
Insult intensity
Age cognitive impairment frailty
Predisposing
Protective
factors
factors
Delirium
Figure 71.1 Relationship between predisposing, protec-
tive and precipitating factors in delirium. (From Cerejeira,
J. and Mukaetova-Ladinska, E.B., Nursing Research and
Practice, 2011, 875196, 2011. With permission under CC
attribution.)
71.4 CLINICAL PRESENTATIONS OF
DELIRIUM
71.4.1 SUBTYPES
Three different subtypes of delirium have been defined
(O’Keeffe and Lavan, 1999; Santana Santos et al., 2005).
The hypoactive subtype, which is more prevalent in a
nursing home care setting accounts for approximately
one-third of delirium presentations. Patients with this pre-
sentation will be acutely drowsy, perhaps, unable to have
a conversation. Hyperactive subtypes are more common
in those without dementia, and these patients account
for a further one–third; mixed subtypes account for the
remainder. Though typically medications are used to treat
hyperactive delirium (Morandi et al., 2013), increasingly,
some clinicians’ medication for hypoactive delirium when
risks are present (Leentjens et al., 2014). In practice, the
hypoactive subtype is most easily missed (O’Keeffe, 1999)
and may carry a worse prognosis for this reason.
71.4.2 PERSISTENT DELIRIUM
Dedicated follow-up of persons with delirium demon-
strate that it may persist in 20% after 1 year (Cole et al.,
2009). This presentation is associated with worsening out-
comes though not necessarily greater mortality (Klein
Klouwenberg et al., 2014). Clinically it may be difficult to
differentiate from a dementia illness, however, the cardi-
nal features of inattention, fluctuations and disorganiza-
tion to thoughts would help differentiate from dementia,
which is characterized by clear consciousness and a differ-
ent symptom profile.
Delirium: A clinical overview 825
Table 71.1 Common risk and precipitating factors in
delirium
Precipitating factors
Vulnerability factors (insults)
Age Infections
Cognitive impairment Medications
Depression Hypoxia
Frailty and functional Metabolic disturbance/
dependency dehydration
Co-morbidity Physical restraints
Nutritional state Urinary catheterization
Sensory impairment Constipation
Pain
Environmental changes
71.4.3 SUBSYNDROMAL DELIRIUM
Subsyndromal delirium is an emerging clinical concept
that refers to a delirium-like illness that does not reach the
diagnostic criteria for full delirium. Typically symptoms
may be of a lesser severity. Symptoms include impaired
cognitive function, increased motor activity (restlessness,
agitation, sensitivity to stimuli) and perceptual mood dis-
turbance. However, circadian rhythm may be preserved and
the degree of fluctuation less in comparison to delirium. A
study by Meagher (2012) demonstrated in a heterogeneous
group of patients with subsyndromal delirium that the syn-
drome was present in 27% of patients with post-delirium.
However, the prevalence of subsyndromal delirium across
all settings, whether it is commoner in older adults or those
with dementia is not fully established.
Studies have shown that patients who develop sub-
syndromal delirium after an episode of delirium are less
likely to be discharged to the community, have longer hos-
pital stays and greater medical complications including
higher risk of falls (Marcantonio et al., 2005). Presently, it
is unclear whether subsyndromal delirium should form a
distinct treatment target and further studies are warranted.
However, non-pharmacological interventions (perhaps sim-
ply representing good clinical care) are vital and low-risk
in delirium. Given a diagnosis of subsyndromal delirium,
it is, therefore, prudent to implement non-pharmacological
approaches.
71.5 INCIDENT AND PREVALENT
DELIRIUM
Delirium can also be differentiated in terms of incident or
prevalent delirium in a hospital setting (Siddiqi et al., 2007;
Young et al., 2010). Prevalent delirium relates to patients
who present to hospital with a delirium syndrome. Incident
delirium, however, relates to patients who develop delirium
during hospitalization as a result of further insult or insults
826 Dementia
in the hospital. The drive of guidelines, such as The National
Institute for Health and Care Excellence (NICE) in the
United Kingdom (NICE, 2010), is to prevent the develop-
ment of such incident delirium.
71.6 PREVALENCE
Delirium’s prevalence in different populations alters
depending upon the level of insult. As such, in a general
hospital upon admission, the prevalence is between 10% and
40%, depending upon setting (Vasilevskis et al., 2012). This
rises to 25%–60% of incident delirium during admission.
In high-risk areas, such as vascular surgery (Balasundaram
and Holmes, 2007) and orthopaedics (Bruce et al., 2007),
the prevalence of delirium rises even further. Indeed, in
the ITU population, the incidence can be up to 80% (Pisani
et al., 2003). In the hospital, delirium has been described as
the most common complication. A recent study of all medi-
cal admissions aged over 70 found the total prevalence of
delirium was 27% (Whittamore et al., 2014). Delirium was
complicated by dementia in 19% and 37% of patients admit-
ted with delirium died within 6 months.
71.7 PROGNOSIS
Delirium has been demonstrated in various studies to be
associated with an increased mortality rate, length of stay
and rates of institutionalization (McCusker et al., 2003;
Witlox et al., 2010). Delirium has also been shown to acceler-
ate cognitive decline in patients with dementia (see Sections
71.8 and 71.9). Interestingly, though lack of apolipoprotein
E (ApoE) ε4 allele, being female and lower levels of insulin-
like growth factor 1 (IGF-1) have been associated with a full
recovery from delirium; severity of delirium, underlying
presence of dementia and advanced age do not appear to be
associated with a complete recovery (Adamis et al., 2007).
71.8 ASSESSMENT OF DELIRIUM
Guidelines suggest that all patients who are at high risk,
that is to say have vulnerability factors for delirium as listed
above, should be assessed for delirium within 24 hours of
admission (NICE, 2010). Typically, assessments should
involve talking with carers to determine if there has been
an acute change in mental status. Also, it is important to be
vigilant for behaviour that may indicate a hypoactive delir-
ium. Along with a full medical history and examination,
particular emphasis is needed to ensure an accurate drug
history is taken, including any recently stopped medication.
In terms of investigations for the assessment of delirium, a
full screening of blood is necessary to look for physiological
causes. In addition, a midstream specimen of urine (MSU)
test to assess urinary tract infection (UTI) is indicated.
Computed tomography (CT) is only recommended if there
is a history of falls or neurology on examination or sus-
pected metastases.
71.8.1 ASSESSMENT TOOLS
Increasingly, assessment screening tools are entering
clinical practice. Commonly used tools include the CAM,
DOSS and 4AT. Whichever tool is chosen is dependent
upon sensitivity and specificity for the particular group
of healthcare professionals using the tool. In general, the
CAM tends to be better when undertaken by medically
trained staff (Lemiengre et al., 2006), whereas the DOSS
mainly lends itself to nursing staff for usage (Detroyer
et al., 2014).
Once the patient has been assessed, the delirium sta-
tus should be clearly recorded in the notes. This will help
to initiate delirium management pathways, as well as raise
awareness for other professionals involved in the care of the
patient. If they are in a high-risk state but do not suffer from
delirium, it is important to put into place measures to pre-
vent delirium: promote good nursing care, mobility to the
patient and vigilant to the possibility of medical deteriora-
tion are some of them.
71.9 MANAGEMENT OF DELIRIUM
Treatment of an identified delirium falls into three catego-
ries, which are as follows:
1. Treating the underlying cause
2. Optimizing brain function by non-pharmacological
measures
3. Symptom relief through medication if a patient is
distressed or in a high-risk state
The guiding principle for the treatment of delirium is to
promote non-pharmacological interventions as a treatment
of choice before attempting pharmacological interventions.
Crucially, a clear and comprehensive non-pharmacological
treatment plan involving optimal brain protection follows
from a good understanding of aetiology of the delirium of
each patient.
71.9.1 TREATING THE UNDERLYING
CAUSE
The most common causes for delirium include medica-
tion changes. As such, potentially deliriogenic medications
should be stopped. Inappropriate medications to remove as
indicated by the American Geriatrics Society Beers Criteria
Update Expert Panel (2012) include tricyclic antidepres-
sants, anticholinergics, benzodiazepines, chlorpromazine,

steroids, pethidine, H2 antagonists, sedative hypnotics and
thioradazine.
Other easily identifiable causes for treatment include
pain, nutrition and constipation. Dehydration should be
attended to, as evidenced by urea and electrolytes. Infection
must be treated, in particular UTIs and pneumonias. As
indicated above, in a vulnerable patient, there are likely to
be numerous causes for delirium and a multifactorial treat-
ment plan addressing all insults should be developed.
71.9.2 BRAIN OPTIMIZATION
In terms of brain optimization, further non-pharmacolog-
ical measures include orientation of the patient. Involving
carers to help with this, in addition to managing a patient
is essential. Furthermore, environmental measures can be
put into place to promote orientation by means of clocks
and calendars. Other environmental strategies to promote
brain function include appropriate lighting for the time of
day. Reducing change of hospital or wards is particularly
important in the treatment of delirium. Avoiding catheters
and restraints is to be supported. Addressing risk factors,
such as sensory impairment using hearing aids and glasses
is a particularly high-yield non-pharmacological measure.
Early and safe mobilization of patients by means of phys-
iotherapy will also help to optimize brain function. Lastly,
attending to sleep difficulties by means of noise reduction
strategy and promoting good sleep hygiene is indicated
where possible.
71.9.3 SYMPTOM RELIEF IN THE
DISTRESSED PATIENT
If a patient is particularly distressed, or there are risks to
their (or others’) safety, it would be appropriate to consider
a short course of medication. In England and Wales, the
NICE guidelines support the use of antipsychotics, such as
olanzapine and haloperidol, for a short course of 1 week to
help manage complex delirium (NICE, 2010). It is important
to note that there is no indication for prescribing benzodi-
azepines to help with the management of a distressed delir-
ium in routine clinical practice of hospital wards (Breitbart
et al., 1996).
The evidence for treating delirium with antipsychotics is
weak and initiating antipsychotics involve carefully weigh-
ing the risks and benefits on an individual patient basis.
Nonetheless, 75% of patients who do receive a short course
of antipsychotics will respond (Meagher et al., 2013). It is
not clear if delirium itself is being treated or if the psychotic
symptoms are being reduced. In general, atypical antipsy-
chotics are to be promoted rather than haloperidol due to the
reduced incidence of extrapyramidal side effects (EPSEs). In
patients with Parkinson’s dementia or Lewy body disease,
it may be appropriate to treat a severe delirium with low
dose quetiapine, though cautious attendance to worsening
of EPSEs is necessary. The evidence for antipsychotic use in
delirium prevention is less clear. As yet, their use in delirium
Delirium: A clinical overview 827
prevention, for example, in preoperative settings, is not
recommended routinely (American Geriatrics Society, 2014).
There is growing evidence that melatonin may as well
be beneficial in the treatment of delirium (Al-Aama et al.,
2011), though the largest trial till date did not show a reduc-
tion in delirium incidence in the ICU (de Jonghe et al.,
2014). Melatonin is well tolerated and can help with the
sleep–wake cycle.
The place of cholinesterase inhibitors (ChEIs) in the
management of delirium is unclear. In ITU patients initi-
ated with rivastigmine for delirium, there was significantly
higher mortality (van Eijk et al., 2010). However, it is unclear
as to the extent to which these findings would apply to the
population outside critical care (Skrobik, 2010). Good prac-
tice, until further studies are undertaken, would be not to
initiate a ChEI in a patient with delirium. If a patient suf-
fers from delirium and is already on a ChEI, then it could
reasonably be continued. To date there are no studies con-
ducted on the relationship between memantine and delir-
ium. Further studies are warranted.
71.10 PATHOPHYSIOLOGY
Delirium pathophysiology is poorly understood. Clearly,
certain pathophysiological processes can result in direct
brain injury. Examples might include hypoxaemia, stroke,
hypoglycaemia or medication effects. However, more com-
plex explanations are required to account for the interplay
between predisposing pathology and acute precipitants.
An emerging strategy is that aberrant stress responses
mediate between peripheral stimuli and the brain
(MacLullich et al., 2008; Cunningham and MacLullich,
2013). Systemic inflammation can communicate with
neural substrates through a variety of mechanisms. These
include areas where blood-brain barrier is deficient, directly
through the vagus nerve and where endothelial glial cells
directly transmit cytokines into the brain.
There may be a neuroendocrine basis to some of the cog-
nitive dysfunction seen in delirium and acute illness. The
normal adaptive stress response is understood to become
dysregulated in dementia, especially given the higher lim-
bic control of the hypothalamus–pituitary–adrenal axis
(O’Brien et al., 1996). In such situations, relatively trivial
physiological stressors may lead to exaggerated and sus-
tained levels of cortisol. In itself, cortisol cytotoxicity could
account for some of the long-term sequelae of delirium.
Evidence supporting these hypotheses comes from a small
range of clinical studies and is also available. One strategy
that has yielded interesting results has been the examina-
tion of cerebrospinal fluid in individuals undergoing spinal
anaesthesia for elective or emergency surgery. A number of
biomarkers have been considered, though, general studies
conducted have been limited with little overlap (Hall et al.,
2011). Nevertheless, cortisol, interleukin-1beta (IL-1β), IL-6,
IL-8 and S-100 (β-subunit) all have been demonstrated as
828 Dementia
altered in the cerebrospinal fluid (CSF) of delirium patients
(Pearson et al., 2010; MacLullich et al., 2011; Hall et al., 2013;
Westhoff et al., 2013; Cape et al., 2014). These changes are
consistent with stress, pro-inflammatory and cause direct
injury to astrocytes as mediators of delirium. The degree to
which these results might be confounded by age and pre-
existing cognitive impairment has not always been fully
addressed. The largest investigation examining demen-
tia biomarkers directly (beta-amyloid [Aβ] 1-42, tau and
phosphorylated-tau) did not show association to delirium
suggesting that delirium pathophysiology might be distinct
from dementia (Witlox et al., 2011).
The potential for neuroimaging to elucidate delirium
pathophysiology is also of interest, but such studies are
difficult to conduct (Soiza et al., 2008). There is a general
limitation arising from the fact that usually only a fraction
of people with delirium can be successfully diagnosed. In a
cohort of critically ill patients, longer duration of delirium
was associated with smaller brain volumes and evidence
of disruption of the white matter (Gunther et al., 2012;
Morandi et al., 2012) was found. These findings were in
turn associated with worse cognition after 1 year follow-up.
Preoperative leukoaraiosis has been demonstrated to pre-
dict post-operative delirium after elective cardiac surgery
(Hatano et al., 2013).
Compared to the number of clinical studies, relatively less
work has been undertaken using animal models. Finding
meaningful cognitive behavioural animal models to explore
possible hypotheses has not been straightforward. Any clini-
cally relevant experimental approach must capture both
predisposing and precipitating dimensions. Mouse models
for this have been specifically developed using methods for
mimicking and predisposing dementia (prior pathology),
superimposed with inflammatory challenge to simulate bac-
terial or viral infection (Field et al., 2010; Murray et al., 2012).
Here, prior pathology can be modelled by inducing neuro-
degeneration or selective partial lesioning of the cholinergic
system (Cunningham et al., 2005; Field et al., 2012). In these
mice, acute peripheral inflammation leads to acute deficits in
cognition and these behavioural effects are consistent regard-
less of the underlying prior pathology. The pathophysiological
pathways that underpin these relationships is beginning to be
described, perhaps identifying future targets for intervention.
Emerging findings from mouse models suggest that
microglial priming and exaggerated responses to systemic
inflammatory events may sometimes play a role in the
pathophysiology of delirium. Microglia express cyclooxy-
genase (COX) and inhibition of this using COX-1 has been
shown to be protective against systemic inflammation-
induced deficits (Griffin et al., 2013). Similarly, the same
deficits reproduced in cholinergically-deficient mice could
be blocked by donepezil (Field et al., 2012). In support,
the role of cholinergic deficiency in aetiology of delirium
leads to the fact that anticholinergic drugs are particularly
deliriogenic.
The pathophysiology of delirium is undoubtedly multi-
dimensional. Other important neurotransmitters that have
been implicated include dopamine (Maldonado, 2008). The
challenge is that delirium is a highly heterogeneous con-
struct and hence, the pathophysiological mechanism(s)
may vary markedly, for example, between the ITU setting
and geriatric clinical environments. There is not yet direct
evidence that delirium per se causes concurrent neuronal
death by the same mechanisms.
71.11 RELATIONSHIP BETWEEN
DELIRIUM AND DEMENTIA
The association between delirium and dementia is complex.
Studies of individuals with delirium followed up for wors-
ened cognition are usually biased by unrecognized (and
unquantified) pre-existing cognitive deficits. Nonetheless,
it is clear that delirium does not recover in all persons and
prospectively linking delirium with permanent decrements
in cognitive function challenges the construct of dementia,
since it suggests that chronic cognitive impairment may be
affected by incomplete recovery from acute illness.
Prospective studies more reliably establish the tempo-
ral sequence between baseline cognitive function, incident
delirium and subsequent cognitive impairment. These have
shown cognition can decline after hospitalization (from any
cause) though these studies have not specifically considered
delirium (Mathews et al., 2013). Equally, it is possible that
systemic inflammation may lead to accelerated rates of cog-
nitive decline in dementia, even in the absence of delirium
(Holmes et al., 2009).
Ascertaining delirium in the context of an epidemiological
study is challenging. Three cohort studies have investigated
this and each could only determine delirium retrospectively.
Nonetheless, the consistent finding is that delirium (or symp-
toms plausibly attributable to delirium) resulted in an acceler-
ated degree of cognitive decline, over and above that expected
from pre-existing cognitive function (Fong et al., 2009; Gross
et al., 2012; Davis et al., 2012, 2014).
71.12 FUTURE DIRECTIONS FOR
DELIRIUM RESEARCH AND
PRACTICE
Acknowledging delirium as a determinant of chronic cog-
nitive impairment positions delirium as a critical event in
the path towards dementia. In recognizing that neurode-
generative processes may interact with delirium and/or its
precipitants, future work needs to consider the long-term
impact of acute illness on the brain.
A greater breadth of experimental work is necessary,
even more pressing for delirium as it is for dementia. The
biological substrates of both these conditions might best be
investigated in tandem rather than separately. Researchers
carrying out experiments in dementia may not even be fully

aware of delirium as a construct and this is likely leading to
missed opportunities for translational collaboration.
Currently, the specification of arousal stated in the
DSM-5 as an explicit manifestation of inattention is highly
relevant. Acute illness, underlying dementia and superim-
posed delirium, each have an impact on the level of arousal.
Therefore, the extent to which each has an impact (individu-
ally and in concert) on cognitive and functional outcomes
urgently warrants research.
A number of assessment scales is available for delirium
in clinical practice. Clearly, no single instrument is suitable
for all patient groups. The diagnostic accuracy will vary
with setting. The degree of training required, along with
the length of time to administer any such tool is crucial
if widespread improvements in delirium recognition are
to be effective. Change in diagnostic accuracy when there
is underlying dementia is important to measure and war-
rants specific study. Where low arousal states are intrinsic
to delirium, formal cognitive testing is usually not possible,
though, few instruments allow for this. Individual tools
may be compared in randomized controlled trials and this
will help clarify which will work best in practice. In general,
greater detail reporting the exact operationalization of ref-
erence standards within validation studies is essential.
While the public health impact of dementia is widely
acknowledged, the relevance of delirium in highlight-
ing vulnerabilities to cognitive impairment arguably will
become increasingly prominent. Delirium and dementia
care within acute hospitals must be closely aligned. The eco-
nomic costs of delirium should be a potent driver for change.
Innovations in delirium education may facilitate this as will
a more conscious approach to knowledge translation.
71.13 CONCLUSIONS
Delirium is a distressing, under-recognized and expensive
clinical entity that influences cognitive outcomes in both
patients with and without dementia. Treating delirium
hinges on addressing the underlying cause, brain optimiza-
tion and symptom relief if distressed. Given that it is pre-
ventable and treatable, substantial clinical efforts should be
directed to its identification in high-risk groups and there-
after management in its own right.
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c3704.

Depression with cognitive impairment
SARAH SHIZUKO MORIMOTO, GENEVIEVE S. YUEN, STEPHEN BERES AND
GEORGE S. ALEXOPOULOS
72.1 INTRODUCTION
Major depression in the elderly is often accompanied by
cognitive impairment. Although estimates vary, studies
show that combined depression and cognitive dysfunction
is present in roughly 25% of the subjects (Arve et al., 1999).
In addition, the number of community residents with both
depressive symptoms and impaired cognition doubles every
5 years after the age of 70 years. In some cases, the syndromes
of depression and cognitive impairment may be related to the
same underlying disorders (e.g. vascular dementia, hypo-
thyroidism), whereas in other cases, depression and cogni-
tive impairment may be relatively independent and simply
coexist. Differential diagnosis and treatment decisions can
be complicated because depressive cognitive changes can be
severe, incipient dementia often can have physical and cog-
nitive symptoms that overlap with depression and the two
can coexist (Bayles et al., 1987). The relationships between
the prominent cerebrovascular changes, other structural
abnormalities, specific forms of cognitive dysfunction and
increased risk for developing dementias in geriatric depres-
sion have yet to be reconciled. The varied and most current
findings suggest that there are likely multiple pathways to
poor cognitive outcomes (Butters et al., 2008).
72.2 COGNITIVE IMPAIRMENT IN
NON-DEMENTED DEPRESSED
PATIENTS
Neuropsychological impairments spanning many cogni-
tive domains including impairment in executive functions
(Lockwood et al., 2000, 2002), episodic memory (Beats
et al., 1996; Kramer-Ginsberg et al., 1999; Story et al., 2008),
recognition memory, visuospatial skills (Boone et al., 1994;
832
72
Lesser et al., 1996; Elderkin-Thompson et al., 2004), verbal
fluency and psychomotor speed (Hart et al., 1987; Butters
et al., 2004b), have been reported consistently in late-life
depression. These impairments, particularly memory
impairments, were attributed to dysfunction in subcortical
structures related to mood regulation, such as the hippo-
campus (Hickie et al., 2005). Recent research has focused
on the role of executive functions, such as impaired plan-
ning, organizing, initiating, perseverating, sequencing and
attentional set-shifting in geriatric depression (Lesser et al.,
1996; Alexopoulos et al., 2000; Butters et al., 2000; Murphy
and Alexopoulos, 2004; Potter et al., 2004). Executive func-
tion is impaired in depressed older adults relative to healthy
controls, and this impairment persists even when control-
ling for processing speed (Dybedal et al., 2013). Further,
abnormal performance on specific aspects of executive
function predicts both poor and unstable antidepressant
response in late-life depression (Kalayam and Alexopoulos,
1999; Alexopoulos et al., 2000, 2004, 2005; Sneed et al.,
2007; Morimoto et al., 2011), although some disagreement
exists (Butters et al., 2004a). The specifics of this topic are
discussed in Section 72.5.1.
Although focal deficits or even severe global impair-
ment are observed in some depressed elderly patients, the
cognitive functioning of others remains intact. Studies of
cognitive response to psychopharmacological treatment
of late-life depression indicate that a substantial number
of patients continue to experience residual symptoms and
neuropsychological deficits. Executive dysfunction, pro-
cessing speed and working memory impairment may per-
sist after remission of geriatric depression (Butters et al.,
2000; Nebes et al., 2000; Aizenstein et al., 2009). Multiple
pathways may lead to depression and cognitive impairment.
However, clinical as well as structural and functional neu-
roimaging studies suggest that depressive symptoms and
executive impairment originate from related brain dys-
functions (Alexopoulos et al., 2001a; Murphy et al., 2007;

Alexopoulos et al., 2008; Morimoto et al., 2011, 2012a),
at least in a subgroup of elderly patients. We described
a ‘depression-executive dysfunction (DED) syndrome’
(Alexopoulos, 2001), characterized by symptoms and signs
resembling a medial frontal lobe syndrome, including
psychomotor retardation, anhedonia, apathy, mild vegeta-
tive symptoms and pronounced functional disability dis-
proportional to the severity of the depressive syndrome
(Alexopoulos et al., 1996, 2000; Lockwood et al., 2002).
72.2.1 NEUROBIOLOGICAL
UNDERPINNINGS OF COGNITIVE
DEFICITS
The structural and functional abnormalities that contribute
to the symptoms of this disorder remain unclear, although
several abnormalities have been reported (Alexopoulos
et al., 2005). Recently, structural and functional neuroim-
aging have documented both frontostriatal impairment
and the relationship between frontostriatal impairment
and executive dysfunction in geriatric depression (Murphy
et al., 2007, Aizenstein et al., 2009).
Structural abnormalities have been identified in the
orbitofrontal cortex (Van Otterloo et al., 2009; Sexton et al.,
2013), particularly in the gyrus rectus bilaterally (Ballmaier
et al., 2004; Yuan et al., 2008), the anterior cingulate (Drevets
et al., 1997; Ballmaier et al., 2004), the caudate (Krishnan
et al., 1992; Hannestad et al., 2006), putamen (Husain et al.,
1991; Sexton et al., 2013), hippocampus (Sheline et al., 1996;
Lai et al., 2000; Sawyer et al., 2012) and amygdala (Sheline
et al., 1998; Burke et al., 2011).
In addition to grey matter reductions, bilateral white
matter hyperintensities are prevalent in geriatric depression
(Boone et al., 1992; Steffens et al., 1999; Kumar et al., 2000;
Alexopoulos et al., 2008; Gunning-Dixon et al., 2008) and
mainly occur in the subcortical structures and their fron-
tal projections (MacFall et al., 2001; Gunning-Dixon et al.,
2008). There is evidence that white matter hyperintensities
disrupt frontostriatal circuits (Hannestad et al., 2006) and
have been associated with executive dysfunction (Boone
et al., 1992; Lesser et al., 1996). Poorer executive function
is related to white matter lesions in specific tracts, such as
the superior longitudinal fasciculus and uncinate fasciculus
(Sheline et al., 2008; Mettenburg et al., 2012). Furthermore,
depressed older adults with impaired response inhibition
exhibited reduced white matter integrity, as measured by
fractional anisotropy, in multiple frontostriatal-limbic
regions including areas lateral to the anterior and posterior
cingulate cortex, and prefrontal, insular and parahippo-
campal regions (Murphy et al., 2007).
Abnormal metabolism has also been noted in limbic
regions, including the amygdala (Wu et al., 1992; Drevets,
1999; Drevets et al., 2002), the pregenual and subgenual ante-
rior cingulate (Drevets, 1998), the posterior orbital cortex
(Drevets et al., 1992), the posterior cingulate and the medial
cerebellum (Bench et al., 1992). Recent research demonstrates
Depression with cognitive impairment 833
cortical glucose metabolism in both anterior and posterior
cortical regions in patients with geriatric depression relative
to controls, particularly in areas where there has been cere-
bral atrophy, which may represent a compensatory response
(Smith et al., 2009). In fact, positive correlations between
anxiety and depressive symptoms and cortical glucose
metabolism have been observed (Smith et al., 2009).
72.3 DEPRESSION IN PATIENTS WITH
DEMENTING DISORDERS
Estimates of the rates of depression in dementing disor-
ders range from 30% to 50% (Taylor et al., 2003). Clinically
significant depressive symptoms occur in 10% to 50% of
Alzheimer’s disease (AD) patients, with estimates of major
depression occurring in 30% of them (Wragg and Jeste,
1989; Holtzer et al., 2005; Even and Weintraub, 2010;
Enache et al., 2011; Chi et al., 2014). Depression in AD is
notable for increased disturbances in initiation or moti-
vation, such as fatigue, psychomotor slowing and apathy
(Chemerinski et al., 2001; Janzing et al., 2002; Teng et al.,
2008). Patients with subcortical dementias, including vas-
cular dementia (VaD) and Parkinson’s disease (PD), are
more likely to experience depression than patients with
AD (Sobin and Sackeim, 1997; Enache et al., 2011). Rates
of clinically significant depressive disturbances in PD
reach about 35% to 50% (Lagopoulos et al., 2005; Aarsland
et al., 2012; Marsh, 2013). Depression associated with PD
can produce severe negative symptoms and contributes to
an increased rate of decline of both cognitive and motor
function. Diagnosing depression in PD patients is often
challenging due to the overlap of certain somatic and core
depressive symptoms (Lagopoulos et al., 2005; Aarsland
et al., 2012; Marsh, 2013).
A first episode of depression presenting in late life is,
sometimes, a prodrome of a dementing disorder. A recent
meta-analysis, which included 23 community-based pro-
spective cohort studies, concluded that late-life depression
significantly increased the risk of AD incidence 1.65 fold,
even after controlling all possible cofounders (Chi et al.,
2014). Another meta-analysis of community-based cohort
studies reported individuals with late-life depression had
a significantly higher risk for incident all-cause dementia,
AD and VaD compared with the elderly controls (Diniz
et al., 2013). Depressed mood has been associated with
an increased risk of incident dementia in some samples
(Devanand et al., 1996). For example, depressive symptoms
predicted cognitive decline of elderly women during a 4-year
follow-up study (Yaffe et al., 1999). In addition, in patients
with subthreshold cognitive symptoms, those suffering con-
current depressive symptoms are more likely to progress to
dementia (Ritchie et al., 1999). However, more recent data
suggest that there is a significant decline in functioning that
precedes late-onset depressive symptoms in AD and that
cognition declines subsequently (Holtzer et al., 2005).
834 Dementia
The prevalence of depressive symptoms in AD decreases
over time as patients exhibit fewer affective symptoms,
increased agitation and psychomotor slowing. Data suggest
that rates of depression in this population remain stable for
roughly the first 3 years of follow-up. Rates appear to drop
in the fourth and fifth year of follow-up by as much as 30%
(Holtzer et al., 2005).
The National Institute of Mental Health’s Provisional
Diagnostic Criteria for Depression of AD were developed
to promote research on the mechanisms and treatment of
this disorder (Olin et al., 2002). The criteria require diag-
nosis of AD and clinically significant depressive symp-
toms. The criteria specify that the patient must have three
(reduced from five) or more of the following symptoms
during the same 2-week period (reduced from ‘most of
the day, nearly every day’) and represent a change from
previous functioning: depressed mood, anhedonia, social
isolation, appetite disturbance, sleep disturbance, psy-
chomotor changes, irritability, fatigue or loss of energy,
worthlessness, hopelessness or inappropriate or excessive
guilt and recurrent thoughts of death or suicidal ideation,
plan or attempt. At least one of the symptoms must be
depressed mood or anhedonia. Symptoms due to a medi-
cal condition other than AD, or as a direct result of non-
mood-related dementia symptoms (e.g. loss of weight due
to difficulties with food intake), should not be used in
making the diagnosis of depression or AD. These diag-
nostic criteria have less stringent guidelines about the
duration and number of symptoms and, therefore, are
likely more sensitive than other diagnostic approaches
(Engedal et al., 2011).
72.4 DEPRESSION AS A RISK FACTOR
FOR DEMENTIA
Individual studies attempting to link geriatric depression
with subsequent dementia have mixed results. Although
one recent meta-analysis showed an almost twofold risk
for the development of AD with previous history of depres-
sion (Ownby et al., 2006), another found this association
only when depressive symptoms had appeared within
the 10 years before onset of dementia (Jorm et al., 1991).
Other individual studies have failed to find this association
(Ganguli et al., 2006). Recent research suggests that only the
most severe cases of depression increase risk for later devel-
opment of dementia (Chen et al., 2008).
Some data suggest that the experience of multiple
depressive episodes may promote the clinical expression
of dementia in patients with AD. Some volumetric studies
have found reductions in hippocampal volumes in patients
with recurrent major depression (Sheline et al., 1996, 2003).
Lifetime duration of depression correlated with hippo-
campal volume reduction and with behavioural measures
of hippocampal function, such as verbal memory (Sheline
et al., 1999). Depression leads to an acute dysregulation of
the hypothalamic–pituitary–adrenal (HPA) axis, which in
turn can result in hypercortisolaemia (Carroll et al., 1981).
Depression disrupts the fast feedback control of corti-
sol secretion (Young et al., 1991) at various levels, includ-
ing limbic structures such as the hippocampus (Young
and Vazquez, 1996). The precise relationship between
hypercortisolaemia, hippocampal volume loss and hip-
pocampal inhibitory control is unknown, although ani-
mal studies show that neurotoxic tissue damage may be
one possible mechanism. Another theory postulates that
excess and chronic secretion of glucocorticoid hormones
can reduce neurotrophic factors, inhibit neurogenesis and
render neurones vulnerable to the toxic effect of amyloid.
These changes may then compound the neuropathologi-
cal changes of AD and accelerate the clinical expression of
dementia (Zhu et al., 2005).
One such neurotrophic factor is the brain-derived neu-
rotrophic factor (BDNF), which is widely distributed in the
adult brain and has been implicated in structural abnor-
malities of the human hippocampus (Pezawas et al., 2004;
Bueller et al., 2006). Several antidepressants elevate BDNF
in the rat hippocampus. Recent research suggests that
BDNF protein is rapidly elevated by antidepressant treat-
ments through post-transcriptional mechanisms (Musazzi
et al., 2009). Through this action, antidepressants may pre-
vent stress-induced inhibition of neurogenesis and increase
dendritic branching (Duman et al., 1997). Whether this
action delays the onset or inhibits the progression of AD
is unclear; systematic studies have not yet explored this
question.
72.5 COGNITIVE IMPAIRMENT AND
THE COURSE OF GERIATRIC
DEPRESSION
The neuropsychological impairments, seen frequently
in geriatric depression, span multiple cognitive domains
(Lockwood et al., 2002). These impairments, particularly
memory impairments, were attributed to dysfunction in
subcortical structures related to mood regulation, such as
the hippocampus (Hickie et al., 2005).
Recent research has focused on the role of executive
functions, such as impaired planning, organizing, initiat-
ing, perseverating, sequencing and attention set shifting
in the clinical course of geriatric depression (Boone et al.,
1994; Lesser et al., 1996; Alexopoulos et al., 2000; Murphy
and Alexopoulos, 2004; Potter et al., 2004; Morimoto et al.,
2011). Abnormal performance on some tests of executive
function predicts both poor and unstable antidepressant
response (Kalayam and Alexopoulos, 1999; Alexopoulos
et al., 2000; Morimoto et al., 2011, 2012a), as well as cur-
rent and future disability (Kiosses et al., 2001; Alexopoulos
et al., 2005). In addition, executive dysfunction predicts
suicidality, even after controlling for co-morbid conditions
(Dombrovski et al., 2008, 2010).

The specific structural and functional abnormalities
that contribute to the symptoms of depression remain to
be identified, although several abnormalities have been
reported (Alexopoulos et al., 2004). Recently, structural and
functional neuroimaging have documented both frontostri-
atal impairment and a relationship between frontostriatal
impairment and executive dysfunction in geriatric depres-
sion (Murphy et al., 2007; Aizenstein et al., 2009).
Structural abnormalities have been identified in the orbi-
tofrontal cortex (Van Otterloo et al., 2009), particularly the
gyrus rectus bilaterally (Ballmaier et al., 2004; Yuan et al.,
2008), the anterior cingulate (Drevets et al., 1997; Ballmaier
et al., 2004), the caudate head (Krishnan et al., 1992), puta-
men (Husain et al., 1991), hippocampus (Sheline et al., 1996;
Lai et al., 2000) and amygdala (Sheline et al., 1998).
In addition to grey matter reductions, bilateral white
matter hyperintensities are prevalent in geriatric depres-
sion (Boone et al., 1992; Kumar et al., 2000; Alexopoulos
et al., 2008; Gunning-Dixon et al., 2008), and mainly occur
in the subcortical structures and their frontal projections
(MacFall et al., 2001; Gunning-Dixon et al., 2008). White
matter hyperintensitites disrupt frontostriatal circuits
(Hannestad et al., 2006) and have been associated with
executive dysfunction (Boone et al., 1992; Lesser et al., 1996,
Murphy et al., 2007).
Abnormal metabolism has also been noted in limbic
regions, including the amygdala (Wu et al., 1992; Drevets,
1999; Drevets et al., 2002), the pregenual and subgenual
anterior cingulate (Drevets, 1998), the posterior orbital cor-
tex (Drevets et al., 1992), the posterior cingulate and the
medial cerebellum (Bench et al., 1992). Recent research has
shown increased cortical glucose metabolism in both ante-
rior and posterior cortical regions in patients with geriatric
depression relative to controls, particularly in areas where
there has been cerebral atrophy, which may represent a
compensatory response (Smith et al., 2009). Cortical glu-
cose metabolism was correlated with anxiety and depressive
symptoms (Smith et al., 2009).
72.5.1 NEUROCOGNITIVE DEFICITS
INFLUENCING TREATMENT
RESPONSE OF GERIATRIC
DEPRESSION
Abnormal performance on select executive function
tests predicted poor and/or slow antidepressant response
(Alexopoulos et al., 2002b; Sneed et al., 2007, 2008;
Morimoto et al., 2011, 2012a) and a higher level of func-
tional disability (Kiosses et al., 2001) in geriatric depression.
These include processing speed, perseveration, seman-
tic strategy and response inhibition, which were associ-
ated with both poor and unstable antidepressant response
and low remission rate in non-demented elderly patients
with major depression treated with ‘adequate’ dosages of
various antidepressants (Simpson et al., 1998; Kalayam
and Alexopoulos, 1999; Alexopoulos et al., 2000, 2004;
Depression with cognitive impairment 835
Potter et al., 2004; Sneed et al., 2007, 2008; Story et al., 2008;
Morimoto et al., 2011 2012). Dysfunction in the neural
circuits related to remission may produce multiple down-
stream cognitive abnormalities that are similar (i.e. seman-
tic strategy deficits vs. response inhibition deficits) but not
identical, perhaps because of individual differences in net-
work abnormalities, premorbid network characteristics and
network interactions with other brain systems necessary for
completion of tasks (Morimoto et al., 2012b).
Decrements in performance on the Initiation/
Perseveration (I/P) domain of the Dementia Rating Scale
(DRS) predict poor response to antidepressant treatment
in geriatric depression (Kalayam and Alexopoulos, 1999;
Alexopoulos, 2003b). A meta-analysis examining the rela-
tionship between pretreatment cognitive impairment and
response to antidepressants demonstrated that the DRS
I/P domain was a reliable predictor of poor antidepres-
sant treatment response (McLennan and Mathias, 2010).
Approximately 42% of elders with major depression have
abnormal I/P scores as measured by the Mattis Dementia
Rating Scale (MDRS) (Alexopoulos et al., 2002). Though not
a classic test of executive function, the I/P domain of the
DRS tests multiple coordinated cognitive skills that require
executive functioning.
Among the functions tested by the I/P, only the Complex
Verbal portion (CV/IP) predicted remission during treat-
ment with escitalopram (Morimoto et al., 2011). The CV/IP
tests word generation ability by asking patients to name all
of the items they can think of in a supermarket (i.e. seman-
tic fluency). Performance on speeded verbal tasks such as
the CV/IP can be improved by the use of strategies, such
as the organization of responses into super ordinate verbal
categories (semantic organization), e.g. replying with words
belonging to the same category (fruit), e.g. grapes, strawber-
ries, bananas, oranges, rather than separate categories, e.g.
bread, bananas, milk. Completing strategic semantic tasks
such as the CV/IP also requires selection of words from
multiple activated responses and suppression of semanti-
cally or phonemically related but inapplicable words. In
the aforementioned study, the use of semantic strategy,
explained performance differences between remitters and
non-remitters (Morimoto et al., 2011).
These findings were followed by a second study demon-
strating the use of the same executive function; semantic
organizational strategy, explained both verbal memory
performance and remission rates of geriatric depression
(Morimoto et al., 2012a). These studies defined a single exec-
utive function that is predictive of remission with antide-
pressant drug treatment, regardless of the task by which the
function is elicited. If these findings are replicated, testing
semantic strategy could be a useful tool added to the clini-
cal assessment of depressive symptoms. Results could help
improve the clinician’s ability to identify patients at risk for
poor antidepressant response (Morimoto et al., 2011).
These neuropsychological findings parallel structural
and functional neuroanatomical changes associated both
with cognitive control dysfunction and with poor response
836 Dementia
of late-life depression to antidepressants. Structural and
functional imaging findings, including white matter hyper-
intensities (Gunning-Dixon et al., 2010), microstructural
white matter changes (Alexopoulos et al., 2008), low volume
of the anterior cingulate (Gunning et al., 2009) and reduced
resting functional connectivity of the cognitive control
network (Alexopoulos et al., 2012), are observed in late-
life depression. Taken together, these findings lend support
to the hypothesis that depression with cognitive control
dysfunction is a distinct syndrome of late-life depression
(Alexopoulos, 2001) with poor antidepressant response.
72.6 PSEUDODEMENTIA
The concept of reversible dementia was introduced in the
mid-nineteenth century (Berrios, 1985; Emery, 1988) and
became the focus of clinical attention in the early 1960s
when the term ‘pseudodementia’ was used to describe a
broad range of reversible cognitive impairments associated
with psychiatric syndromes (Kiloh, 1961). The current con-
cept of pseudodementia is that of an initially reversible cog-
nitive impairment that both occurs in the context of diverse
psychiatric disorders and influences their course.
The clinical presentation of depression with cognitive
impairment is heterogeneous; the signs and symptoms are
principally influenced by the patients’ age and underly-
ing psychiatric disorders (Kiloh, 1961; Wells, 1979; Rabins
et al., 1984; Alexopoulos, 1990; Emery and Oxman, 1992).
In a non-geriatric series, pseudodementia was reported
in patients with Ganser syndrome, personality disorders,
melancholic depression, hypomania, atypical psychosis,
paraphrenia, catatonia, depersonalization and malinger-
ing (Kiloh, 1961; Wells, 1971). Non-geriatric patients with
pseudodementia in this sample had a history of prior psy-
chiatric disorders, a recent and abrupt onset of current ill-
ness, complained about their cognitive loss and experienced
distress and were able both to identify precisely the onset
and describe in detail the course of their illness (Kiloh,
1961; Wells, 1979). On cognitive tests, these patients often
said they did not know the correct answers even though the
tasks were within their abilities. Performance on tasks of
similar difficulty was markedly variable and accompanied
by an overdramatization of failures.
As many younger patients with pseudodementia have
psychiatric syndromes other than depression, their clinical
presentation is dissimilar from that of geriatric patients with
pseudodementia in whom depression is the most common
diagnosis. Depressed older patients with pseudodemen-
tia usually have a severe depression syndrome, but a mild
dementia. The clinical profile of major depression accom-
panying pseudodementia of older adults is characterized by
motor retardation, depressive delusions, hopelessness and
helplessness (Alexopoulos and Abrams, 1991). Geriatric
inpatients with major depression and pseudodementia dif-
fer from those with uncomplicated major depression in that
they often have a later age of onset of illness (Alexopoulos
et al., 1993). When compared to AD patients with concomi-
tant depression, pseudodementia patients have more psy-
chic and somatic anxiety, early morning awakening and loss
of libido (Reynolds et al., 1986).
Neuropsychological assessment is generally considered
the gold standard in differentiating between depression
and the early stages of dementia. Decrements in memory,
attention, visuospatial ability, processing speed and execu-
tive functioning have been reported in pseudodemen-
tia. Although these deficits are also seen in AD, cognitive
impairments seen in early AD are more severe in nearly
every cognitive domain. For example, depressed patients
perform better than AD patients on measures of initial
learning and recall as well as delayed recall (Kang et al.,
2014). In addition, although memory may be impaired in
both conditions, AD patients will often exhibit ‘rapid for-
getting’ (Gray et al., 1986) pointing to deficits in memory
systems, as well as difficulty with recognition memory. AD
patients also produce more ‘false-positive’ errors or ‘intru-
sions’, whereas depressed elderly patients tend to produce
more false negatives (Whitehead, 1973; Kang et al., 2014).
Patients with true AD tend to present with additional spe-
cific impairments, such as impaired temporal orientation,
abstraction, calculation, visual recognition, visuoconstruc-
tion and language functions (Chaves and Izquierdo, 1992).
As a rule, the symptoms of depression also precede those of
cognitive dysfunction in patients with true pseudodemen-
tia, making it important to take a thorough history of the
symptoms.
Studies of pseudodementia in depressed geriatric
patients challenge the concept of pseudodementia as a truly
reversible dementia syndrome. Notably, although cognitive
impairment associated with depressive pseudodementia
may diminish upon remission of depression, follow-up stud-
ies show that a large percentage of these patients progress
into irreversible dementia within 2–3 years of onset. This
supports the claim that reversible cognitive impairment
associated with pseudodementia is more likely the result of
a preclinical or early-stage dementing disorder exacerbated
by concomitant depression (Alexopoulos, 2003).
72.7 DIAGNOSTIC ASSESSMENT AND
TREATMENT PLANNING
Identifying and characterizing the cognitive impairment of
depressed elderly patients has important clinical implica-
tions. Depressed elders often develop delirium in response
to drug side effects, dehydration, infections and other fac-
tors. Therefore, cognitive examination should focus on
manifestations of delirium, including inattention, fluctuat-
ing state of consciousness and sleep–wake disturbances. Of
course, making a diagnosis of delirium does not exclude a
diagnosis of dementia. As dementing disorders predispose
to delirium, delirious patients should be re-examined for an

underlying dementia after the delirium resolves. Identifying
treatable causes of dementia (e.g. dementia due to drug
intoxication, organ failure, endocrinopathies, B12 deficiency,
normal pressure hydrocephalus and space-occupying
lesions) is important, as treatment of these conditions may
reverse or arrest the progress of dementia.
The identification of depression or cognitive impairment
in the elderly should lead to an examination for identifying
possibly undetected vascular disease and to consideration
of factors that might predispose to vascular disease, because
both of these conditions are associated with cerebrovascu-
lar disease (Thomas et al., 2004; Roman, 2006; Kelly and
Alexopoulos, 2009). Most brain infarcts do not manifest
with neurological signs (Fried et al., 1991; Longstreth et al.,
1998; Vermeer et al., 2002), so depression and/or cognitive
impairment can be the first sign of cerebrovascular disease.
The relationship between depression and cardiovascular
disease appears to be bidirectional (Thomas et al., 2004).
Therefore, care should be coordinated to ensure that both
psychiatric and cardiovascular health issues are addressed
(Alexopoulos et al., 2002). Since many medications, includ-
ing psychotropic medications, increase cardiovascular risk
factors, including hyperlipidaemia, hyperglycaemia, hyper-
tension and obesity, a careful overview of the patient’s regi-
men is needed (Kelly and Alexopoulos, 2009).
When dementia is identified, the clinical character-
ization of the dementia syndrome can guide treatment.
Among the dementia syndromes, subcortical dementia
is the syndrome most likely to be complicated by depres-
sion. Subcortical dementia is characterized by significant
memory impairment, executive dysfunction and psycho-
motor retardation. Disorders causing subcortical dementias
include mixed AD and VaD, VaD, PD and dementia with
Lewy bodies (DLB). These disorders require specific treat-
ments, e.g. VaD is often treated with aspirin, statins and
management of hypertension, PD with dopamine-acting
agents, and DLB with cholinesterase inhibitors. Unlike
subcortical dementias, cortical dementias manifest broader
impairment of cognitive functions, including memory
impairment, apraxia, aphasia with paraphasic errors and
graphomotor construction problems. The most common
cause of cortical dementia is AD for which cholinester-
ase inhibitors and memantine are the available treatments
(see Chapter 52). Frontal lobe syndromes are characterized
by rather mild memory impairment and pronounced per-
sonality changes, apathy, socially inappropriate behaviour
and disinhibition, often resulting in irritability. Frontal lobe
syndromes may be due to frontotemporal dementia, head
trauma or stroke and no specific treatments are available.
Identification of executive dysfunction is important even
in non-demented depressed elderly patients. Depressed
patients with psychomotor retardation, reduced interest in
activities, suspiciousness and disability are likely to have
executive dysfunction (Alexopoulos et al., 2002). Depression
with executive dysfunction may have a poor and unstable
response to antidepressants (Kalayam and Alexopoulos,
1999; Alexopoulos et al., 2000, 2005). For this reason,
Depression with cognitive impairment 837
patients with the DED syndrome of late life require carefully
planned psychopharmacological treatment and vigilant fol-
low-up, since they are at high risk for relapse or recurrence
(Alexopoulos et al., 2000). Non-pharmacological interven-
tions should be considered, particularly in medication non-
responders. These are further discussed in Section 72.7.2.
Evaluation of depressive syndromes in cognitively
impaired patients is complicated by the symptom overlap
with dementia, the instability of depressive manifestations
over time and the poor ability of elderly patients to report
their symptoms. If criteria for one of the depressive syn-
dromes are met, an antidepressant treatment trial should
be offered. The Expert Consensus Guideline recommends
antidepressant drug therapy combined with psychosocial
intervention as the treatment of choice for geriatric depres-
sion (Alexopoulos et al., 2001). Variability in the course of
elders with depression and cognitive impairment suggests
the need for careful follow-up. About 40% of these patients
are expected to receive the diagnosis of dementia within 2
years after the diagnosis of pseudodementia. Prompt iden-
tification and treatment of the dementing disorder may
increase the time during which the patient can function
independently.
72.7.1 ASSESSMENT AND DIAGNOSIS:
NEUROPSYCHOLOGICAL AND
CLINICAL EXAMINATION
Tests of executive function should be part of the initial
assessment of late-life depression. Clinicians can employ
bedside screening tests for executive dysfunction, such as
a verbal fluency task (e.g. ask patients to name as many
items as possible that can be purchased in a supermarket,
in 1 minute) or the Stroop Colour Word test of cognitive
inhibition. Abnormal performance on each of these tests
may predict poor antidepressant response, relapse and
greater functional disability (Baldwin et al., 2004; Potter et
al., 2004; Alexopoulos et al., 2005; Kiosses and Alexopoulos,
2005; Sneed et al., 2007; Morimoto et al., 2011).
A more comprehensive neuropsychological assessment
can aid the differential diagnosis of patients likely to expe-
rience cognitive decline from depressed patients who are
likely to remain cognitively stable. Rushing et al. found that
out of a battery of multiple cognitive measures, impaired
recall of verbal contextual information (short stories) pre-
dicted conversion to dementia in a study of older adults with
major depression who developed AD dementia 13 years
later (Rushing et al., 2014).
Initial evaluation of the depressed older adult with
cognitive impairment should also include a physical and
neurological examination with laboratory tests (including
comprehensive chemistry screen, complete blood count,
thyroid stimulating hormone levels, electrocardiogram,
serum B12 levels, folate levels, urinalysis and drug blood
levels) to rule out medical causes of cognitive impairment.
Identifying treatable causes of cognitive dysfunction (e.g.
drug or medication intoxication/withdrawal, organ failure,
838 Dementia
endocrinopathies, B12 deficiency, normal pressure hydro-
cephalus and space-occupying lesions) is important, as
treatment of these conditions may reverse or arrest progres-
sion to dementia.
Coexisting depression and cognitive impairment may
have a common aetiology, most frequently vascular disease.
Therefore, physicians should examine for previously unde-
tected cardiovascular disease and risk factors that predis-
pose to cardiovascular disease. The ‘vascular depression’
hypothesis postulates that cerebrovascular disease can pre-
dispose, precipitate or perpetuate a depressive syndrome in
older adults. Patients with vascular depression often have
impairment of executive function, psychomotor slowing,
apathy, impaired insight, disability disproportional to the
severity of their depression and poor response to antide-
pressants (Alexopoulos et al., 1997). Neuroimaging in these
cases will often reveal white matter hyperintensities, likely
caused by cerebrovascular lesions (Taylor et al., 2013).
Management of depression with cognitive impairment
should therefore include optimization of vascular risk fac-
tors by carefully controlling hypertension, hypercholes-
terolaemia, hyperglycaemia and obesity as well as using
aspirin or other anticoagulants in patients with atrial fibril-
lation (Alexopoulos et al., 2002; Avari et al., 2014). One
study suggested that augmentation of fluoxetine with the
calcium channel blocker nimodipine results in more effec-
tive treatment of vascular depression and lower recurrence
rates (Taragano et al., 2005).
72.7.2 TREATMENTS: PHARMACOLOGIC
AND TARGETED PSYCHOTHERAPY
If criteria for depression are met, an antidepressant treat-
ment trial should be offered. Beyond the benefits of alleviat-
ing the suffering and complications of depression, remission
of the depressive syndrome can increase the clinician’s
ability to evaluate the severity of the remaining cognitive
impairment and plan for further treatment and follow-up.
The Expert Consensus Guideline recommends antidepres-
sant drug therapy combined with a psychosocial inter-
vention as the treatment of choice for geriatric depression
(Alexopoulos et al., 2001).
Several antidepressants are available for the treat-
ment of unipolar, non-psychotic, late-life major depres-
sion. Selective serotonin reuptake inhibitors (SSRIs) or
serotonin-norepinephrine reuptake inhibitors (SNRIs) are
first-line agents (Alexopoulos et al., 2001). Some SSRIs can
improve cognitive function but mainly in patients whose
depressive symptoms respond to the SSRI antidepressant.
Treatment with sertraline in depressed elders with cogni-
tive impairment, improved performance on tests of atten-
tion, episodic memory and executive function, but again
only in patients whose depression responded to this antide-
pressant (Devanand et al., 2003). Treatment with citalopram
improved psychomotor speed and visuos
depressed (Culang et al., 2009). Second-line psychotropic
options may include bupropion, mirtazapine and tricyclic
antidepressants (TCAs). TCAs, however, do not improve
cognitive function in depressed older adults. In fact, nor-
triptyline compromised verbal learning performance com-
pared to placebo (Meyers et al., 1991).
Antidepressant treatment improves symptoms in some
but not all patients, and those who benefit may not return to
the cognitive and functional level of non-depressed elderly.
(Butters et al., 2000; Frasch et al., 2000; Beekman et al.,
2002; Doraiswamy et al., 2003; Nebes et al., 2003, Murphy
and Alexopoulos, 2004; Bhalla et al., 2006; Lee et al., 2007).
Therefore, separate treatment for cognitive impairment may
be necessary to improve outcomes in late-life depression.
Antidepressant augmentation with existing cognitive
enhancing drugs has received little research attention.
Open-label and placebo-controlled trials of the combination
of citalopram with the psychostimulant methylphenidate,
showed improved depressive symptoms in older depressed
patients, but these studies did not report effects on cogni-
tion (Lavretsky and Kumar, 2001; Lavretsky et al., 2003,
2006). A small placebo-controlled study found no effect of
memantine, on mood or functional independence (Lenze
et al., 2012) and augmentation of an antidepressant with
donepezil modestly improved cognition but increased the
risk of depression recurrence (Reynolds et al., 2011).
The cholinergic system is well established as important
to cognition. Cholinesterase inhibitors increase acetylcho-
line, while negatively affecting mood (Reynolds et al., 2011),
selective stimulation of nicotinic acetylcholine receptors
may benefit cognition without worsening mood (Zurkovsky
et al., 2013). As reviewed by Newhouse and colleagues
(Zurkovsky et al., 2013), some studies of nicotinic receptor
agonists show promise in improving cognitive performance
in patients with AD dementia or mild cognitive impairment
(MCI). However, this has not yet been demonstrated in a
population of depressed elderly with cognitive impairment.
Given the poor and unstable response to antidepres-
sants that frequently characterizes depression with execu-
tive dysfunction (Alexopoulos et al., 2000, 2005), adjunctive
non-pharmacological interventions should be considered
(Alexopoulos et al., 2001). Targeted therapies can improve
the behavioural deficits of depressed elders with cogni-
tive impairments that are associated with poor response to
antidepressant. Problem-solving therapy, as modified by
Alexopoulos and Arean to address the behavioural deficits
of depression with executive dysfunction, is efficacious in
reducing depression and disability in cognitively unim-
paired depressed older adults and in older adults with cog-
nitive impairment (Alexopoulos et al., 2003, 2008; Arean
et al., 2010; Kiosses et al., 2011b). Other targeted therapies
for depressed elderly patients incorporate modification of
the patient’s environment or ‘ecosystem’, which includes the
patient, caregiver and home environment. We have devel-