Dementia.2019 Continuum PDF

FEBRUARY 2019
VOL. 25 NO. 1 Dementia

Guest Editor: Jonathan Graff-Radford, MD
12 Editor’s Preface
Editor-in-Chief: Steven L. Lewis, MD, FAAN
REVIEW ARTICLES
14 Late-onset Alzheimer Disease

Gil D. Rabinovici, MD
34 Early-onset Alzheimer Disease and Its Variants

Mario F. Mendez, MD, PhD, FAAN
52 Posterior Cortical Atrophy

Jonathan M. Schott, BSc, MD, FRCP, FEAN, SFHEA;
Sebastian J. Crutch, PhD, CPsych
76 Behavioral Variant Frontotemporal Dementia

William W. Seeley, MD
101 Primary Progressive Aphasias and Apraxia of Speech

Hugo Botha, MBChB; Keith A. Josephs, MD, MST, MSc
128 Lewy Body Dementias

Melissa J. Armstrong, MD, MSc, FAAN
147 Vascular Cognitive Impairment

Jonathan Graff-Radford, MD
165 Normal Pressure Hydrocephalus

DENOTES CONTINUUM
Neill R. Graff-Radford, MBBCH, FRCP, FAAN; David T. Jones, MD
AUDIO INTERVIEW
DENOTES SUPPLEMENTAL 187 Chronic Traumatic Encephalopathy

DIGITAL CONTENT Katherine W. Turk, MD; Andrew E. Budson, MD
DENOTES VIDEO
CONTENT
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

208 Hippocampal Sclerosis, Argyrophilic Grain Disease, and Primary
Age-related Tauopathy
Gregory A. Jicha, MD, PhD; Peter T. Nelson, MD, PhD
234 Reversible Dementias

Gregory S. Day, MD, MSc
MEDICOLEGAL ISSUES
254 Prescribing Antipsychotic Medications to Patients With Dementia:

Boxed Warnings and Mitigation of Legal Liability
Rachel V. Rose, JD, MBA; Joseph S. Kass, MD, JD, FAAN
SELF-ASSESSMENT AND CME
4 Learning Objectives and Core Competencies
261 Instructions for Completing Postreading Self-Assessment and CME

Test and Tally Sheet
263 Postreading Self-Assessment and CME Test
277 Postreading Self-Assessment and CME Test—Preferred Responses
288 Index
List of Abbreviations (Back Cover)

CONTRIBUTORS
Jonathan Graff-Radford, MD, Hugo Botha, MBChB

Guest Editor Assistant Professor of Neurology,
Assistant Professor of Neurology, Mayo Clinic College of Medicine
Mayo Clinic College of Medicine and Science, Rochester,
and Science, Rochester, Minnesota
Minnesota
Relationship Disclosure: Dr Botha receives
Relationship Disclosure: Dr Graff-Radford research/grant support from the National
receives research/grant support from Institutes of Health (R01 DC012519-06).
the National Institute on Aging/National
Institutes of Health (K76AG057015). Unlabeled Use of Products/Investigational
Use Disclosure: Dr Botha reports
Unlabeled Use of Products/Investigational no disclosure.
Use Disclosure: Dr Graff-Radford discusses
the unlabeled/investigational use of
acetylcholinesterase inhibitors and
memantine for vascular cognitive impairment. Andrew E. Budson, MD
Chief, Cognitive and Behavioral
Neurology, VA Boston Healthcare
Melissa J. Armstrong, MD, System; Professor of Neurology,
MSc, FAAN Boston University School of
Assistant Professor of Neurology, Medicine, Boston, Massachusetts
University of Florida College of
Relationship Disclosure: Dr Budson has
Medicine; Director, University served as a consultant for Axovant Sciences,
of Florida Mangurian Clinical Inc, and Eli Lilly and Company and has
Research Headquarters for received personal compensation for speaking
engagements from Eli Lilly and Company.
Lewy Body Dementia, Dr Budson receives research/grant support
Gainesville, Florida from the US Department of Veterans Affairs
(I01CX000736) and publishing royalties from
Relationship Disclosure: Dr Armstrong
Elsevier and Oxford University Press.
serves on the evidence review board of
Neurology journals and as a guideline
Unlabeled Use of Products/Investigational
consultant for the American Academy
Use Disclosure: Dr Budson discusses the
of Neurology and has received personal
unlabeled/investigational use of several
compensation for speaking engagements
classes of medications for chronic traumatic
from the American Academy of Neurology
encephalopathy, including cholinesterase
and Medscape CME. Dr Armstrong receives
inhibitors for memory-related issues,
research/grant support from the Agency
selective serotonin reuptake inhibitors for
for Healthcare Research and Quality
mood and behavioral issues, memantine for
(K08HS24159), 1Florida Alzheimer’s Disease
attentional issues in those with advanced
Research Center (AG047266), and the
dementia, and atypical antipsychotics for
Lewy Body Dementia Association
those who are disinhibited and violent.
Research Center of Excellence program
and receives publishing royalties from
Oxford University Press.

Use Disclosure: Dr Armstrong discusses the
unlabeled/investigational use of biomarkers
for the diagnosis of dementia with Lewy
bodies and the unlabeled/investigational
use of donepezil, galantamine, and
memantine for cognitive symptoms in Lewy
body dementia; clozapine and quetiapine
for psychosis in Lewy body dementia; and
clonazepam and melatonin for rapid eye
movement sleep behavior disorder.
6 F EB R UA R Y 2 0 1 9

Sebastian J. Crutch, PhD, Neill R. Graff-Radford,
CPsych MBBCH, FRCP, FAAN
Professor of Neuropsychology, David Eisenberg Professor,
Dementia Research Centre, Mayo Clinic College of
University College London Medicine and Science,
Institute of Neurology, Jacksonville, Florida
University College London,
Relationship Disclosure: Dr Graff-Radford
London, United Kingdom serves on the editorial board of Alzheimer’s
Research & Therapy and receives research/
Relationship Disclosure: Dr Crutch grant support from AbbVie Inc; Axovant
receives research/grant support from Sciences, Inc; Biogen; Eli Lilly and Company;
the Alzheimer’s Society (AS-PG-14-022), the National Institutes of Health (P50AG16574,
The Dunhill Medical Trust (R337/0214), the 1R01AG045390-01A1, R56AG057195,
Economic and Social Research Council- UF1AG032438, U54NS092089, U01AG24904,
National Institute of Health Research U01NS100620); Novartis AG; and the US
(ES/L001810/1), and the Engineering and Department of Defense (WEI1872).
Physical Sciences Research Council
(EP/M006093/1). Unlabeled Use of Products/Investigational
Use Disclosure: Dr Graff-Radford reports
Unlabeled Use of Products/Investigational no disclosure.
Use Disclosure: Dr Crutch reports no
disclosure.
Gregory A. Jicha, MD, PhD

Gregory S. Day, MD, MSc Professor of Neurology and
Assistant Professor of Behavioral Science, University
Neurology; Associate Leader, of Kentucky, Lexington, Kentucky
Knight Alzheimer Disease Relationship Disclosure: Dr Jicha serves as
Research Center Clinical Core, a consultant for the Cure Alzheimer’s Fund
and provides contract research for AbbVie
Washington University in St.
Inc; Alltech; Axovant Sciences, Inc; Eli Lilly
Louis, St. Louis, Missouri and Company; Eisai Inc; Janssen Global
Services, LLC; Novartis AG; Suven Life
Relationship Disclosure: Dr Day has Sciences Limited; and VTV Therapeutics.
served as a topic editor on dementia for Dr Jicha receives research/grant support
DynaMed Plus (EBSCO Industries, Inc) from the National Institutes of Health
and as clinical director for the Anti-NMDA (UH2 NS100606, R01 AG054130, U19 AG010483,
Receptor Encephalitis Foundation. Dr Day U24 AG057437, P30 AG028383, R01 HD064993,
receives research/grant support from Avid R01 AG057187, R01 AG042419, R01 NR014189).
Radiopharmaceuticals, the Foundation
for Barnes Jewish Hospital, and the Unlabeled Use of Products/Investigational
National Institutes of Health (P01AG03991, Use Disclosure: Dr Jicha reports no
R56AG057195) and holds stock in ANI disclosure.
Pharmaceuticals, Inc. Dr Day has provided
record review and expert medical testimony
on legal cases pertaining to management of
Wernicke encephalopathy.

Use Disclosure: Dr Day reports no disclosure.
C O N T I N U U M J O U R N A L .C O M 7

CONTRIBUTORS (CONTINUED)
David T. Jones, MD Joseph S. Kass, MD, JD, FAAN

Senior Associate Consultant, Associate Dean, Office of
Department of Neurology, Student Affairs; Professor
Mayo Clinic; Assistant of Neurology, Psychiatry,
Professor of Neurology and and Medical Ethics; Director,
Radiology, Mayo Clinic College Alzheimer’s Disease and
of Medicine and Science, Memory Disorders Center,
Rochester, Minnesota Baylor College of Medicine;
Chief of Neurology, Ben Taub
Relationship Disclosure: Dr Jones receives
research/grant support from the Minnesota General Hospital,
Partnership for Biotechnology and Medical Houston, Texas
Genomics (P006598701) and the National
Institutes of Health (U01EB 24450-1, Relationship Disclosure: Dr Kass serves
R01DC14942-1, U01AG52943, as associate editor of medicolegal issues
U01AG45390, U19AG24904). for Continuum, as an associate editor for
Continuum Audio, as a neurology section
Unlabeled Use of Products/Investigational editor of Ferri’s Clinical Advisor for Elsevier,
Use Disclosure: Dr Jones reports no and as co-editor of Neurology Secrets,
disclosure. Sixth Edition. Dr Kass has received personal
compensation for CME lectures from
Pri-Med Medical Group and has received
personal compensation as a medicolegal
Keith A. Josephs, MD, MST, MSc consultant in legal cases involving
Professor of Neuroscience and criminal proceedings, malpractice,
and personal injury.
Neurology, Mayo Clinic College
of Medicine and Science, Unlabeled Use of Products/Investigational
Use Disclosure: Dr Kass reports no
Rochester, Minnesota disclosure.
Relationship Disclosure: Dr Josephs
receives research/grant support from the
National Institutes of Health (R01 AG37491,
R01NS89757, R01 DC14942).

Use Disclosure: Dr Josephs reports no
disclosure.
8 F EB R UA R Y 2 0 1 9

Mario F. Mendez, MD, PhD, Gil D. Rabinovici, MD
FAAN Edward Fein and Pearl Landrith
Behavioral Neurology Program Distinguished Professor,
Director; Professor of Department of Neurology,
Neurology, Psychiatry, and University of California San
Biobehavioral Sciences, David Francisco, San Francisco,
Geffen School of Medicine at California
the University of California,
Relationship Disclosure: Dr Rabinovici
Los Angeles; Director of receives research/grant support from the
Neurobehavior, VA Greater Los National Institutes of Health (P01-AG019724,
P50-AG23501, R01 AG032289, R01-AG045611,
Angeles Healthcare System, R01-AG048234, R01 AG057204, R56-AG057195)
Los Angeles, California and the National Institute of Neurological
Disorders and Stroke (R01-AG038791). Dr
Relationship Disclosure: Dr Mendez serves Rabinovici receives research support from
as a section editor for UpToDate, Inc, Avid Radiopharmaceuticals, Eli Lilly and
and as an associate editor of the Journal Company, General Electric Healthcare, and
of Alzheimer’s Disease. Dr Mendez has Life Molecular Imaging. Dr Rabinovici has
received personal compensation for served on scientific advisory boards for AXON
speaking engagements from the Medical Neuroscience SE; Eisai Co, Ltd; F. Hoffman-
Education Speakers Network and receives La Roche Ltd; Genentech, Inc; and Merck &
research/grant support from Biogen and Co, Inc. Dr Rabinovici serves as an associate
the National Institutes of Health/National editor for JAMA Neurology.
Institute on Aging (R01AG050967).
Dr Mendez receives publishing royalties Unlabeled Use of Products/Investigational
from Cambridge University Press. Use Disclosure: Dr Rabinovici discusses the
investigational use of the positron emission
Unlabeled Use of Products/Investigational tomography (PET) radiotracers [¹¹C]Pittsburgh
Use Disclosure: Dr Mendez reports no Compound B and [¹⁸F]flortaucipir in the
disclosure. diagnosis of Alzheimer disease.
Peter T. Nelson, MD, PhD Rachel V. Rose, JD, MBA

Professor of Pathology and Attorney, Rachel V. Rose
Laboratory Science, University Attorney at Law PLLC; Affiliated
of Kentucky College of Faculty, Baylor College of
Medicine, Lexington, Kentucky Medicine, Houston, Texas
Relationship Disclosure: Dr Nelson serves Relationship Disclosure: Ms Rose serves
on the National Institutes of Health/National on the editorial board of BC Advantage and
Institute on Aging external advisory boards receives book royalties from the American
of Mayo Clinic and Rush University and as an Bar Association.
associate editor for Acta Neuropathologica
and the Journal of Neuropathology & Unlabeled Use of Products/Investigational
Experimental Neurology. Use Disclosure: Ms Rose reports no
disclosure.
Use Disclosure: Dr Nelson reports no
disclosure.

Jonathan M. Schott, BSc, MD, Katherine W. Turk, MD

FRCP, FEAN, SFHEA Cognitive and Behavioral
Professor of Neurology, Neurologist, VA Boston
Honorary Consultant Healthcare System; Assistant
Neurologist, University College Professor of Neurology, Boston
London, London, United Kingdom University School of Medicine,
Boston, Massachusetts
Relationship Disclosure: Dr Schott serves
on advisory boards for Biogen; Eli Lilly and Relationship Disclosure: Dr Turk receives
Company; F Hoffman-La Roche Ltd; and research/grant support from the
Merck & Co, Inc, and on the drug safety Alzheimer’s Association.
monitoring board for AXON Neuroscience SE.
Dr Schott has received personal Unlabeled Use of Products/Investigational
compensation for speaking engagements Use Disclosure: Dr Turk discusses the
for Biogen, Eli Lilly and Company, and GE unlabeled/investigational use of several
Healthcare Worldwide and receives research/ classes of medications for chronic traumatic
grant support from Alzheimer’s Research UK, encephalopathy, including cholinesterase
Avid Radiopharmaceuticals, Brain Research inhibitors for memory-related issues,
UK, British Heart Foundation, Engineering selective serotonin reuptake inhibitors for
and Physical Sciences Research Council mood and behavioral issues, memantine for
(EP/J020990/1), European Commission Horizon attentional issues in those with advanced
2020, Medical Research Council Dementias dementia, and atypical antipsychotics for
Platform UK (MR/L023784/1), Weston Brain those who are disinhibited and violent.
Institute, and Wolfson Foundation. Dr Schott
receives royalties from Henry Stewart Talks
and Oxford University Press.

Use Disclosure: Dr Schott reports no
disclosure.
Professor of Neurology and
Pathology, University of
California San Francisco,
San Francisco, California
Relationship Disclosure: Dr Seeley
serves on the editorial boards of Acta
Neuropathologica, Annals of Neurology, and
NeuroImage: Clinical and as a consultant
for Biogen; Merck & Co, Inc; and Third Rock
Ventures, LLC. Dr Seeley receives research/
grant support from the Bluefield Project to
Cure FTD, the National Institutes of Health/
National Institute on Aging (AG023501,
AG019724), and the National Institutes of
Health/National Institute of Neurological
Disorders and Stroke (NS1104437, NS092474).
Dr Seeley has provided expert medical
testimony on legal cases related to violence
in patients with neuropsychiatric illness.

Use Disclosure: Dr Seeley discusses the
unlabeled/investigational use of medications
for the treatment of behavioral variant
frontotemporal dementia, none of which
are approved by the US Food and Drug
Administration.
10 F EB R UA R Y 2 0 1 9

Self-Assessment and CME Test Writers
D. Joanne Lynn, MD, FAAN Allyson R. Zazulia, MD

Associate Dean for Student Professor of Neurology and
Life, Clinical Professor Radiology, Associate Dean for
of Neurology, The Ohio Continuing Medical Education,
State University College of Washington University,
Medicine, Columbus, Ohio St. Louis, Missouri
Relationship Disclosure: Dr Lynn receives Relationship Disclosure: Dr Zazulia reports
book royalties from Lippincott Williams no disclosure.
& Wilkins and holds stock in Abbott
Laboratories; AbbVie Inc; Amgen Inc; Unlabeled Use of Products/Investigational
Bristol-Myers Squibb Company; CVS Health Use Disclosure: Dr Zazulia reports no
Corporation; Express Scripts Holding disclosure.
Company; General Electric; Merck & Co, Inc;
and Zimmer Biomet.

Use Disclosure: Dr Lynn reports no disclosure.

EDITOR’S PREFACE
Dementia Untangled
This issue of Continuum is devoted to the diagnosis and management
of our patients with dementia. I am delighted that Dr Jonathan
Graff-Radford accepted my invitation to be the guest editor of
this issue. I am also so appreciative that Dr Graff-Radford brought
together such an esteemed group of experts to share their
extensive experience and insights regarding the many causes of dementia we
encounter in our practices.
The issue begins with the article by Dr Gil D. Lewy bodies and Parkinson disease dementia and
Rabinovici on the risk factors, diagnosis (including highlighting the management issues we need to be
use of biomarkers), and management of late-onset aware of as we treat patients with these overlapping
Alzheimer disease (AD), defined as having an age of entities. Dr Jonathan Graff-Radford then reviews
onset of 65 years and older and likely the most vascular cognitive impairment, clarifying the
common cause of dementia we encounter. Dr Mario most up-to-date terminology for the various vascular
F. Mendez next reviews early-onset AD and its syndromes that may be primary causes of dementia
variants, highlighting the clinical, genetic, and as well as pathologies that may coexist with the
pathologic differences from late-onset AD. Drs neurodegenerative causes of dementia discussed in
Jonathan M. Schott and Sebastian J. Crutch then this issue.
review the syndrome of posterior cortical atrophy, Drs Neill R. Graff-Radford and David T. Jones
including its striking clinical presentation, diagnosis, next discuss the pathophysiology and current
pathologic considerations (most commonly a form recommendations on diagnosis and management
of early-onset AD), and the unique management of normal pressure hydrocephalus, an important,
considerations for improving the quality of life of our albeit rare, reversible cause of dementia. Drs
patients with this disorder. Katherine W. Turk and Andrew E. Budson then
Dr William W. Seeley next reviews the current provide a review of the current state of knowledge
clinical, genetic, and pathologic considerations in regarding the clinical features, epidemiology, risk
behavioral variant frontotemporal dementia and factors, and pathophysiology of chronic traumatic
provides us with the diagnostic strategies and pitfalls encephalopathy. Drs Gregory A. Jicha and
we need to be aware of when we encounter patients Peter T. Nelson next review hippocampal sclerosis,
with this clinical syndrome. Drs Hugo Botha and argyrophilic grain disease, and primary age-related
Keith A. Josephs then discuss primary progressive tauopathy, three pathologic entities associated
aphasias (PPAs)—specifically nonfluent/agrammatic with dementia that many of our readers may
variant PPA and semantic variant PPA—and primary not have heard of yet but, it turns out, are
progressive apraxia of speech, focusing on the surprisingly common and important for us to
current classification, evaluation, diagnosis, genetics, now have on our diagnostic radar. In the final
and neuropathology of these disorders of language review article of the issue, Dr Gregory S. Day
and speech. uses a number of very instructive brief illustrative
Dr Melissa J. Armstrong next reviews the Lewy cases to discuss the diagnosis and management
body dementias, clarifying the terminology and of the very important reversible causes
diagnostic considerations of both dementia with of dementia.
12 FEBRUARY 2019

In the Medicolegal Issues article, Ms Rachel V. Drs D. Joanne Lynn and Allyson R. Zazulia, you may
Rose and Dr Joseph S. Kass provide a familiar earn up to 20 AMA PRA Category 1 CreditsTM toward
scenario as a prologue to their practical and clinically self-assessment and CME or, for Canadian
relevant discussion regarding the issues neurologists participants, a maximum of 20 hours toward the
need to consider when prescribing antipsychotic Self-Assessment Program (Section 3) of the
medications to patients with dementia, especially Maintenance of Certification Program of the Royal
given the US Food and Drug Administration (FDA) College of Physicians and Surgeons of Canada.
boxed warnings for their use in this scenario. Additional credit can be obtained by listening to
After reading the issue and taking the Postreading Continuum Audio interviews associated with this
Self-Assessment and CME Test written by and other Continuum issues, available to all
subscribers, and completing tests on the Continuum
Audio web platform or app. Continuum Audio is also
accredited by the Royal College of Physicians and
Surgeons of Canada.
My sincere thanks to Dr Graff-Radford and the
My sincere thanks to Dr Graff- renowned dementia experts who contributed to
this issue for their state-of-the art and skillful
Radford and the renowned dementia
unraveling of the current and rapidly growing
experts who contributed to this knowledge of the clinicopathologic underpinnings
issue for their state-of-the art and and the diagnostic and management considerations
skillful unraveling of the current and of these disorders.
rapidly growing knowledge of the
—STEVEN L. LEWIS, MD, FAAN
clinicopathologic underpinnings and
EDITOR-IN-CHIEF
the diagnostic and management
considerations of these disorders. © 2019 American Academy of Neurology.
CONTINUUMJOURNAL.COM 13

REVIEW ARTICLE
Late-onset Alzheimer
Disease

C O N T I N UU M A UD I O
I NT E R V I E W A V AI L A B L E
ONLINE
By Gil D. Rabinovici, MD
ABSTRACT
PURPOSE OF REVIEW: Alzheimer disease (AD) is the most common cause of
late-onset dementia. This article describes the epidemiology, genetic and
environmental risk factors, clinical diagnosis, biomarkers, and treatment
CITE AS:
CONTINUUM (MINNEAP MINN) of late-onset AD, defined by age of onset of 65 years or older.
2019;25(1, DEMENTIA):14–33.
RECENT FINDINGS: An estimated 5.7 million Americans are living with AD

Address correspondence to
Dr Gil D. Rabinovici, University of
dementia, with the number of affected individuals growing rapidly because
California San Francisco Memory of an aging population. Vascular risk factors, sleep disorders, and
and Aging Center, 675 Nelson traumatic brain injury are associated with an increased risk of AD, while
Rising Ln, Ste 190, San Francisco,
CA 94158,
increased cognitive and physical activity throughout the lifespan reduce
Gil.Rabinovici@ucsf.edu. the risk of disease. The primary genetic risk factor for late-onset AD is the
apolipoprotein E (APOE) ε4 allele. AD typically presents with early and
RELATIONSHIP DISCLOSURE:
Dr Rabinovici receives prominent episodic memory loss, although this clinical syndrome is neither
research/grant support from sensitive nor specific for underlying AD neuropathology. Emerging CSF
the National Institutes of Health
and imaging biomarkers can now detect the key neuropathologic
(P01-AG019724, P50-AG23501,
R01 AG032289, R01-AG045611, features of the disease (amyloid plaques, neurofibrillary tangles, and
R01-AG048234, R01 AG057204, neurodegeneration) in living people, allowing for characterization of
R56-AG057195) and the National
Institute of Neurological
patients based on biological measures. A comprehensive treatment plan
Disorders and Stroke for AD includes use of symptomatic medications, optimal treatment of
(R01-AG038791). Dr Rabinovici comorbid conditions and neuropsychiatric symptoms, counseling about
receives research support from
Avid Radiopharmaceuticals, Eli safety and future planning, and referrals to community resources.
Lilly and Company, General
Electric Healthcare, and Life SUMMARY: AD is very common in older neurologic patients. Neurologists
Molecular Imaging. Dr Rabinovici
has served on scientific advisory should set the standard for the diagnosis and care of patients with AD and
boards for AXON Neuroscience should be familiar with emerging biomarkers that have transformed AD
SE; Eisai Co, Ltd; F. Hoffman-La
Roche Ltd; Genentech, Inc; and
research and are primed to enter the clinical arena.
Merck & Co, Inc. Dr Rabinovici
serves as an associate editor for
JAMA Neurology.
INTRODUCTION
B
UNLABELED USE OF
PRODUCTS/INVESTIGATIONAL
eginning with Alois Alzheimer’s seminal report “On an Unusual
USE DISCLOSURE: Illness of the Cerebral Cortex” in a 51-year-old woman1 and for most
Dr Rabinovici discusses the of the 20th century, Alzheimer disease (AD) was considered a rare
investigational use of the
positron emission tomography cause of presenile dementia. In the 1970s, it became apparent that the
(PET) radiotracers [11C]Pittsburgh “neurofibrils” (neurofibrillary tangles) and “miliary foci” (senile
Compound B and [18F]flortaucipir
in the diagnosis of Alzheimer
plaques) described by Alzheimer were present in the majority of people who
disease. developed dementia in late life. In subsequent decades, it has become clear that
AD is very common, with a prevalence that rivals the most common age-related
© 2019 American Academy
diseases and continues to grow in the setting of an aging population. This article
of Neurology. focuses on late-onset AD, defined as symptom onset at age 65 or older, reviewing
14 FEBRUARY 2019

the epidemiology of the disease and known environmental and genetic risk factors. KEY POINTS
Current approaches to clinical diagnosis and treatment are discussed, and a
● Alzheimer disease is the
growing armamentarium of biomarkers that are already transforming AD research most common cause of
and are likely to have an increasing future role in clinical care are introduced. dementia, affecting an
estimated 5.7 million
EPIDEMIOLOGY Americans. The number of
affected individuals is
An estimated 5.7 million Americans are living with AD dementia, and an
expected to triple by 2050
additional 11.6 million Americans have mild cognitive impairment (MCI).2,3 The because of an aging
incidence and prevalence of AD increase dramatically with age. Approximately population.
80% of patients with AD are older than age 75, with disease incidence increasing
from 2 per 1000 at ages 65 to 74 to 37 per 1000 at age 85 and older.2,4,5 The number ● Vascular risk factors,
sleep disturbances, and
of patients with AD in the United States is projected to nearly triple by 2050, with traumatic brain injury
the majority of growth attributed to the 85 and older age group.5 Nearly two-thirds increase the risk of
of patients with AD are women, likely reflecting both increased life duration and Alzheimer disease.
biological factors.5 Compared to non-Hispanic whites, the incidence of AD is Increased years of
education and greater
higher in African Americans/blacks and Hispanics/Latinos and lower in Asian cognitive and physical
Americans.6 The overall lifetime risk for AD at age 65 is 21.1% for women and activity throughout the
11.6% for men.2,7 Average survival after diagnosis varies between 4 and 8 years lifespan decrease the risk
across studies and is impacted by multiple factors, including age at diagnosis, of Alzheimer disease.
sex, psychotic features, motor system involvement, and medical comorbidities.8
In otherwise healthy individuals, survival can extend to 15 to 20 years. The public
health impact of AD and other forms of dementia cannot be overstated, with an
estimated cost of $277 billion in the United States in 2018.2
ENVIRONMENTAL RISK FACTORS

Prospective population-based studies provide strong evidence that the risk
of late-life cognitive impairment and dementia is modified by medical
comorbidities, lifestyle choices, and other environmental factors.9 The risk of
dementia is increased in patients with vascular risk factors, and growing
evidence suggests that aggressive treatment of these risk factors as early as
midlife can attenuate the risk of developing cognitive impairment in older
age.10,11 Common sleep disturbances such as insomnia and obstructive sleep
apnea are also associated with late-life cognitive decline.12,13 Traumatic brain
injury is a potentially preventable risk factor for AD and other neurodegenerative
disorders.14 Late-life depression is associated with increased risk of cognitive
decline, although it is unclear whether this represents a risk factor or a
consequence of early AD neuropathology in serotonergic and noradrenergic
brainstem nuclei.15 Conversely, increased years of formal education, physical
activity, and social engagement across the lifespan moderate the risk of late-life
dementia.9 Links between many of these factors and the specific pathobiology
of AD are less established, since few studies included autopsy or biomarker
confirmation of AD in assessing outcomes. Nevertheless, aggressive treatment of
dementia risk factors and encouragement of beneficial lifestyle choices should
be considered universal recommendations for promoting healthy brain aging.
GENETIC RISK FACTORS

Late-onset AD is a complex genetic disorder, with an estimated heritability
of 60% to 80%.16 The strongest genetic risk factor for late-onset AD is
apolipoprotein E (APOE) genotype. APOE, which encodes the brain’s major
cholesterol transporter, has three common alleles: ε2 (8.4% estimated allele

LATE-ONSET ALZHEIMER DISEASE
frequency in the population), ε3 (77.9%), and ε4 (13.7%).17 APOE ε4 is associated

with an increased risk of developing AD, with odds ratios of approximately
3 in heterozygotes and 8 to 12 in homozygotes compared to individuals with the
ε3/ε3 genotype.17,18 Each APOE ε4 allele reduces the average age of symptom
onset by about a decade. Female carriers of APOE ε4 are at increased risk
compared to male carriers, particularly between the ages of 65 and 75.18 Conversely,
the ε2/ε2 and ε2/ε3 genotypes are protective (odds ratio approximately 0.5 to
0.7 versus ε3/ε3). APOE ε4 contributes to AD risk via a multitude of mechanisms,
including enhanced aggregation and decreased clearance of the amyloid-β
(Aβ) polypeptide; increased tau phosphorylation; network hyperexcitability;
reduced glucose metabolism, vascular, and mitochondrial function; and
neurodevelopmental differences.17,19 APOE genotyping is currently not
recommended in the clinical evaluation of patients with suspected AD, since the
ε4 allele represents a risk factor rather than a deterministic gene.20
Genome-wide association studies have identified more than 20 additional
common genetic variants that modify the risk of late-onset AD.16 These genes
converge in biological pathways involving lipid metabolism, innate immunity,
and endocytosis. The effects of each gene on AD risk is small (odds ratios of
approximately 0.8 to 0.9 for protective alleles and 1.1 to 1.2 for risk alleles) and not
clinically meaningful. Assessing the overall burden of AD risk alleles via polygenic
hazard scores may enhance individual risk prediction.21 With the advent of
next-generation sequencing, rare genetic variants with large effects on disease risk
are coming to light. For example, rare variants in the triggering receptor expressed
on myeloid cells 2 (TREM2) gene are associated with an odds ratio of approximately
3 to 4 for developing AD,22 highlighting the importance of immune and
inflammatory pathways in disease pathogenesis. Mutations in amyloid-β precursor
protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) that lead to familial
early-onset AD are rare in older patients, although pathogenic mutations in
PSEN2 and rare variants in APP have been associated with late-onset disease.16
CLINICAL APPROACH TO PATIENTS WITH COGNITIVE SYMPTOMS

The clinical evaluation of patients with cognitive symptoms begins with a
thorough clinical history and examination. It is important to obtain corroborative
information from an additional source (eg, family member or close friend), since
patient recall or insight may be limited. The history of present illness should query
symptoms referable to specific cognitive domains and neuropsychiatric symptoms
as well as motor and autonomic symptoms, sleep, dietary habits, emotional
function, and social behavior (TABLE 1-1). First and early symptoms are
particularly salient, since they can help localize the earliest brain regions involved
and thus inform the differential diagnosis. Determining the level of functional
impairment (ie, the impact of cognitive symptoms on instrumental and basic
activities of daily living) is critical for disease staging and appropriate counseling.
The first goal of the clinical evaluation is to rule out potentially reversible
causes of cognitive decline by reviewing medical comorbidities, medication and
substance use, and environmental exposures. Neurodegenerative diseases
typically have an insidious onset and are characterized by slow gradual
progression. Thus, an acute or subacute change in mental status should raise
concern for a nondegenerative process. Screening with brief cognitive tests such
as the Mini-Mental State Examination (MMSE) or Montreal Cognitive
Assessment (MoCA) represents a reasonable first step, but more detailed
16 FEBRUARY 2019

neuropsychological testing is often helpful in defining the pattern of KEY POINTS
cognitive deficits.
● The estimated heritability
Per American Academy of Neurology (AAN) guidelines, the following of late-onset Alzheimer
laboratory tests should be ordered in the routine evaluation of patients with disease is approximately
cognitive decline: complete blood cell count, serum electrolytes, liver and renal 60% to 80%. The primary
function tests, thyroid function tests, and serum vitamin B12.20 Additional genetic risk factor for
sporadic late-onset
laboratory testing may be appropriate depending on the clinical context. Brain
Alzheimer disease is the
imaging with CT or MRI without contrast is recommended to exclude structural apolipoprotein E (APOE)
lesions and can be helpful in identifying characteristic patterns of brain atrophy ε4 allele.
and white matter injury.
● The clinical evaluation of
patients with cognitive
CLINICAL DIAGNOSIS OF ALZHEIMER DISEASE symptoms should first and
Patients with acquired cognitive impairment that represents a decline from their foremost exclude reversible
previous level of performance and is objectively corroborated by history and causes based on history,
examination, yet does not interfere with daily function, are considered to have examination, and laboratory
testing.
MCI.3,23 When cognitive decline interferes with independent function, patients
meet criteria for dementia.23 Equivalent categories of mild and major neurocognitive ● Mild cognitive impairment
disorder are defined in the Diagnostic and Statistical Manual of Mental Disorders, is defined as objectively
Fifth Edition (DSM-5).24 In reality, these distinct categories represent a continuum of confirmed cognitive decline
that does not interfere with
cognitive decline that begins with subjective changes and culminates in dementia.23
independent function. When
A number of common neurodegenerative diseases can present with late-life cognitive decline interferes
cognitive decline, including the following: with independent function,
patients meet criteria
u Alzheimer disease for dementia.
u Vascular cognitive impairment ● Late-onset Alzheimer

u Dementia with Lewy bodies disease typically presents
with progressive decline in
u Primary age-related tauopathy episodic memory, with
u Hippocampal sclerosis of aging (cerebral age-related transactive response DNA-binding variable involvement of
protein 43 [TDP-43] and sclerosis) other cognitive domains.
Progressive memory
u Argyrophilic grain disease impairment can also be
u Frontotemporal lobar degeneration caused by other
neurodegenerative
processes affecting the
Late-onset AD manifests most commonly as a progressive amnestic disorder medial temporal lobes.
characterized by early and prominent deficits in episodic memory, with varying
degrees of executive, language, and visuospatial impairment (CASE 1-1).25,26
Patients often show a gradient of memory impairment, with greatest difficulty
recalling recent events and relative sparing of remote memory. On memory tests
(eg, word list or story learning), patients show impaired learning, rapid
forgetting, and poor delayed recall, characteristic of dysfunction of the
hippocampal circuit.27 However, this clinical presentation is not specific for AD
and may also occur in other conditions that affect the medial temporal lobes
(CASE 1-2), such as vascular cognitive impairment, primary age-related
tauopathy, hippocampal sclerosis of aging (cerebral age-related TDP-43 and
sclerosis), and argyrophilic grain disease. For more information on primary
age-related tauopathy, hippocampal sclerosis of aging, and argyrophilic grain
disease, refer to the article “Hippocampal Sclerosis, Argyrophilic Grain Disease,
and Primary Age-Related Tauopathy” by Gregory A. Jicha, MD, PhD, and Peter
T. Nelson, MD, PhD,29 in this issue of Continuum. Nonamnestic syndromes
associated with AD neuropathology (eg, logopenic variant primary progressive

TABLE 1-1 Symptoms Associated With Neurodegenerative Dementia
Episodic Memory
◆ Forgetting recent eventsa
◆ Misplacing personal itemsa
◆ Asking repetitive questionsa
◆ Missing appointmentsa
◆ Paying bills latea
◆ Poor long-term/autobiographical memory
Visuospatial
◆ Navigational problems/getting losta
◆ Difficulty locating items in plain sight
◆ Problems visually recognizing faces or objects
Language
◆ Difficulty retrieving words or namesa
◆ Problems comprehending words or sentences
◆ Effortful or nonfluent speech
◆ Grammar errors or omissions
◆ Spelling errors
◆ Problems reading and writing
Executive Functions
◆ Problems organizing, multitasking, or maintaining focusa
◆ Distractibilitya
◆ Difficulty reasoning, problem solving, or making decisionsa
◆ Poor judgment
Other Cognitive
◆ Problems with calculationsa
◆ Difficulty using devices/technologya
◆ Disorientation to time and place
CONTINUED ON PAGE 19
18 FEBRUARY 2019

CONTINUED FROM PAGE 18
Psychiatric/Behavioral
◆ Depressiona
◆ Apathya
◆ Anxietya
◆ Irritabilitya
◆ Agitation
◆ Poor impulse control, lability
◆ Delusions
◆ Hallucinations or misperceptions
◆ Changes in personality
◆ New hobbies or interests
◆ Obsessive or compulsive behaviors
◆ Loss of empathy
◆ Disinhibition
◆ Poor hygiene
Motor
◆ Repetitive/restless behavior
◆ Muscle weakness
◆ Poor balance/falls
◆ Problems using hands or feet
◆ Incoordination
◆ Tremor or other adventitial movements
◆ Muscle cramps
◆ Fasciculations
Sleep
◆ Insomniaa
◆ Loud snoring/gasping for air
◆ Dream enactment behavior
General and Autonomic
◆ Weight lossa or gain
◆ Changes in eating behavior and dietary preferences
◆ Positional dizziness
◆ Bladder or bowel incontinence
◆ Sexual dysfunction
a
Symptoms that are common in early stages of Alzheimer disease.

CASE 1-1 A 73-year-old woman presented for evaluation of 3 years of progressive

memory loss. Her husband reported that she frequently misplaced
personal items, forgot passwords, and repeated the same questions. She
had trouble locating her car in the parking lot and had been late paying
bills. She had difficulty completing tasks and recently seemed
overwhelmed when trying to plan travel for a vacation. She had shown
less interest in previous hobbies but did not report low mood. She denied
motor problems or disruption of sleep. Her husband had taken over
managing finances and bill paying and had to remind her to take her
medications. She was otherwise independent with day-to-day function.
Her past medical history was notable for long-standing hypertension,
diabetes mellitus, and hyperlipidemia. She had an episode of delirium
5 years prior when hospitalized for a total hip replacement. Review of
medications did not reveal any substances known to affect cognition.
Family history was notable for late-onset dementia in her mother, brother,
and maternal grandmother. She had 16 years of formal education, rarely
drank alcohol, and did not smoke tobacco or use recreational drugs.
During the interview, she had difficulty describing her symptoms and
often deferred to her husband to answer questions. Recall of recent
personal and public events was impaired and lacked detail. Insight was
limited. On cognitive testing, she scored 21/30 on the Mini Mental State
Examination (MMSE), losing points for orientation, word recall, and serial
7s. She showed moderate impairment on tests of verbal and visual
memory and mild deficits on tests of executive, language, and visuospatial
functions. The rest of her neurologic examination was normal.
Laboratory evaluations for reversible causes of cognitive impairment
were within normal limits. Brain MRI showed moderate atrophy of the
hippocampus and medial temporal lobes bilaterally, mild atrophy of the
lateral temporal and parietal lobes, and no significant vascular lesions.
The patient was diagnosed with dementia due to probable Alzheimer
disease (AD) and started on an acetylcholinesterase inhibitor.
A driving evaluation at the Department of Motor Vehicles was ordered.
Regular exercise was recommended. The husband was provided
information about attending a caregiver support group and working with a
social worker.
COMMENT This patient’s clinical presentation is highly suggestive of underlying AD,

with early and prominent involvement of episodic memory and mild
involvement of other cognitive domains. Her medical comorbidities and
family history put her at elevated risk for AD. Her MRI showed an atrophy
pattern that was consistent with the diagnosis and did not show evidence
of significant vascular burden. Biomarker tests of amyloid and tau are not
currently recommended for patients with “typical” age of onset and clinical
symptoms. The care plan for this patient included a combination of drug
treatment, lifestyle and safety recommendations, and referral to
community resources.
20 FEBRUARY 2019

An 83-year-old man was evaluated for 2 years of progressive cognitive CASE 1-2
decline. He reported increasing problems remembering the names of
distant acquaintances, thinking of words, and learning to use new
devices. He started keeping a detailed to-do list and daily calendar
because he had missed several medical appointments. His wife agreed
that he had become more forgetful in the previous 2 years and
commented that he now repeated himself in daily conversations. He
remained active in local community organizations and was fully
independent with all instrumental activities of daily living. His medical
history was notable for well-controlled hypertension. He had been taking
diphenhydramine at bedtime for many years for insomnia.
Examination was notable for a lack of detail when describing events in
the news. His Mini-Mental State Examination (MMSE) score was 26/30,
losing points for orientation and recall.
On formal cognitive testing, he scored 1.0 to 1.5 standard deviations
below age-matched norms on tests of episodic memory and in the normal
to above average range on tests of other cognitive domains. Laboratory
evaluation was unremarkable, and brain MRI showed moderate to severe
hippocampal atrophy, mild generalized cortical atrophy, and mild to
moderate subcortical white matter changes.
Based on this evaluation, he was diagnosed with mild cognitive
impairment (MCI) impacting primarily episodic memory.
Diphenhydramine was discontinued, and sleep hygiene measures were
instituted to help with insomnia. Amyloid positron emission tomography
(PET), obtained as part of an observational research study, was negative
for cortical tracer retention. He started exercising regularly under the
supervision of a personal trainer at the local senior center and enrolled in
adult classes offered at the local university. On follow-up 2 years later,
he and his wife reported a mild decline in his memory, but cognitive
testing was stable, and he remained highly functional and fully
independent.
This patient presented with amnestic MCI, which can represent the COMMENT
prodromal stage of Alzheimer disease (AD) but is also associated with other
age-related neuropathologies and nondegenerative causes. In this case,
negative amyloid PET reduces the likelihood of underlying AD, while his MRI
findings support the possibility of a non-AD degenerative process
affecting the medial temporal lobes as well as a vascular contribution. The
treatment plan involved discontinuation of anticholinergic medication and
lifestyle recommendations. He remained clinically stable with follow-up,
consistent with studies that suggest slower decline in patients with MCI
who are negative on amyloid biomarkers.28

FIGURE 1-1
MRI findings in Alzheimer disease (AD). Axial (A), sagittal (B), and coronal (C) T1-weighted
images demonstrate prominent hippocampal and medial temporal lobe atrophy, moderate
diffuse cortical atrophy, and ventricular enlargement in an 81-year-old with AD dementia,
subsequently confirmed at autopsy. D, Fluid-attenuated inversion recovery (FLAIR) sequence
demonstrates subcortical and periventricular white matter hyperintensities in a 78-year-old
with a clinical diagnosis of AD, likely representing comorbid small vessel ischemic disease.
E, Hallmarks of cerebral amyloid angiopathy, including scattered microbleeds and superficial
siderosis, are revealed on susceptibility-weighted imaging (SWI) in a 75-year-old with acute
altered mental status superimposed on progressive memory and executive dysfunction. F,
Confluent white matter hyperintensities on FLAIR in a 75-year-old with pathology-proven
severe cerebral amyloid angiopathy and AD neuropathology. In all panels, key findings are
highlighted by arrows.
L = left; R = right.
aphasia, posterior cortical atrophy) are less common in late-onset disease than in
younger patients.30 For more information on posterior cortical atrophy, refer
to the article “Posterior Cortical Atrophy” by Jonathan M. Schott, BSc, MD,
FRCP, FEAN, SFHEA, and Sebastian J. Crutch, PhD, CPsych,31 in this issue of
Continuum. Rarely, underlying dementia with Lewy bodies or frontotemporal
lobar degeneration can mimic AD clinically, but these conditions are typically
associated with differentiating clinical features.
Common neuropsychiatric symptoms in AD include depression, anxiety, mild
apathy, irritability, and sleep disturbances (eg, insomnia or disrupted circadian
rhythm).32 Social and emotional function are generally preserved early in the
disease course, and agitation and psychotic symptoms are uncommon. The
22 FEBRUARY 2019

general neurologic examination is either normal or shows minor signs (eg, KEY POINTS
restricted upgaze, paratonia, or mild rigidity).
● Common
neuropsychiatric symptoms
BRAIN IMAGING in Alzheimer disease include
AAN guidelines support the use of brain imaging with CT or MRI in the initial depression, anxiety, mild
assessment of dementia to exclude structural lesions such as neoplasms, subdural apathy, irritability, and sleep
disturbances.
hematomas, and normal pressure hydrocephalus.20 CT and MRI can also inform
the differential diagnosis of neurodegenerative diseases by identifying characteristic ● MRI findings in Alzheimer
brain atrophy patterns and assessing for vascular injury. The hallmark MRI changes disease include medial
of late-onset AD include atrophy of the hippocampus and medial temporal lobes, temporal lobe and
cortical atrophy (primarily involving temporoparietal cortex), and ventricular posterior-predominant
cortical atrophy.
enlargement (FIGURES 1-1A, 1-1B, and 1-1C).33 Compared to early-onset AD, Iron-sensitive sequences
patients with late-onset disease show greater medial temporal atrophy and less should be performed to
cortical atrophy.34 While these changes are not entirely specific to AD versus assess for hemorrhages
normal aging or other causes of dementia, they can support the clinical impression associated with cerebral
amyloid angiopathy.
of AD in the appropriate clinical context. Patients show varying degrees of white
matter hyperintensities on T2-weighted/fluid-attenuated inversion recovery
(FLAIR) sequences, which are nonspecific but most often associated with small
vessel ischemic disease (FIGURE 1-1D).35 Cerebral amyloid angiopathy (CAA),
which can co-occur with AD, is suggested by the presence of cortical microbleeds
or superficial siderosis on iron-sensitive sequences such as gradient recalled echo
(GRE) or susceptibility-weighted imaging (SWI) and extensive white matter
lesions on T2-weighted/FLAIR images (FIGURES 1-1E and 1-1F).36
Functional brain imaging with fludeoxyglucose positron emission
tomography (FDG-PET) or single-photon emission computed tomography
(SPECT) perfusion scans can be helpful in differentiating AD from normal aging
and other disorders,37,38 although routine use is not currently recommended. The
classic pattern of hypometabolism (FDG-PET) or hypoperfusion (SPECT)
associated with AD involves reduced activity in the temporoparietal cortex
and posterior cingulate/precuneus. As with MRI, cortical changes are more
prominent in early-onset than late-onset AD.39 In the United States, FDG-PET is
reimbursed by the Centers for Medicare & Medicaid Services for differentiating
between AD and frontotemporal dementia, the latter being associated with
predominant hypometabolism in frontal and anterior temporal regions.40,41
NEUROPATHOLOGY
Gross examination of the postmortem AD brain typically reveals atrophy of the
medial temporal lobes and cerebral cortex (FIGURE 1-2A). On microscopic
examination, evidence of synaptic and (to a lesser degree) neuronal loss is seen.42
The neuropathologic diagnosis of AD is established by the presence of two
pathognomonic lesions, senile plaques and neurofibrillary tangles (FIGURES 1-2B,
1-2C, 1-2D, and 1-2E).43 Senile plaques are extracellular deposits composed
primarily of aggregated Aβ1-42 polypeptides. These appear as diffuse structures
or as neuritic plaques when associated with dystrophic neurites. Aβ plaques first
appear in the neocortex, then spread successively into the hippocampus and
limbic structures, striatum and diencephalon, brainstem, and cerebellum.44 CAA
is defined by vascular deposits consisting of aggregated Aβ1-40 polypeptides
(FIGURE 1-2F). Neurofibrillary tangles are composed of aggregated,
hyperphosphorylated forms of the microtubule binding protein tau. The
distribution of tangles typically follows a hierarchical pattern described by Braak

FIGURE 1-2
Neuropathologic features of Alzheimer disease (AD). A, Gross neuropathologic features
of AD include cortical atrophy (arrow), ventricular enlargement (dashed arrow) and
hippocampal atrophy (arrowhead). B, Low-power photomicrograph (1x) of hippocampus
stained with anti–phosphorylated tau (p-tau) antibody (CP13), demonstrating an abundance
of p-tau deposition, most prominent in CA1 (arrow). C, Thioflavin S staining identifies senile
amyloid plaques (arrowhead) and tau neurofibrillary tangles (arrow), the pathologic
hallmarks of AD. D, High-power photomicrographs (40 x) of senile plaques (arrow) identified
via anti–amyloid-β immunohistochemistry (1-16, clone DE2, mouse, 1:500). E, High-power
photomicrograph (40 x) of anti–p-tau (CP13) immunohistochemistry illustrates neurofibrillary
tangles (arrow) and dystrophic neurites (arrowhead). F, Low-power photomicrograph (4x)
of anti–amyloid-β immunostaining of cerebellum reveals amyloid deposition in blood vessel
walls (arrow), the pathologic hallmark of cerebral amyloid angiopathy. Bars represent
25 microns.
24 FEBRUARY 2019

stages, appearing first in the transentorhinal and entorhinal cortex (Braak stages KEY POINTS
I and II), followed by limbic (Braak stages III and IV) and isocortical (Braak
● The neuropathology of
stages V and VI) regions.45 The neuropathologic criteria for AD integrate the Alzheimer disease is defined
distribution and density of Aβ plaques with Braak staging of tau pathology in by the presence of senile
describing the overall burden of AD neuropathologic changes.43 amyloid plaques and tau
Cognitive symptoms correlate more strongly with the burden and distribution neurofibrillary tangles. The
burden and distribution of
of neurofibrillary pathology than with Aβ pathology.46 Furthermore, AD
these two lesions define the
neuropathology is rarely found in isolation in older patients. The most common degree of Alzheimer disease
pathologies found in tandem with AD include vascular brain injury, Lewy body neuropathologic changes.
pathology, TDP-43 inclusions, and hippocampal sclerosis.43 Each of these
copathologies contributes synergistically to cognitive decline.47,48 At autopsy, ● Late-life dementia is
often associated with
late-onset dementia and even MCI are nearly always associated with multiple multiple brain pathologies.
pathologies,48 and this is especially true in the very old (age 90 plus).49 The most common are
Alzheimer disease, Lewy
AMYLOID-β AND TAU BIOMARKERS bodies, vascular brain injury,
hippocampal sclerosis, and
In recent years, major progress has been made in developing and validating CSF TDP-43 inclusions.
and imaging biomarkers of Aβ and tau, the core molecular features that define
AD neuropathology.50 The CSF fingerprint of AD includes reductions in levels of ● Amyloid plaques and
Aβ1-42 and increases in total tau (t-tau) and phosphorylated tau (p-tau).51 Changes tau tangles can be detected
in living people based
in Aβ1-42 and p-tau are associated with amyloid plaques and neurofibrillary
on changes in CSF levels
pathology, respectively, while increases in t-tau are a nonspecific marker of of amyloid-β and
neurodegeneration and can be seen in other conditions associated with rapid phosphorylated tau or by
neuronal death (eg, Creutzfeldt-Jakob disease, acute ischemia, and traumatic using positron emission
tomography radiotracers
brain injury). When performed in expert laboratories, combined CSF measures
that selectively bind
of Aβ and tau (eg, ratios of t-tau to Aβ1-42 or p-tau to Aβ1-42) show 80% to 90% amyloid-β or tau aggregates.
sensitivity and specificity in discriminating between AD, healthy controls, and
non-AD dementias.51,52 CSF biomarkers are also helpful in predicting clinical
progression in MCI, presumably by identifying those individuals with
underlying AD pathology. However, current assays are sensitive to a number of
preanalytic and analytic factors, resulting in high variability across laboratories,
particularly for Aβ1-42 assays.53 Major efforts around standardization combined
with technical advances in the new generation of assays are likely to improve the
reliability of these markers and increase their clinical use.53
Amyloid plaques can be directly detected in living people using PET ligands
that bind to neuritic plaques.54 Three Aβ PET tracers, [18F]florbetapir,
[18F]flutemetamol, and [18F]florbetaben, are approved for clinical use in the
United States and other countries, and additional ligands are used in the research
setting. For all tracers, a scan is considered “negative” when ligand retention is
limited to white matter, while a “positive” scan is defined by extension of tracer
binding into cortical gray matter (FIGURE 1-3). PET-to-autopsy studies have shown
that scans acquired during life reliably predict the burden of neuritic plaques
found at autopsy.54 However, amyloid deposition is not specific to AD clinical
phenotypes and can be also seen in dementia with Lewy bodies, CAA, and in a
proportion of cognitively healthy older individuals.55 More recently, PET ligands
that bind selectively to paired helical filaments of tau have been developed,
allowing for in vivo visualization of neurofibrillary tangles.54 Early in vivo tau PET
studies largely conform to expectations from neuropathology, with tracer binding
following the topography of Braak staging and showing strong correlations with
disease stage and cognitive performance.56–58 Tau PET is not yet approved for
clinical use and is currently available only through research studies.

Implications of Alzheimer
Disease Biomarkers for
Research and Clinical Care
AD biomarkers allow us to
capture in vivo the key
components that define the
neuropathology of AD and to
prospectively follow these
processes across the disease
continuum (FIGURE 1-4).
FIGURE 1-3
Amyloid positron emission tomography (PET) with
Biomarkers have helped
18
[ F]florbetapir. A, Example of a positive scan in a establish the existence of a
72-year-old with amnestic mild cognitive prolonged preclinical phase of
impairment, as defined by absent gray-white AD, demonstrating that plaques
matter contrast and intense gray matter binding
and tangles deposit in the brain
that exceeds the binding in adjacent white matter.
B, Example of a negative scan in an 80-year-old a decade or more before the
with amnestic mild cognitive impairment, as onset of clinical symptoms.59,60
defined by greater tracer binding in white matter Two sets of diagnostic criteria
compared with gray matter, creating clear
have suggested augmenting
gray-white contrast.
clinical diagnosis with
biomarkers to increase
confidence in underlying AD pathophysiology.25,61 More recently, a proposed
research framework defines AD purely on biological grounds, based on
abnormalities in biomarkers of amyloid, tau, and neurodegeneration,
irrespective of clinical state (TABLE 1-2).23
While biomarkers are used extensively in research and drug development,
their clinical impact has been modest because of several factors, including limited
patient access, cost, and lack of reimbursement by third-party payers. Ongoing
studies are assessing the clinical impact of biomarkers on patient management
and outcomes, which may pave the way for reimbursement in the future.62–64
Appropriate use criteria for amyloid PET state that clinical scans should be
restricted to diagnostically challenging cases in which the cause of cognitive
impairment remains uncertain after a comprehensive evaluation by a specialist and
in which knowledge of amyloid status is likely to change diagnosis and management.65
Broader clinical use can be anticipated in future years, and neurologists should
familiarize themselves with the AD biomarker armamentarium and best practices
around pretest counseling and disclosure of results to patients and families.66
TREATMENT
A comprehensive care plan includes treatment with AD-specific medications;
treatment of vascular risk factors, sleep and mood disorders, and other relevant
comorbid conditions; counseling about safety and future planning; and referrals
to community resources (CASE 1-1).
First approved in 1993, acetylcholinesterase inhibitors (AChEIs) remain the
mainstay of pharmacologic therapy for AD.67 AD is associated with loss of
cholinergic neurons in the basal forebrain. AChEIs enhance cholinergic
transmission by inhibiting the hydrolysis of acetylcholine in the synaptic cleft.
Three AChEIs are used in clinical practice: donepezil, galantamine, and
rivastigmine (TABLE 1-3). Double-blinded randomized controlled trials
demonstrate a symptomatic benefit in cognitive and functional outcomes across
26 FEBRUARY 2019

KEY POINT
● A comprehensive care
plan for patients with
Alzheimer disease includes
treatment with Alzheimer
disease–specific
medications, treatment of
relevant comorbid
conditions, counseling
about safety and future
planning, and referrals to
community resources.
FIGURE 1-4
Amyloid and tau positron emission tomography (PET) of the Alzheimer disease (AD) continuum.
The first column shows a cognitively normal individual with negative amyloid PET (no cortical
tracer retention) and tau PET uptake restricted to the medial temporal lobes. The second
column shows a cognitively normal individual with evidence of both cortical amyloid and
spread of tau into temporal and parietal cortices. The third and fourth columns, representing
patients with mild cognitive impairment (MCI) and dementia, show a plateau of amyloid PET
signal but increased spread of tau with increasing clinical stages of AD.
[18F]FTP = [18F]flortaucipir, a radiotracer selective for paired helical filaments of tau; [11C]PIB = [11C]Pittsburgh
Compound B, an amyloid-β–specific tracer.
the spectrum from mild to severe AD dementia67 but do not show a benefit in
MCI.3 Although subtle differences exist in the biological effects of different
AChEIs, efficacy is similar across agents. While deemed clinically meaningful, the
effects of AChEIs are modest and, in practice, difficult to appreciate, since patients
rarely show improvement when starting treatment and over time inevitably decline.
Common adverse effects include gastrointestinal upset and loss of appetite
(potentially reduced by using the rivastigmine patch instead of the oral
formulations), urinary frequency, muscle cramps, and vivid dreams. Slowing
of cardiac conduction can occur, and AChEIs should be used with caution in patients
at risk for bradycardia. Additional rare, but potentially serious, adverse effects
reported for rivastigmine include increased pulmonary and gastric secretions,
warranting caution in patients with uncontrolled obstructive airway disease,
gastrointestinal bleeding, and gastric ulcer disease. A single study supports the use
of very-high-dose (23 mg/d) donepezil in moderate to severe AD,68 but the added
benefit may be counterbalanced by an increased risk of dose-dependent side effects,
particularly in older patients, and slow titration is recommended for all patients.
Memantine, a noncompetitive N-methyl-D-aspartate (NMDA) receptor
antagonist, is approved for the treatment of moderate to severe AD dementia but

TABLE 1-2 Biomarkers of Amyloid, Tau, and Neurodegeneration Proposed in the

National Institute of Aging-Alzheimer’s Association Research Framework
for Alzheimer Diseasea
Amyloid: Aggregated Amyloid-β (Aβ) or Associated Pathologic State

◆ CSF Aβ1-42 or Aβ1-42 to Aβ1-40 ratio
◆ Amyloid PET
Tau: Aggregated Tau (Neurofibrillary Tangles) or Associated Pathologic State
◆ CSF phosphorylated tau
◆ Tau PET
Neurodegeneration: Neurodegeneration or Neuronal Injury
◆ Anatomic MRI
◆ FDG-PET
◆ CSF total tau
CSF = cerebrospinal fluid: FDG-PET = fludeoxyglucose positron emission tomography; MRI = magnetic
resonance imaging; PET = positron emission tomography.
a
Modified with permission from Jack CR, et al, Alzheimers Dement.23 © 2018 The Authors.
TABLE 1-3 Medications Approved for the Symptomatic Treatment of Alzheimer

Disease Dementiaa
Medication Mechanism Recommended Titrationb

Donepezil Selective acetylcholinesterase inhibitor Begin 5 mg daily; increase in 4 weeks to goal
10 mg daily
Galantamine Acetylcholinesterase inhibitor, allosteric Begin 4 mg 2 times a day; increase by 4 mg per

nicotinic receptor modulator dose increments every 4 weeks to goal of 12 mg
2 times a day
Galantamine ER Acetylcholinesterase inhibitor, allosteric Begin 8 mg daily; increase by 8 mg/d increments

nicotinic receptor modulator every 4 weeks to goal of 24 mg daily
Rivastigmine oral Mixed acetylcholinesterase and Begin 1.5 mg 2 times a day; increase by 1.5 mg
butyrylcholinesterase inhibitor per dose increments every 4 weeks to goal of
6 mg 2 times a day
Rivastigmine Mixed acetylcholinesterase and Begin 4.6 mg daily; increase in 4 weeks to goal of
transdermal patch butyrylcholinesterase inhibitor 9.5 mg daily
Memantine Noncompetitive glutamate NMDA receptor Begin 5 mg daily; increase by 5 mg/d increments
antagonist every week to goal of 10 mg 2 times a dayc
Memantine XR Noncompetitive glutamate NMDA receptor Begin 7 mg daily; increase by 7 mg increments

antagonist every week to goal of 28 mg dailyd
ER = extended release; NMDA = N-methyl-D-aspartate; XR = extended release.

a
Data from Aisen PS, et al, Cold Spring Harb Perspect Med.67
b
Titration schedules represent general guidelines and should be tailored to individual patients.
c
If creatinine clearance is less than 30 mL/min, use 5 mg 2 times a day.
d
If creatinine clearance is less than 30 mL/min, use 14 mg/d.
28 FEBRUARY 2019

does not show a benefit in mild dementia or MCI.67 Similar to AChEIs, the
benefit is purely symptomatic and manifests as less decline compared to placebo
on cognitive and functional scales. Potential adverse effects include constipation,
dizziness, headache, and somnolence. Trials assessing the benefit of combination
therapy with AChEIs and memantine versus monotherapy with each have
yielded mixed results.69 A rational approach to AD drug treatment includes the
initiation of AChEIs in mild AD dementia and the addition of memantine when
patients enter the moderate stage of disease. In the absence of adverse effects,
symptomatic treatment can be continued as long as enhanced cognition is
associated with meaningful quality of life.
Treatment of behavioral symptoms in AD represents a clinical challenge, with
little evidence to support any specific intervention and significant morbidity and
mortality associated with many pharmacologic options.70 Nonpharmacologic
interventions should always be attempted first. A careful history can often
identify provoking factors that can be addressed by modifications to the
environment and caregiver education (CASE 1-3). AChEIs can improve
behavioral symptoms, particularly depression, apathy, and aberrant motor
A 93-year-old man was referred from a skilled nursing facility for CASE 1-3
assistance with managing difficult behaviors. He had been diagnosed with
Alzheimer disease 8 years earlier and was now fully dependent on others
to assist with activities of daily living. He became angry and aggressive
when staff tried to get him out of bed or assist him with daily bathing. He
had previously been taking donepezil and memantine, but these were
stopped when he moved to the skilled nursing facility. He was prescribed
lorazepam at bedtime to help with sleep and was reported to be drowsy
and difficult to arouse in the morning. Examination was notable for diffuse
osteoarthritic changes and tenderness to palpation of the low back and
both knees. He otherwise appeared calm and cooperative during the
examination. Laboratory assessment, including urinalysis, was normal.
The treating neurologist called the supervisor at the nursing facility, and
together they formulated a multipronged care plan. An experienced staff
member at the facility provided staff with training on how to interact with
patients with severe cognitive impairment. His bathing schedule was reduced
to twice a week. Low-dose acetaminophen was started to empirically treat
presumed pain from degenerative joint disease. Memantine was restarted,
while lorazepam was tapered off. On follow-up 8 weeks later, the
frequency and severity of his difficult behaviors had greatly diminished,
and staff felt better able to manage these events when they did occur.
Managing difficult behaviors in Alzheimer disease involves identifying COMMENT

potential triggers, modifying the environment, and training family members
and caregivers. Underlying medical causes such as pain and infection
should be excluded. Nonpharmacologic approaches tend to be more
effective than drug treatment, although acetylcholinesterase inhibitors and
memantine can also be helpful.

KEY POINTS behavior, while memantine has been shown to improve agitation, lability, and
irritability.70 Antidepressants (eg, selective serotonin reuptake inhibitors [SSRIs]
● Acetylcholinesterase
inhibitors are approved for
or serotonin norepinephrine reuptake inhibitors [SNRIs]) should be used as
the treatment of mild to first-line therapy for depression and anxiety and can also reduce agitation. Use
severe Alzheimer disease of tricyclic antidepressants should be avoided because of their anticholinergic
dementia. Memantine is properties. Use of conventional and atypical neuroleptics should be avoided,
approved for the treatment
if possible, because of evidence for increased morbidity and mortality in patients
of moderate to severe
Alzheimer disease with dementia,71,72 leading to a class-wide US Food and Drug Administration
dementia. (FDA) boxed warning. For more information on the boxed warning on
antipsychotic medication use in dementia, refer to the article “Prescribing
● Difficult behaviors in Antipsychotic Medications to Patients With Dementia: Boxed Warnings and
Alzheimer disease should be
addressed primarily with Mitigation of Legal Liability” by Rachel V. Rose, JD, MBA, and Joseph S.
nonpharmacologic Kass, MD, JD, FAAN,73 in this issue of Continuum. Benzodiazepines should
approaches, use of be avoided because of their sedating effects and the potential for further
Alzheimer disease worsening cognition.
symptomatic drugs, and
judicious use of
Many over-the-counter vitamins, supplements, and medical foods claim to
antidepressants. Use of “improve brain function,” and anecdotal reports exist describing benefits for
neuroleptics should be patients with AD. Some of these treatments are founded on a reasonable
avoided, if possible, biological premise, and a number have shown efficacy in AD animal models.
because of increased
morbidity and mortality.
However, to date, no nutraceutical intervention has proven beneficial when
subjected to rigorous clinical trials.67
Despite recent setbacks and high-profile failures, a myriad of biologically
specific AD treatments are currently being tested in clinical trials and in the
drug development pipeline.74 Many experimental therapies target the amyloid and
tau pathways, while others address changes in brain metabolism, network activity,
innate immunity, and modifiable lifestyle factors. Increasingly, clinical trials in AD
are focused on preclinical or early symptomatic stages of the disease, employing
biomarkers for subject selection and to assess target engagement. Ultimately, a
“cocktail” of drugs synergistically targeting different elements of the disease’s
complex pathophysiology may be required to truly modify the course of AD.
CONCLUSION
More than a century following Alzheimer’s initial description of the disease, AD
is recognized as the most common cause of late-life dementia and a major public
health problem. While the current approach to diagnosis and treatment remains
grounded in clinical symptoms, emerging biomarkers for amyloid, tau, and
neurodegeneration enable the detection of the core neuropathologic features of the
disease in living people a decade or more before the onset of cognitive decline.
These advances in diagnostic tools are already having a major impact on AD research
and drug development and raise hope that breakthroughs in therapies will
soon follow.
ACKNOWLEDGMENTS
This work was supported by grants (R01-AG045611, P50-AG23501) from the
National Institutes of Health. The author would like to thank Orit Lesman-Segev,
MD; Lea Grinberg, MD, PhD; Salvatore Spina, MD, PhD; and Adrienne Visani,
BA for assistance in preparing figures.
30 FEBRUARY 2019

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REVIEW ARTICLE

Early-onset Alzheimer
C O N T I N UU M AUDIO
INTERVIEW AVAILABLE
ONLINE
Disease and Its Variants
By Mario F. Mendez, MD, PhD, FAAN
ABSTRACT
PURPOSE OF REVIEW: Early-onset Alzheimer disease (AD) is defined as
having an age of onset younger than 65 years. While early-onset AD is
often overshadowed by the more common late-onset AD, recognition
of the differences between early- and late-onset AD is important for
clinicians.
RECENT FINDINGS: Early-onset AD comprises about 5% to 6% of cases of AD

and includes a substantial percentage of phenotypic variants that differ
from the usual amnestic presentation of typical AD. Characteristics of
early-onset AD in comparison to late-onset AD include a larger genetic
CITE AS: predisposition (familial mutations and summed polygenic risk), more
CONTINUUM (MINNEAP MINN)
2019;25(1, DEMENTIA):34–51.
aggressive course, more frequent delay in diagnosis, higher prevalence of
traumatic brain injury, less memory impairment and greater involvement
Address correspondence to of other cognitive domains on presentation, and greater psychosocial
Dr Mario F. Mendez,
difficulties. Neuroimaging features of early-onset AD in comparison to
Neurobehavior Unit (Bldg 206),
VA Greater Los Angeles late-onset AD include greater frequency of hippocampal sparing and
Healthcare System, 11301 posterior neocortical atrophy, increased tau burden, and greater
Wilshire Blvd, Los Angeles, CA
90073, mmendez@ucla.edu.
connectomic changes affecting frontoparietal networks rather than the
default mode network.
Dr Mendez serves as a section
editor for UpToDate, Inc, and as SUMMARY: Early-onset AD differs substantially from late-onset AD, with
an associate editor of the different phenotypic presentations, greater genetic predisposition, and
Journal of Alzheimer’s Disease. differences in neuropathologic burden and topography. Early-onset AD
Dr Mendez has received
personal compensation for more often presents with nonamnestic phenotypic variants that spare the
speaking engagements from the hippocampi and with greater tau burden in posterior neocortices. The
Medical Education Speakers
Network and receives
early-onset AD phenotypic variants involve different neural networks than
research/grant support from typical AD. The management of early-onset AD is similar to that of
Biogen and the National late-onset AD but with special emphasis on targeting specific cognitive
Institutes of Health/National
Institute on Aging
areas and more age-appropriate psychosocial support and education.
(R01AG050967). Dr Mendez
receives publishing royalties
from Cambridge
University Press.
INTRODUCTION
H
UNLABELED USE OF istorically, Alzheimer disease (AD) was initially characterized as
PRODUCTS/INVESTIGATIONAL a neurodegenerative disorder presenting in early life or midlife,
USE DISCLOSURE:
Dr Mendez reports no
with onset at younger than 65 years of age (what is now called
disclosure. early-onset AD). Alois Alzheimer originally described the
extracellular amyloid-positive neuritic plaques and intracellular
© 2019 American Academy tau-positive neurofibrillary tangles of AD in the brain of a 51-year-old woman
of Neurology. with memory and language impairments and behavioral changes.1 In the late
34 FEBRUARY 2019

1960s and early 1970s, investigators stressed the presence of similar neuritic KEY POINTS
plaques and neurofibrillary tangles in elderly individuals with dementia, thus
● Early-onset Alzheimer
shifting the Alzheimer focus to the far-larger numbers of patients with late-onset disease, which makes up
AD. Despite being overshadowed by late-onset AD, patients with early-onset AD about 5% to 6% of all cases
(about 5% to 6% of all those with AD2) are significantly different in their clinical of Alzheimer disease, is
and neurobiological features and require different management strategies. Some distinct from late-onset
Alzheimer disease in a
investigators even suggest that these differences are sufficient to constitute a
number of clinical, genetic,
distinct form of the disorder.3 neurobiological, and
Early-onset AD is defined as AD with clinical onset younger than 65 years of management features.
age; it is the most common cause of early-onset neurodegenerative dementia.4
Early-onset AD accounts for at least one-third of patients with young-onset ● Early-onset Alzheimer
disease is the most common
dementia, with the rest having vascular cognitive impairment, frontotemporal cause of early-onset
dementia, drug-related conditions, Lewy body disease, or autoimmune or neurodegenerative
infectious causes. In those 45 to 64 years of age, early-onset AD has an incidence dementia.
rate of about 6.3 per 100,000 per year5 and a prevalence rate of about 24.2 per
● Many clinical,
100,000,6 with 2006 estimates of between 220,000 and 640,000 people with neuropathologic, and
early-onset AD in the United States.7 Even within this early-onset group, AD risk management differences
still increases with age, with the number of cases of early-onset AD rising exist between early-onset
exponentially as the age of onset approaches 65.8 and late-onset Alzheimer
disease.
CLINICAL FEATURES ● One major difference

Many differences exist between early-onset and late-onset AD (TABLE 2-19). between early-onset and
Early-onset AD is not just AD at a younger age. First, early-onset AD has a late-onset Alzheimer
significant genetic predisposition involving a direct autosomal dominant disease is that one-third or
more of patients with
transmission in a subgroup and a higher polygenic susceptibility in general. early-onset Alzheimer
Patients with an autosomal dominant familial form of early-onset AD not only disease present with
have an increased risk for the development of AD among relatives, but may also language, visuospatial, or
have atypical clinical features, including headaches, myoclonus, seizures, gait other phenotypes rather
than the usual amnestic
abnormalities, pseudobulbar palsy, or hyperreflexia.10,11 Second, overall disorder seen in late-onset
deterioration is faster in early-onset AD as compared to late-onset AD (not Alzheimer disease.
related to APOE).12 Several studies indicate that patients with early-onset AD
have a potentially more aggressive clinical course.13–15 After controlling for the ● MRI of patients with
early-onset Alzheimer
direct effects of aging on mortality, patients with early-onset AD are at a greater
disease shows more
risk for mortality compared to those with late-onset AD,16 and early-onset AD widespread cortical
accounts for a large number of premature deaths among those 40 to 64 years of atrophy, particularly in the
age.17 Third, patients with early-onset AD have a longer duration of the disease parietal cortex, compared to
the more limited atrophy
before diagnosis (about 1.6 years),12,18 probably reflecting missed or delayed
affecting temporal regions
diagnosis or a greater extent of evaluation for diagnosis.19 Fourth, patients with in patients with late-onset
early-onset AD are more likely to have a history of traumatic brain injury as a risk Alzheimer disease.
factor for dementia.20 However, patients with early-onset AD have decreased
cerebrovascular risk factors, circulatory problems, diabetes mellitus, and obesity ● Fludeoxyglucose positron
emission tomography
than those with late-onset AD.10,21,22 shows greater parietal
Perhaps most important, the overall clinical profile of early-onset AD differs hypometabolism in early-
from that of late-onset AD. A high proportion of patients with early-onset AD onset Alzheimer disease
present with language, visuospatial, or dysexecutive phenotypes rather than the compared to greater
bilateral temporal
usual amnestic disorder seen in late-onset AD.23 In the aggregate, patients with hypometabolism in late-
early-onset AD, compared to similarly impaired patients with late-onset AD, onset Alzheimer disease.
have better memory recognition scores and semantic memory but worse
attention, language, executive functions, ideomotor praxis, and visuospatial
skills.23–26

EARLY-ONSET ALZHEIMER DISEASE
NEUROIMAGING AND CEREBROSPINAL FLUID BIOMARKERS

MRI of patients with early-onset AD demonstrates more widespread cortical
atrophy, particularly in the parietal cortex, compared to patients with late-onset
AD, in which the atrophy is more limited to temporal regions.25 Compared to
late-onset AD, early-onset AD shows larger sulcal widths in the temporoparietal
cortex and less volume loss in hippocampi.27–29 In early-onset AD, prominent
atrophy of the posterior cingulate cortex, compared to the prominent atrophy of
the medial temporal lobe in late-onset AD, is consistent with early involvement
of distinct intrinsic connectivity networks (FIGURE 2-1).26 Resting-state
functional MRI (fMRI) findings support this conclusion, with smaller functional
changes of the cortical regions connected to the hippocampus in early-onset
AD compared to late-onset AD.30
Consistent with the MRI findings, fludeoxyglucose positron emission
tomography (FDG-PET) shows greater parietal hypometabolism in early-onset
AD compared to greater bilateral temporal hypometabolism in late-onset AD.31,32
The parietal hypometabolism in early-onset AD involves the temporoparietal
junctions and the posterior cingulate cortex.25 FDG-PET hypometabolism is
more concentrated in paralimbic regions in amnestic early-onset AD.33
FDG-PET further suggests dysfunction in the salience network among
TABLE 2-1 Characteristics of Early-onset Alzheimer Disease Compared to Late-onset

Alzheimer Diseasea
◆ Large percentage of nonamnestic phenotypic variants (logopenic variant primary progressive

aphasia, posterior cortical atrophy, behavioral/dysexecutive, acalculia, corticobasal syndrome)
◆ Genetic predisposition: About 1 in 10 patients has an autosomal dominant familial Alzheimer
disease (PSEN1, PSEN2, APP), and there is a high polygenic risk score of susceptibility genes
◆ Higher APOE ε4 frequency in amnestic early-onset Alzheimer disease but less in variant
phenotypes
◆ More aggressive course with high rate of mortality
◆ Delay in diagnosis of about 1.6 years
◆ Higher prevalence of traumatic brain injury (which lowers age of onset) and lower vascular
risk factors
◆ Overall less semantic memory impairment and greater attention, executive, praxis, and
visuospatial difficulties
◆ Greater psychosocial problems (unexpected midlife “out-of-step” loss; continued work,
financial, family responsibilities; retained insight with depression, anxiety, suicide risk)
◆ Hippocampal sparing and less mesial temporal lobe disease
◆ Greater posterior (parietal, temporoparietal junction) neocortical atrophy and hypometabolism
versus temporal atrophy and hypometabolism
◆ Higher burden of tau/neurofibrillary tangles per gray matter atrophy and stage of dementia,
especially in focal phenotypic areas (reflected in tau imaging)
◆ Greater involvement of white matter tracts in posterior association areas and frontoparietal
networks and greater involvement of non–default mode neural networks rather than the
default mode network
a
Data from Mendez MF, Neurol Clin.9
36 FEBRUARY 2019

KEY POINTS
● Amyloid positron
emission tomography is
positive in most patients
with early-onset Alzheimer
disease who would not
be expected to have
age-associated brain
amyloid deposition and
can be useful in diagnosis
of the disorder.
● Tau positron emission

FIGURE 2-1 tomography has promise for
Tensor-based morphometry studies of MRI (A) and fludeoxyglucose positron emission future use in early-onset
tomography (FDG-PET) overlaid on normalized T1-weighted MRI (B) showing subtraction of Alzheimer disease,
late-onset Alzheimer disease (AD) changes from those for early-onset AD. Both neuroimaging particularly in correlating
techniques reveal greater involvement of parietal regions in early-onset AD (brown on MRI, localization of changes with
blue on FDG-PET).31 Greater precuneus/parietal atrophy (A) and hypometabolism (B) are clinical symptoms.
seen in early-onset AD compared to with late-onset AD, indicating differences in the
distribution of neuropathology. ● CSF analysis in
disease is similar to
late-onset Alzheimer
disease, showing the
patients with early-onset AD with behavioral disturbances.34 Those with characteristic low
language and dysexecutive presentations have hypometabolism in the amyloid-β1-42 and high total
corresponding areas. tau and phosphorylated tau
levels but with some
Recent developments in amyloid and tau PET imaging may revolutionize variations.
the evaluation of patients with early-onset AD. Since amyloid positivity
increases with age,35 amyloid PET is particularly useful in the differential ● The vast majority of
diagnosis of early-onset AD, in which it usually correlates with low CSF patients with early-onset
Alzheimer disease have a
amyloid-β.36 Amyloid PET imaging with flutemetamol demonstrated positive
nonfamilial, or sporadic, form.
scans in most patients with a pre-PET diagnosis of early-onset AD. Using
amyloid PET in this population changed diagnosis in about one-fifth of patients, ● Only 11% or less of those
altered management in more than one-third of patients, and led to a nearly 20% with early-onset Alzheimer
mean increase in diagnostic confidence.37 Similar to neuropathologic studies, the disease (about 0.6% of the
total of all patients with
relationship between the location of amyloid burden on PET does not tightly Alzheimer disease of any
correspond to clinical symptoms, although amyloid imaging with Pittsburgh age) have familial Alzheimer
compound B (PiB) may show greater retention in the bilateral thalamus and disease associated with one
some parts of the globus pallidus in early-onset AD compared to late-onset AD.38 of the three known autosomal
dominant mutations in APP,
However, tau PET signal better correlates with clinical symptoms.39–41 Using PSEN1, or PSEN2.
[18F]flortaucipir tau imaging, studies show significantly greater uptake in
early-onset AD compared to late-onset AD, not only throughout the neocortex ● An active area of genetic
but also in prefrontal and premotor cortices as well as in the inferior parietal research is the recognition
of a polygenic risk for
cortex, compared to higher [18F]flortaucipir retention in temporal lobe regions in
sporadic early-onset
late-onset AD.42 Tau PET regional uptake patterns also correspond to phenotypic Alzheimer disease from a
variants and cortical atrophy patterns, with greater tau binding in the left number of susceptibility
anterior superior temporal gyrus with language dysfunction and in the genes.
parietooccipital cortex and right lingual gyrus with visuospatial dysfunction.43,44
Similar to typical late-onset AD, CSF analysis in early-onset AD shows the
typical low amyloid-β1-42 and high total tau and phosphorylated tau levels that
characterize AD but with some variations.45 There appears to be a better
correspondence of decreased amyloid-β1-42 levels versus increased tau levels with

gray matter atrophy in early-onset AD compared to late-onset AD.45 Some

studies suggest lower tau levels among the phenotypic variants, particularly
posterior cortical atrophy.46 Additionally, a disproportionate decrease in
amyloid-β1-43, rather than the usual amyloid-β1-42, levels may be seen,47
suggesting differential deposition of amyloid-β peptides in early-onset AD
compared to late-onset AD.
GENETICS
When considering early-onset AD, clinicians are often concerned with a familial
form of the disease. Indeed, some, but not all, investigators have considered a PSEN1
mutation in Auguste Deter, Alzheimer’s original patient.48 In actuality, the vast
majority of patients with early-onset AD have a nonfamilial, or sporadic, form.49
Only approximately 11% of those with early-onset AD (about 0.6% of the total of all
patients with AD, including the late-onset form) have familial AD associated with
one of the three known autosomal dominant mutations: amyloid precursor protein
(APP), presenilin 1 (PSEN1), or presenilin 2 (PSEN2).50 Studies screening for
these genes in patients with early-onset AD report a prevalence of 0.8% for APP,
1.1% for PSEN1, and as high as 13% for potential pathogenic variants of PSEN2,
which can present even after age 65.51–53 These forms of familial AD are usually
inherited from a parent with a similar age of onset of early-onset AD, generally in
the forties or fifties (having a positive family history of late-onset AD has no
effect).51 These three pathogenic mutations, which lead to aberrant cleavage or
aggregation of the amyloid precursor protein, result in the more typical amnestic
AD but can have diagnostic features such as spastic paraparesis, early myoclonus,
seizures, dysarthria, pseudobulbar affect, more extensive amyloid angiopathy,
and atypical amyloid plaque morphology and distribution.54 Some PSEN1
mutations (such as A79V) can be variable and sometimes mild, with ages of onset
ranging from 53 to 84.55
In addition to the familial AD genes, a polygenic risk for AD exists from a
number of susceptibility genes. Compared to patients with late-onset AD, those
with early-onset AD have a higher frequency of two apolipoprotein E (APOE) ε4
alleles12; APOE is the main AD susceptibility gene, and the presence of an APOE
ε4 allele reportedly accounts for about 9.12% of the heritability of early-onset
AD.56 The APOE gene regulates the lipoprotein metabolism that binds soluble
amyloid-β and influences its clearance and aggregation. The presence of an
APOE ε4 allele is associated with extensive white matter disruption; the absence
of any ε4 allele is associated with more focally posterior gray matter changes in
the neocortex.57 For typical amnestic AD, the presence of an ε4 allele decreases
the age of onset,58 whereas ε3 alleles tend to be found in variant phenotypes
(language, visuospatial) of early-onset AD. Beyond APOE, recent whole-genome
and whole-exome studies indicate more than 20 loci for genes involved in
different metabolic pathways, each of which adds a small contributing risk for
early-onset AD.56,59 These include sortilin related receptor 1 (SORL1); the
anti-inflammatory microglial triggering receptor expressed on myeloid cells 2
(TREM2)50; ATP binding cassette subfamily A member 7 (ABCA7); and others
involved in endocytosis or endolysosomal transport, immunologic reactivity,
and lipid metabolism (eg, PLD3, PSD2, TCIRG1, RIN3, and RUFY1).49 An
important development is the combination of these genes into a polygenic risk
score, which may predict the occurrence of early-onset AD with accuracies of
72.9% to 75.5%.60
38 FEBRUARY 2019

NEUROPATHOLOGY KEY POINTS
Both early-onset AD and late-onset AD have neuritic plaques and neurofibrillary
● On neuropathology,
tangles, but patients with early-onset AD have greater tau burdens in parietal and patients with early-onset
precuneus regions and, to a lesser extent, the frontal cortex than patients with Alzheimer disease
late-onset AD.23,61 Early-onset AD has faster atrophy rates in the bilateral (especially with the variants)
precuneus and parietal and superior temporal lobes independent of white matter are more likely to have
hippocampal sparing with
changes or APOE status.62 Patients with early-onset AD are more likely to have
increased neocortical tau
hippocampal sparing, particularly among the nonamnestic variants, and they pathology, particularly in
have more involvement of the corresponding neocortex.61,63 It is possible that the parietal cortex and, to a
the neuropathologic cascade in early-onset AD variants is initiated through lesser extent, the frontal
cortex, than patients with
deposition of different strains of soluble oligomeric amyloid-β. Nevertheless,
tau and neurofibrillary tangles, more than amyloid-β1-42 and neuritic plaques, disease.
correspond with the features of early-onset AD, with a relatively greater tau
burden in early-onset AD than in late-onset AD. Whereas the distribution of ● On neuropathology, tau
amyloid is diffuse, a significant focal correlation exists between the location and and neurofibrillary tangles,
more than amyloid-β1-42
density of neurofibrillary tangles and cognitive symptoms, cerebral blood flow, and neuritic plaques,
and atrophy or functional changes in early-onset AD.64 Early-onset AD variants correspond with the
also develop greater white matter involvement and selective vulnerability of long features of early-onset
projection neurons that involve posterior cingulate and parietal regions and Alzheimer disease, with a
relatively greater tau burden
mediate frontoparietal functions rather than the mesial temporal involvement of in early-onset Alzheimer
late-onset AD.65 disease than in late-onset
Alzheimer disease.
PHENOTYPIC VARIANTS OF EARLY-ONSET ALZHEIMER DISEASE
● Phenotypic variants of
Nonamnestic variant presentations are particularly characteristic of early-onset
AD. No universally accepted classification of the phenotypic variants has been disease include those that
established. Commonly accepted variants are those that present with language present with language
impairment (known as logopenic variant primary progressive aphasia [PPA]); impairment (known as
those that present with visuospatial or visuoperceptual impairments (known as logopenic variant primary
progressive aphasia),
posterior cortical atrophy); frontal or behavioral/executive variants; and a number those that present with
of parietal syndromes, such as the acalculia variant of early-onset AD.66–71 In visuospatial or
addition, patients who meet criteria for corticobasal syndrome, with progressive visuoperceptual
limb apraxia and asymmetric motor changes, have AD in up to 25% at impairments (known as
posterior cortical atrophy),
autopsies,72 indicating another phenotypic variant of early-onset AD. These frontal or behavioral/
variants, which account for one-fifth to two-thirds of those with sporadic executive variants, a number
early-onset AD,73 overlap with one another but, as a group, are distinct from the of parietal syndromes (such
earliest typical amnestic forms of AD (FIGURE 2-274). Compared to the more as the acalculia variant of
typical amnestic form of early-onset AD, the phenotypic variants are more likely disease), and a subgroup of
to be hippocampal sparing and develop prominent early posterior neocortical patients with corticobasal
neurofibrillary tangles.61 The phenotypic variants appear to have early syndrome.
involvement of frontoparietal networks rather than the decreased posterior
● Phenotypic variants of
default mode network and medial temporal lobe-hippocampal connectivity of
typical amnestic AD.75,76 Also, unlike amnestic early-onset AD, the phenotypic disease may involve
variants tend to be less associated with APOE ε4.74,77 alternative frontoparietal
neural networks rather than
Logopenic Variant Primary Progressive Aphasia the posterior default mode
network implicated in
The most common phenotypic variant of early-onset AD presents with a late-onset Alzheimer
progressive decline in language with relatively spared memory and cognition due disease.
to focal Alzheimer neuropathology in temporoparietal language areas in the left
hemisphere, especially the superior/midtemporal gyrus, angular gyrus, and
midfrontal cortex (TABLE 2-2).66,78 This progressive aphasia has “logopenic”

FIGURE 2-2
Phenotypic variants of early-onset Alzheimer disease compared to typical amnestic Alzheimer
disease across the age spectrum. The different colored lines in the graph are meant to
represent the probable distributions of different phenotypic variants of early-onset Alzheimer
disease, such as posterior cortical atrophy, logopenic variant primary progressive aphasia,
the behavioral/dysexecutive variant, and the acalculic variant.
Modified with permission from van der Flier WM, et al, Lancet Neurol.74 © 2010 Elsevier Ltd.
aspects, including word-finding difficulty with hesitations or false starts and

repetition difficulty for both long sentences and forward digit span (CASE 2-1).79
In logopenic variant PPA, left temporoparietal degeneration disturbs the
phonologic loop of verbal working or echoic memory,80 resulting in an impaired
phonologic buffer for holding words or digits online, hence the characteristic
inability to repeat long sentences. In addition, a history of dyslexia is common
among patients with logopenic variant PPA,65 suggesting a preexisting
vulnerability in language networks. Other forms of PPA, such as the nonfluent/
agrammatic and semantic variants, are non-Alzheimer syndromes due to
frontotemporal lobar degeneration. The presence of some degree of difficulty
in episodic memory and visuospatial skills helps distinguish logopenic variant
PPA from these other PPAs.
TABLE 2-2 Characteristics of Logopenic Variant Primary Progressive Aphasia
◆ An insidious onset and progressive disorder of language

◆ Word-finding difficulty with frequent word-finding pauses; may have circumlocutions
(intermediate fluency between the nonfluent/agrammatic and semantic primary
progressive aphasia variants)
◆ Overall decreased verbal output and slower rate
◆ Decreased word retrieval with phonologic paraphasias (errors)
◆ Disproportionately decreased repetition of sentences (hallmark finding)
◆ Decreased comprehension for long (not complex) sentences but not for words
◆ Preserved grammar (although it may be syntactically simple)
◆ Preserved motor articulation
◆ Other evidence of decreased phonologic store (eg, decreased digit or word span)
◆ Left posterior temporal/inferior parietal dysfunction on neuroimaging
40 FEBRUARY 2019

In logopenic variant PPA, neuroimaging and CSF studies usually reveal
abnormalities consistent with early-onset AD. Neuroimaging shows focal
atrophy and decreased metabolism in the left temporoparietal junction.81
Word-finding difficulty and anomia in logopenic variant PPA correlate with
thinning in the left superior temporal gyrus,82 which is less responsive to some
characteristics of auditory speech,83 and early memory impairment may also
be due to this nonhippocampal temporal involvement.84 The analysis of white
matter tracts and connections in logopenic variant PPA reveals bilateral but
predominantly left-sided alterations in frontoparietal pathways (FIGURE 2-3)80,85,86
and less involvement of the hippocampal-associated default mode network
that is associated with episodic memory impairment in typical Alzheimer
disease. Amyloid PET scans are positive in about 85% of patients diagnosed with
A 53-year-old woman presented with a 2-year history of a progressive CASE 2-1

decline in her ability to find words and pronounce them correctly. She
also could not repeat or understand sentences when they were too long.
She underwent an evaluation before presenting to clinic, which included
an unremarkable MRI of the brain, normal routine laboratory results, and
neuropsychological testing that showed normal intellectual abilities
except for a decline in verbal fluency, with more minor changes in
auditory attention and visual memory.
On examination, she had a Mini-Mental State Examination (MMSE)
score of 17/30. She could not do the serial reversals and could not come
up with the word watch. Memory examination was intact on delayed
recall; however, her language examination was quite abnormal. She
showed word-finding pauses, hesitations, and frequent phonemic
paraphasic errors but no agrammatism or difficulty comprehending single
words or simple commands. However, she had prominent difficulty with
repetition, quickly breaking down if a sentence was more than a few
words. She was unable to give the names of more than seven animals in
1 minute or name more than seven of 20 objects. On the naming task, she
made phonemic paraphasic errors, such as Campbell for camel and
volcan for volcano. The rest of the neurologic examination was normal.
The workup included fludeoxyglucose positron emission tomography
(FDG-PET) imaging that showed asymmetric hypometabolism in the
temporoparietal regions, worse on the left. In addition to treatment for
Alzheimer disease with an acetylcholinesterase inhibitor and memantine,
the patient underwent an extended and targeted program of speech
therapy.
This case is a typical example of logopenic variant primary progressive COMMENT

aphasia, with initial word-finding difficulty, phonemic paraphasic errors but
not agrammatism, and prominent difficulty with repetition but intact single-
word and short-phrase comprehension. The vast majority of patients who
present with this progressive aphasia prove to have Alzheimer disease on
neuropathology.

KEY POINTS
● Logopenic variant
primary progressive
aphasia, the most common
nonamnestic phenotypic
variant of early-onset
Alzheimer disease, presents
with a progressive decline in
language with relatively
spared memory and
cognition due to focal
Alzheimer neuropathology
in temporoparietal language
areas in the left hemisphere, FIGURE 2-3
especially the superior/ Voxel-based morphometry of parietal overlap of early-onset Alzheimer disease phenotypes,
midtemporal gyrus, showing cortical atrophy in 10 patients with logopenic variant primary progressive aphasia
angular gyrus, and midfrontal compared to 64 normal controls. These two composite images show the pattern of atrophy
cortex. in this aphasic variant of Alzheimer disease when subtracted from the healthy controls. The
dark regions show the foci of greater atrophy in logopenic variant primary progressive aphasia
● In logopenic variant asymmetrically affecting the left parietal and posterior temporal region in the left hemisphere
primary progressive with much less involvement of the right hemisphere. The composite images particularly
aphasia, neuroimaging and illustrate how this variant of Alzheimer disease results from asymmetric involvement of the
CSF studies usually reveal left hemisphere.
abnormalities consistent Courtesy of Maria Luisa Gorno-Tempini, MD, PhD, University of California, San Francisco.
with early-onset Alzheimer
disease, including focal
atrophy and decreased
metabolism in the left logopenic variant PPA, compared to only 13% to 27% in other forms of PPA,87,88
temporoparietal junction.
and prominent FDG-PET hypometabolism of the left temporoparietal region is
● Posterior cortical seen in patients with amyloid-positive logopenic variant PPA.89 On tau PET
atrophy, the second most imaging, patients with logopenic variant PPA have increased uptake throughout
common early-onset the cortex, but particularly temporoparietal, in comparison to not only healthy
Alzheimer disease variant,
presents with progressive
controls but also patients with other PPA variants.90 In logopenic variant PPA,
and disproportionate loss this regional tau deposition in the left inferior parietal lobule is more closely
of visuospatial or linked to hypometabolism than to amyloid density.91 Finally, in the CSF, low
visuoperceptual functions, amyloid-β1-42 and high tau levels are seen in about 75% of patients diagnosed with
usually due to Alzheimer
logopenic variant PPA.92
neurodegeneration of
posterior visual cortical
regions. Posterior Cortical Atrophy
The second most common early-onset AD variant is posterior cortical atrophy,
● The frontal variant of
a syndrome characterized by progressive and disproportionate loss of
Alzheimer disease, now
known as behavioral/ visuospatial or visuoperceptual functions, usually due to Alzheimer
dysexecutive Alzheimer neurodegeneration of posterior cortical regions. Patients with posterior
disease, presents with cortical atrophy usually present with visuospatial problems in reading,
features suggestive of
manipulating or finding objects, navigating their surroundings, getting
frontotemporal lobar
degeneration but most dressed, and driving. These visual symptoms frequently lead to consultations
commonly with apathy or with optometrists or ophthalmologists before the suspicion is raised that the
abulia. problem is from the visual brain and not the eyes. On neurologic examination,
patients with posterior cortical atrophy prove to have a range of visuospatial or
visuoperceptual difficulties up to and including Balint syndrome along with
associated regional neurocognitive features.68,93 For more information, refer
to the article “Posterior Cortical Atrophy” by Jonathan M. Schott, BSc, MD,
FRCP, FEAN, SFHEA, and Sebastian J. Crutch, PhD, CPsych,94 in this issue
of Continuum.
42 FEBRUARY 2019

Other Variants
Beyond logopenic variant PPA and posterior cortical atrophy, the most common
early-onset AD variant phenotypes, several other less recognized variants exist.
Frontal variant AD, now known as behavioral/dysexecutive AD,69 presents with
features suggestive of frontotemporal lobar degeneration (TABLE 2-3). Most
commonly, patients with behavioral/dysexecutive AD have early apathy (or,
more correctly, abulia), with decreased initiation or completion of productive
behavior (CASE 2-2). Up to half, however, can have positive behaviors, notably
disinhibition and impulsivity, which can contribute to a misdiagnosis of clinically
possible behavioral variant frontotemporal dementia. However, when carefully
evaluated, behavioral/dysexecutive AD is distinguishable from behavioral
variant frontotemporal dementia because of the presence of prominent
dysexecutive features accompanied by evidence of memory impairment.69
Neuroimaging in behavioral/dysexecutive AD shows significant involvement
of bilateral temporoparietal regions along with milder involvement in the frontal
cortex, especially noteworthy on FDG-PET.69
Other phenotypic variants of early-onset AD have prominent parietal lobe
symptoms and signs, exemplified by the acalculia variant from early Alzheimer
neuropathology in the left inferior parietal lobule, particularly the intraparietal
sulcus (TABLE 2-4).71 Patients with the acalculia variant of early-onset AD
present with predominant and progressive difficulty with calculations out of
Characteristics of Behavioral/Dysexecutive Alzheimer Disease Compared TABLE 2-3

to Other Dementiasa
Behavioral Variant
Clinical Typical Amnestic Behavioral Early-onset Dysexecutive Early-onset Frontotemporal
Features Alzheimer Disease Alzheimer Disease Alzheimer Disease Dementia
Phenotype Memory A behavioral predominant A dysexecutive predominant Behavioral
variant predominant subtype most commonly subtype most often presents
presents with apathy with decreased organization
and executive functioning
APOE ε4 Frequent (~60%) Frequent (59.5%) Intermediate (40.0%) Rare (<20%)

positive
Age at onset Late onset Early onset Early onset Early onset
First Cognitive (memory) Cognitive > behavioral Cognitive (executive) Behavioral

symptom
Episodic Impaired Impaired Relatively spared Typically spared

memory
Executive Relatively spared Impaired Very impaired Impaired

function
Behavior Relatively spared Impaired Mostly spared Impaired
MRI atrophy Medial temporal, Temporoparietal Temporoparietal Frontal and anterior

temporoparietal temporal
a
Reprinted with permission from Ossenkoppele R, et al, Brain.69 © 2015 The Authors.

proportion to any other cognitive impairment (CASE 2-3). Their acalculia is

consistent with a primary acalculia (anarithmia) not explained by language or
visuospatial impairments. Many also have anomia, ideomotor apraxia, and a
complete Gerstmann syndrome, changes reflective of inferior parietal lobular
dysfunction. Neuroimaging generally shows biparietal involvement, greater on
the left. These patients overlap with or may eventually meet current criteria for
posterior cortical atrophy or corticobasal syndrome.
MANAGEMENT
The management of patients with early-onset AD is, in many ways, identical
to the management of late-onset AD, but it differs in several respects.
Acetylcholinesterase inhibitor medications, such as donepezil, galantamine, and
rivastigmine, are indicated in the management of patients with early-onset AD,
with the usual titration schedules. These medications, although they target
CASE 2-2 A 64-year-old man presented with several years of declining activity
and failure to initiate and complete work tasks. The patient would often
just sit at his desk. The patient additionally reported a significant decline
in his memory. His wife described him as unable to “think properly,”
reflected in wrong business decisions or judgments. She also reported he
tended to eat the same foods, but he showed no inappropriate or
compulsive behaviors. The patient and his wife denied that he was
primarily depressed or that he was nonempathic or emotionally disengaged.
On the Mini-Mental State Examination (MMSE), he scored 28/30. In
general, he had decreased spontaneous behavior and showed
perseverations. Language was fluent, but he only generated four words
beginning with the letter F in 1 minute, compared to 13 animal names.
Memory testing was 5/10 in delayed recall. On visuospatial construction, he
was able to copy intersecting pentagons but had difficulty with more
complex constructions. The patient gave concrete interpretations of idioms
and proverbs and had difficulty with the Luria hand sequences (repetitive
fist-edge-palm motor sequences), making two mistakes in six movements.
The rest of the neurologic examination was normal.
Brain MRI suggested more frontal than parietal atrophy; however,
fludeoxyglucose positron emission tomography (FDG-PET) showed
prominent bilateral temporoparietal hypometabolism with further
involvement of the frontal lobes. After follow-up and reassessment of a
progressive cognitive decline in memory and visuospatial skills, he was
diagnosed with behavioral/dysexecutive early-onset Alzheimer disease
(AD) and treated accordingly.
COMMENT This case is a typical example of the behavioral/dysexecutive variant of

early-onset AD, with prominent early apathy or abulia, decreased executive
functioning without the entire range of abnormal behaviors characteristic
of behavioral variant frontotemporal dementia, and memory and imaging
evidence of early-onset AD.
44 FEBRUARY 2019

memory, may also help some patients with logopenic variant PPA, posterior
cortical atrophy, behavioral/dysexecutive AD, acalculia, and other variants. In
these early-onset AD phenotypes, clinicians should carefully monitor response
as these medications could exacerbate some behaviors. In one study, the
cognitive and global responses to acetylcholinesterase inhibitor treatment and
the longitudinal outcomes after 3 years did not differ between patients with
early-onset AD and patients with late-onset AD.12 Another study of
acetylcholinesterase inhibitors that evaluated 6-month functional responses,
3-year changes in activities of daily living, times to nursing home placement,
and subsequent survival times also failed to find differences between patients
with early-onset AD and patients with late-onset AD.95 Limited information is
available on the use of memantine, but the aforementioned studies do not suggest
a difference depending on age of onset of AD. Finally, many patients and families
are eager to participate in clinical drug trials.
The management of early-onset AD may differ from late-onset AD when
targeting the management of specific cognitive and behavioral deficits. For
example, patients with logopenic variant PPA should have speech therapy
assessment and, wherever possible, a dedicated course of therapy to improve
their communication. Patients with posterior cortical atrophy benefit from
techniques and services for those who are partially sighted. Patients with
behavioral/dysexecutive AD may require use of psychoactive medications to
manage egregious behaviors, when present. Those with the acalculia variant can
benefit from the use of electronic calculation devices and those with corticobasal
syndrome from referral to occupational therapists for help with ideomotor apraxia.
An important part of assessing patients with early-onset AD is determining
their family history and the need for genetic testing and genetic counseling.
If a family history of early-onset AD exists, genetic counseling should occur
Characteristics of the Acalculia Variant of Early-onset Alzheimer Disease TABLE 2-4
Acalculia
◆ Primary anarithmia not due to language or spatial impairment
◆ Difficulty with simple written calculations with transcoding and syntax errors
Other Elements of Gerstmann Syndrome
◆ Finger (digit) agnosia
◆ Right-left disorientation
◆ Agraphia (transitional with linguistic elements)
Alexia With Agraphia (Left)
Ideomotor Apraxia
◆ Both transitive (with pretend tool use) and intransitive (gestural-symbolic)
◆ Difficulty with imitation as well as pantomime
Disorders of the Dorsal Visual Stream
◆ Visuospatial localization
◆ Depth perception

before performing genetic analysis for the PSEN1, PSEN2, and APP genes.
In the presence of familial AD, implications exist for other family members,
including the possibility of recognizing presymptomatic carriers of these
genes, with corresponding implications for their psychological well-being
and future. Currently, the polygenic risk score remains a research tool, but
it may become available for increasing diagnostic certainty in diagnosing
early-onset AD.
Another area that is disproportionately important in the management of
early-onset AD is the provision of age-appropriate psychosocial support.
Patients with early-onset AD are often in the time of life when they are most
productive and in the midst of careers and families. Early-onset AD is more
often associated with a sense of an unexpected loss of independence in midlife;
anticipatory grief about the future; and difficulty with continued work,
financial, and family responsibilities than late-onset AD.96 Moreover, patients
and families need information and education on this form of AD and what it
means in someone who is middle-aged or relatively young. Compared to
patients with late-onset AD, patients with early-onset AD often have higher
levels of disease awareness and early generalized anxiety97 with a potentially
increased risk of suicide.98 Special efforts are required to provide psychological
CASE 2-3 A 62-year-old woman presented with several years of progressive

difficulty with mathematics, which she used in her job. She first noticed
an inability to do very simple calculations in her head as well as problems
with using a tape measure and reading analog clocks or watches. The
patient could not write a check or manage her checkbook and finances.
She had also lost understanding of distances, such as from New York to
Los Angeles. Other than some visuospatial difficulty, the patient had
limited cognitive difficulty.
On examination, she had a Mini-Mental State Examination (MMSE)
score of 27/30, intact language, and mildly impaired memory.
However, she could not do simple written calculations, made errors in
mathematical syntax in borrowing and carrying over, had transcoding
difficulty (Arabic numerals to written form or vice versa), and had
overall difficulty in applying numeric concepts. There were less
prominent visuospatial difficulties in constructions and in interpreting
overlapping or crosshatched figures. The neurologic examination
was otherwise normal.
Brain MRI was nondiagnostic, but fludeoxyglucose positron emission
tomography (FDG-PET) showed parietal hypometabolism, and an
amyloid PET scan was positive. Treatment included donepezil
(10 mg/d), memantine XR (28 mg/d), and an antidepressant for both
depression and anxiety.
COMMENT This case is a typical example of the acalculic variant of early-onset

Alzheimer disease presenting with disproportionate and progressive
difficulty in all aspects of numbers and calculations.
46 FEBRUARY 2019

or psychiatric support and utilize local age-appropriate support groups and KEY POINTS
community resources. In many situations, support groups and other services
● Less common phenotypic
for the elderly may not be the best fit for these patients and families. It is most variants of early-onset
helpful when support groups and services are specifically targeted to the Alzheimer disease may
particular phenotypic variant. have prominent parietal
lobe symptoms and
signs, exemplified by the
acalculia variant from early
CONCLUSION Alzheimer neuropathology
Early-onset AD differs significantly from late-onset AD, particularly in the in the left inferior parietal
substantial percentage of patients with early-onset AD who have phenotypic lobule, particularly the
intraparietal sulcus.
variants as well as the larger percentage of those with a familial form of the
disease. Compared to typical late-onset AD, early-onset AD variants have ● Acetylcholinesterase
hippocampal sparing, focal parietal and other neocortical involvement with a inhibitors, such as
range of syndromes, more regional amyloid and tau accumulation, and evidence donepezil, galantamine,
of an alternative frontoparietal network spread of the disease.61,85,99 These and rivastigmine, are
indicated in the
variants tend to differ as a group from typical amnestic AD, with a converging management of patients
pattern of atrophy as the disease advances,100 as evidenced by neuroimaging with early-onset Alzheimer
studies showing overlap in posterior neocortical involvement rather than the disease, with the usual
mesial temporal cortical changes of typical amnestic AD.81,101 Recognition of precautions and titration
schedules.
early-onset AD and its variants as a specific group of dementias facilitates not
only neurobiological understanding of early-onset AD but also the unique ● The management of
differences and issues involved in the management of these patients and early-onset Alzheimer
helping their caregivers and families. disease may differ from
disease when targeting the
management of specific
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REVIEW ARTICLE

Posterior Cortical
ONLINE
Atrophy
By Jonathan M. Schott, BSc, MD, FRCP, FEAN, SFHEA;
 Sebastian J. Crutch, PhD, CPsych
VIDEO CONTENT
A VA I L A B L E O N L I N E
CITE AS: ABSTRACT

CONTINUUM (MINNEAP MINN) PURPOSE OF REVIEW: This article presents an overview of the clinical syndrome
2019;25(1, DEMENTIA):52–75.
of posterior cortical atrophy (PCA), including its pathologic underpinnings,
clinical presentation, investigation findings, diagnostic criteria, and
Dr Jonathan M. Schott, management.
Dementia Research Centre, UCL
Queen Square Institute of
Neurology, Box 16, Queen RECENT FINDINGS: PCA is usually an atypical form of Alzheimer disease with
Square, London WC1N 3BG, UK, relatively young age at onset. New diagnostic criteria allow patients to be
j.schott@ucl.ac.uk.
diagnosed on a syndromic basis as having a primary visual (pure) form or
more complex (plus) form of PCA and, when possible, on a disease-
Dr Schott serves on advisory specific basis using biomarkers or underlying pathology. Imaging techniques
boards for Biogen; Eli Lilly and have demonstrated that some pathologic processes are concordant
Company; F Hoffman-La Roche
Ltd; and Merck & Co, Inc, and on
(atrophy, hypometabolism, tau deposition) with clinical symptoms and
the drug safety monitoring board some are discordant (widespread amyloid deposition). International
for AXON Neuroscience SE. efforts are under way to establish the genetic underpinnings of this
Dr Schott has received personal
compensation for speaking
typically sporadic form of Alzheimer disease. In the absence of specific
engagements for Biogen, Eli Lilly disease-modifying therapies, a number of practical suggestions can be
and Company, and GE Healthcare offered to patients and their families to facilitate reading and activities of
Worldwide and receives
research/grant support from daily living, promote independence, and improve quality of life
Alzheimer’s Research UK, Avid
Radiopharmaceuticals, Brain
SUMMARY: While rare, PCA is an important diagnostic entity for neurologists,
Research UK, British Heart
Foundation, Engineering and ophthalmologists, and optometrists to recognize to allow for early
Physical Sciences Research accurate diagnosis and appropriate patient management. PCA provides
Council (EP/J020990/1), European
Commission Horizon 2020,
an important opportunity to investigate the causes of selective
Medical Research Council vulnerability in Alzheimer disease.
Dementias Platform UK
(MR/L023784/1), Weston Brain
Institute, and Wolfson
Foundation. Dr Schott receives
royalties from Henry Stewart Talks INTRODUCTION
P
and Oxford University Press. Dr osterior cortical atrophy (PCA) is a neurodegenerative syndrome
Crutch receives research/
that primarily affects the parietal and occipital lobes.1 While patients
grant support from the
Continued on page 75 with progressive visual impairment with normal acuity had previously
been described, the term posterior cortical atrophy was introduced by
Benson and colleagues,2 who described a series of patients with
UNLABELED USE OF
deficits in higher-order visual processing and features consistent with aspects of
USE DISCLOSURE: Gerstmann and Balint syndromes but with relatively preserved episodic
Drs Schott and Crutch report memory until later in the disease. Subsequent case series determined that the
no disclosures.
most common underlying pathology was Alzheimer disease (AD),3–5 leading to
© 2019 American Academy alternative nomenclature including the visual variant of AD and biparietal AD.4,6
of Neurology. However, as PCA can be due to alternative pathologies, including corticobasal
52 FEBRUARY 2019

degeneration,7 Lewy body disease, and (very rarely) prion disease, the KEY POINTS
overarching term posterior cortical atrophy is now preferred to describe the
● A striking feature of
syndrome, with contemporary criteria allowing for subdivisions into PCA-pure, posterior cortical atrophy is
PCA-plus, and pathologic subtypes depending on the clinical presentation and that the majority of affected
availability of biomarker evidence of underlying pathology.8 individuals have an unusually
early age at disease onset,
typically presenting
EPIDEMIOLOGY
between 50 and 65 years
The changing definitions of PCA over recent years and its relative rarity make of age.
estimation of incidence and prevalence difficult. However, a striking feature of
this syndrome is that the majority of affected individuals have an unusually early ● Most patients with
age at disease onset, typically presenting between 50 and 65 years of age, posterior cortical atrophy
have underlying Alzheimer
although patients with onset in the ninth decade are described.5,9 In the largest disease.
series to date studying PCA, of 302 patients, the mean age of onset was 58.9 years
(standard deviation 6.9), with 82.5% fulfilling criteria for early-onset dementia
(onset before 65 years of age) (FIGURE 3-1).9 The proportion of patients with AD
presenting with PCA varies and is likely to depend on clinical context but has
been estimated to be about 5% in a specialist cognitive clinic10 and up to 13% in
cases of early-onset AD.11 In addition to patients with a clear PCA presentation, a
population-based study showed that 14% of patients diagnosed with AD had
cognitive profiles consistent with prominent visuospatial problems,12 suggesting
that visual problems are underrecognized in individuals diagnosed with “typical”
AD and raising questions as to whether PCA is a distinct entity13 or on a phenotypic
continuum.14 While some PCA studies have reported a slight overrepresentation
of women9 (which may simply reflect that AD is more prevalent in women),
others have reported no sex differences.15–17 Few prospective studies have
examined disease duration in PCA; while patients with early-onset AD may have
faster disease progression than those with later-onset disease, many patients
with PCA have a more protracted course extending well over a decade.
PATHOLOGIC UNDERPINNINGS
Most patients with PCA have underlying AD,4,5,17,18 although cases of PCA can
be associated with Lewy body pathology5,17 (either in isolation or, commonly,
in combination with AD) and,
very rarely, with subcortical
gliosis or prion disease.17,19 On
postmortem examination, most
cases will naturally have
end-stage disease, but even at
late stages, differences in the
distribution of neurofibrillary
tangles compared to patients
with typical AD have been
noted, with particular
involvement of primary visual
cortices and visual association
areas.3,18 Conversely, most
studies have not found major FIGURE 3-1
Age of disease onset in posterior cortical atrophy.
differences in amyloid burden Data from an international study9 of 302 patients
across the cortex compared to shows a peak between 50 and 60 years of age,
other forms of AD.5,17 with diminishing incidence with increasing age.

POSTERIOR CORTICAL ATROPHY
CASE 3-1 A 57-year-old woman presented because of progressive visual

difficulties. She had initially presented to an optometrist at age 50, having
noted difficulties when driving and problems while filling syringes and
taking stitches out in her work as a hospital nurse. The optometrist noted
a “difficulty with peripheral vision” and referred her to an
ophthalmologist, who determined no ophthalmic basis for her
difficulties. She subsequently returned to the optometrist, who
prescribed multifocal lenses followed by two additional pairs of
eyeglasses. The patient moved to a general practice nursing role but
noticed further difficulties with visually demanding tasks, such as writing
patient notes, reading prescriptions, and transcribing information to a
computer. Her husband was also increasingly aware that the patient did
not always see everything around her, particularly on the left side; she
became lost during barn dances, and on one occasion they became
separated when he turned left into the subway station they were walking
to, while she continued straight ahead. Over the course of the next
6 years, the patient had five physician visits, including one visit to a
memory clinic, which noted “there does not appear to be any evidence of
a dementia.” It was only when her husband and son went through the
radiologist report from a brain scan and noted the terms posterior,
cortex, atrophy, and parietal that diagnostic progress was made. Her
husband reported, “I just searched for those words online and what came
up was posterior cortical atrophy.”
Neuropsychological assessment revealed significant early visual,
visuoperceptual, and visuospatial dysfunction; despite good visual acuity
(Snellen equivalent: 6/9), she failed tests of shape discrimination, dot
counting, and fragmented letter perception. She had additional deficits
in numeracy, praxis, and auditory-verbal short-term memory. These
deficits were observed in the context of relatively well-preserved
episodic memory on verbal recognition tasks and only occasional errors
in the phonologic components of word retrieval. This cognitive profile
was consistent with the posterior cortical atrophy (PCA) syndrome, as
per the PCA consensus criteria (classification level 1).
Neurologic examination and review of neuropsychiatric symptoms
revealed no evidence of symptoms consistent with any additional
neurodegenerative syndromes (therefore, consistent with PCA-pure at
classification level 2). Standard visual rating of [18F]amyloid imaging
yielded results consistent with Alzheimer disease pathology (supportive
of PCA-Alzheimer disease at classification level 3).
COMMENT This case is a typical example of the delayed diagnosis of PCA. The visual
symptoms that typify this condition are commonly inaccurately presumed
to result from ocular rather than cortical pathology, and, in the absence of
“typical” memory problems, a neurodegenerative dementia is often not
considered.
54 FEBRUARY 2019

CLINICAL PRESENTATION KEY POINTS
The core features of PCA include visuospatial and perceptual deficits as well as
● The core features of
features of Gerstmann syndrome (acalculia, left-right disorientation, finger posterior cortical atrophy
agnosia, and agraphia), Balint syndrome (ocular motor apraxia, optic ataxia, and include visuospatial and
simultanagnosia), alexia, and apraxia.1,16 In contrast to typical AD, episodic perceptual deficits as well
memory is relatively preserved at onset; compared with frontotemporal as features of Gerstmann
syndrome (acalculia, left-
dementia, aside from the common feature of anxiety,20 personality and behavior
right disorientation, finger
are not usually affected in PCA and insight is preserved. agnosia, and agraphia),
Balint syndrome (ocular
History motor apraxia, optic ataxia,
and simultanagnosia),
Because of its relative rarity, PCA is often diagnosed late, and by the time
alexia, and apraxia.
patients present to neurologists, symptoms will often have been present for
many months or years (CASE 3-1). Very early symptoms can be rather nebulous: ● Patients with posterior
patients often describe nonspecific anxiety and a sense that something is wrong, cortical atrophy may have a
before more concrete problems (usually centered on vision) become apparent. history of repeated visits to
optometrists and
Patients may have a history of repeated visits to optometrists or ophthalmologists ophthalmologists and
and multiple unsuccessful changes in eyeglasses or surgical procedures in an multiple unsuccessful
attempt to correct acuity. Patients can often express themselves very clearly and changes in eyeglasses or
so are not considered as having a “dementia”21 or are diagnosed as having had a surgical procedures in an
attempt to correct acuity.
stroke before progressive problems emerge.22 Patients often describe causing
minor damage to their cars because of problems judging distances while parking. ● Over time, difficulties
Problems reading analog clocks and digitized pixelated signs are common with reading emerge in
early features. the vast majority of
patients with posterior
Over time, difficulties with reading emerge in the vast majority of patients.15,16
cortical atrophy.
Patients typically get lost while reading text, particularly when moving from line
to line or when there is too much competing textual information (so-called ● Patients with posterior
crowding)23 or may describe a sense that words are moving or slipping off the cortical atrophy often
page.24 Most patients with PCA will be unable to read within a few years of become anxious about riding
on escalators, particularly
symptom onset. Occasionally, patients may describe abnormalities with color when going down; can be
vision, describing washes of color or prolonged afterimages.25 Patients may cautious when crossing the
describe difficulties in finding items in front of them, particularly in more road because of difficulties
cluttered environments (simultanagnosia, discussed later in this article) or a in judging the speed of
traffic; and can have
sensation that items are moving.26 Patients often become anxious about riding on difficulty with revolving
escalators, particularly when going down; can be cautious when crossing the doors.
road because of difficulties in judging the speed of traffic; and can have difficulty
with revolving doors or identifying steps or slopes when walking on patterned ● Combinations of visual
problems and dyspraxia in
carpets. Featureless environments, such as white-tiled bathrooms and shiny
patients with posterior
surfaces, can be particularly disorienting. Patents will often develop impaired cortical atrophy have
facial recognition (prosopagnosia),5,15,16 often while still being able to identify significant functional
people by voice. Some individuals describe unusual symptoms that can be consequences, including
misconstrued as nonorganic, including finding it easier to read small rather than difficulty in getting dressed;
cooking; and using cell
large text, and difficulties in identifying static objects while being able to track phones, remote controls,
items in motion. An extreme example of this phenomenon is rare patients who and computers.
can play sports such as tennis or badminton but are unable to locate the ball or
shuttlecock when it is on the floor.
Outside of the visual domain, common symptoms are those attributable to
impairments of dominant parietal lobe function,5,16 including difficulty with
calculation and handling money or spelling. Dyspraxia (acquired deficits in
performing complex motor programs) is very common.16,27 Combinations of
visual problems and dyspraxia have significant functional consequences,

including difficulty in getting dressed (eg, problems buttoning or zipping, tying

neckties, or finding the sleeves of coats or putting on clothes backward); cooking;
and using cell phones, remote controls, and computers.
Episodic memory and executive impairments are typically not observed in the
early stages, although patients may fail certain memory and executive tasks
owing to visual, imagery, and other deficits, but emerge as the disease progresses.
Language impairment is typically considered a late feature of this disorder,
although evidence exists that early anomia is relatively common when
specifically looked for.5,28–30 This may reflect that while in their purest forms, the
different established symptoms of AD dementia can easily be distinguished, in
practice and as expected for a neurodegenerative process that spreads over time,
a degree of overlap exists between different syndromic variants; this becomes
increasingly apparent as the disease advances.
Aside from dyspraxia, a number of other motor features can be seen in PCA,
including limb rigidity, myoclonus, and tremor.31 While these can reflect
underlying pathologies other than AD (eg, corticobasal degeneration16 or, when
parkinsonism is present, dementia with Lewy bodies), these can also be seen in
PCA underpinned by Alzheimer pathology.31
As PCA progresses, symptoms inevitably worsen. The majority of
patients will become functionally blind, which has major implications for
the level of care that is required and can be the cause of considerable
distress to the individual, who will often have good insight into his/her
problems. Being unable to read or use other communication devices and
becoming increasingly dependent on others often leads individuals to feel
disempowered and depressed.32 Patients who already have severe visual
problems will become at high risk of falls as other cognitive and motor
problems emerge. In its later stages, PCA is often indistinguishable from
advanced typical AD.
Atypical Presentations
Considerable debate has existed as to whether the presence of early visual
symptoms is essential for a diagnosis of PCA20 or whether presentations with
other parietal features (eg, early prominent dyspraxia) with subsequent
emergence of more typical visual features should still be classified under the PCA
umbrella. This has implications for diagnostic criteria, as patients with early
motor features can overlap with other conditions, such as corticobasal syndrome,
an issue that is now addressed in the most recent consensus criteria.8 Some
patients with a pure PCA phenotype may have corticobasal degeneration or
Lewy body pathology rather than AD. However, the presence of features typical
for these conditions (eg, alien limb phenomena for corticobasal degeneration or
early hallucinations, rapid eye movement [REM] sleep behavior disorder, or
parkinsonism for dementia with Lewy bodies) may provide evidence for these
alternative pathologies. While the Heidenhain variant of Creutzfeldt-Jakob
disease (which presents with early visual impairment) can, in theory, be
mistaken for PCA, other clinical features, including the (usual) rapidity of the
presentation and the nature of the visual disturbance (which, in prion disease, is
often associated with frightening visual distortions), usually mean this is not a
major diagnostic challenge. In rare overlap cases, the MRI features and evidence
of diffusion changes, in particular in Creutzfeldt-Jakob disease, are
particularly valuable.19
56 FEBRUARY 2019

BEDSIDE COGNITIVE ASSESSMENT KEY POINTS
The bedside cognitive examination can be particularly revealing in PCA.
● Simultanagnosia (the
Screening cognitive tests such as the Mini-Mental State Examination (MMSE)33 inability to interpret the
or Addenbrooke’s Cognitive Examination III (ACE-III)34 will often clearly entirety of a visual scene)
demonstrate preservation of orientation, repetition, and recall, with severe can often be demonstrated
difficulties in dominant parietal tasks (eg, calculation and spelling) and right by asking an individual to
describe a complex picture;
parietal function (eg, copying complex figures or clock drawing).
rather than describing it in
On additional testing, a marked discrepancy is often seen between patients’ its entirety, individuals with
ability to read single letters and short words compared to blocks of texts as they posterior cortical atrophy
will often get lost moving from word to word or line to line (FIGURE 3-2 35); this will often hone in on specific
features and fail to see the
may improve if they are allowed to use a finger to track. Simultanagnosia (the
picture as a whole.
inability to interpret the entirety of a visual scene) can often be demonstrated by
asking an individual to describe a complex picture; rather than describing it in ● A particularly striking and
its entirety, individuals with PCA will often hone in on specific features and fail very common feature of
to see the picture as a whole. This can be demonstrated on a research basis using posterior cortical atrophy is
the presence of an
eye tracking (FIGURE 3-3). A particularly striking and very common feature of apperceptive agnosia.
PCA is the presence of an apperceptive agnosia. This can be easily demonstrated
by showing patients degraded letters (FIGURE 3-4 36), numbers, or objects, which ● Visual disorientation
they typically cannot make sense of, and then showing them the same letters in (likely reflecting
combinations of
completed form, which they can recognize. Right parietal dysfunction can also be
simultanagnosia and optic
demonstrated through difficulties in dot counting, line bisection, or clock drawing. ataxia), when present, is a
Dominant parietal dysfunction can be demonstrated through bedside tests of striking sign in patients with
calculation and spelling, although these should be administered verbally. Similarly, posterior cortical atrophy.
when testing for apraxia, to exclude problems solely related to visual difficulties,
patients should be asked, for example, to put their thumb on their ring finger or to
salute, rather than asking them to copy the examiner’s hand movements.
Visual disorientation (likely reflecting a combination of simultanagnosia and
optic ataxia), when present, is a striking sign. The patient is seated in front of the
examiner and asked to concentrate on the examiner’s nose, as would be done
with visual field testing. The patient is instructed to reach out and take the
examiner’s moving hand in the patient’s peripheral vision. Typically, a patient
with PCA will be able to see the hand and will often copy the hand movements
but will have difficulties locating the examiner’s hand in space (VIDEO 3-1, links.
lww.com/CONT/A266). This phenomenon may be much more apparent
in one hemifield than the other or may be present in both and is often present in
central vision, distinguishing the misreaching in PCA from classic optic ataxia.
In more advanced cases, the patient will reach instead toward the examiner’s tie
(the tie sign) or face instead of reaching for the target hand.
NEUROLOGIC EXAMINATION
In patients with typical PCA due to AD, aside from demonstrating the higher-order
visual signs and dyspraxia described above, the neurologic examination is typically
unremarkable, although, as mentioned, a proportion of individuals will have mild
motor signs or myoclonus.31 Specific features that should be assessed include the
presence of significant parkinsonism, which may reflect underlying Lewy body
pathology, and very asymmetric motor features (dystonia, dyspraxia, myoclonus,
and alien limb), which might reflect a corticobasal syndrome. Patients will not
typically have upper motor neuron signs or features of amyotrophy. Watching
the patient walk may be very informative, as mild balance problems are not
infrequently encountered by patients with PCA, and the functional consequences

FIGURE 3-2
Eye tracking demonstrates preserved reading in typical Alzheimer disease (tAD) (A) and
impaired reading in posterior cortical atrophy (PCA) (B, C). Blue arrows outline reading order,
red arrows indicate omission of subsequent words through reading later sections of text, and
yellow arrows indicate reading of earlier sections of text. Transcripts of the participants'
corresponding spoken output are beneath each example (italicized text). Each hyphen in the
transcript beneath each example indicates a pause of 3 seconds. Numbers refer to where
words were repeated.
Reprinted with permission from Yong KX et al, Neurology.35 © 2015 American Academy of Neurology.
58 FEBRUARY 2019

FIGURE 3-3
Visual dysfunction in posterior cortical atrophy (PCA). Eye tracking studies in healthy
individuals (A) and patients with PCA (B) demonstrate simultanagnosia in PCA. Circles represent
fixation locations and circle size (and corresponding figure in milliseconds) indicates fixation
durations. Individuals with PCA fixate on prominent features initially (eg, the dome on the
pier) but subsequently fixate on relatively uninformative aspects of the scene (eg, the sea or
sky), missing important contextual details (eg, the beachfront or near the end of the pier).
Reprinted from Crutch SJ, et al, Lancet Neurol.1 © 2012 Elsevier Ltd.
of higher-order visual problems may be demonstrated if patients bump into walls

or doorframes while walking.
INVESTIGATIONS
While a syndromic diagnosis of PCA is usually apparent on the basis of the
history and bedside examination, investigations can provide additional
evidence for both the extent and nature of the cognitive and visual deficits and
for the underlying causal pathology.

Visual Fields
While formal ocular assessment
performed carefully can
demonstrate normal acuity and
fundi, visual field testing in PCA
FIGURE 3-4 often reveals hemifield
Fragmented letters. Individuals with posterior impairments or constriction,37
cortical atrophy will often be able to read individual including unusual and variable
letters, but not when they are presented in field deficits not confirming to
degraded form (apperceptive agnosia).
Reprinted with permission from Warrington EK.36
classic cortical lesions,38 which
© 2010 National Hospital, Institute of Neurology. can be mistaken as being
nonorganic (FIGURE 3-5).
Neuropsychology
Detailed neuropsychological
assessment provides objective
evidence for the cognitive
domains that are both affected
and preserved in PCA, with
implications for diagnosis and
potentially for management. A
standard neuropsychometric
battery can be employed in
patients with PCA but with a
few caveats. It is important that
the testing psychologist is aware
of the individual’s difficulties
with vision, ensuring that test
material is, whenever possible,
presented in verbal rather than
visual form (eg, nominal skills
may be better determined by
naming to description than to a
picture). Similarly, assessment of
premorbid IQ based on reading
words from the National Adult
Reading Test39 may or may not
be reliable depending on the
extent of visual impairment.
Patients with PCA typically
show a marked discrepancy
between performance IQ (low)
and verbal IQ and deficits in
parietal tasks with preservation
FIGURE 3-5
Visual fields in posterior cortical atrophy. In of memory and executive tests,
patient 2 and patient 10, visual field deficits are provided that imagery and other
principally limited to a hemifield; in patient 3 and deficits are taken into account
patient 4, both hemifields are affected to some (eg, recognition memory
extent.
Reprinted from Millington RS, et al, Neuroimage Clin.38 performance may remain
© 2017 The Authors. preserved when recall appears
60 FEBRUARY 2019

impaired) (FIGURE 3-6 40). On this basis, neuropsychological research criteria for KEY POINTS
PCA have been described that require, for example, evidence for impairments
● When performing
(performance at less than the 5th percentile) on at least two out of four parietal neuropsychological testing
tests (object perception, space perception, calculation, spelling) with evidence of in posterior cortical atrophy,
preservation (greater than the 5th percentile) on a recognition memory test, in it is important that the
addition to fulfilling clinical criteria.41 testing psychologist is aware
of the patient’s difficulties
with vision, ensuring that
Structural Imaging test material is, whenever
As the name of the condition implies, most individuals with PCA will have possible, presented
prominent volume loss reflecting neuronal tissue loss in posterior brain in verbal rather than
visual form.
regions (FIGURE 3-7). On a group level, numerous studies have confirmed
reductions in parietal and occipital volume and thinning in these regions in ● In the presence of a
patients with PCA compared with both controls and patients with typical typical history for posterior
AD.41,42 In practice, posterior volume loss is very clear in some cases, but cortical atrophy, the
others with very clear symptoms can have little volume loss, made more absence of marked
parietooccipital volume
difficult to discern by natural variability of parietal lobe anatomy. Volumetric loss should not exclude
T1-weighted acquisitions in the coronal plane supplemented by sagittal views the diagnosis.
are often best for appreciating the distribution and extent of atrophy, and
visual rating scales such as those introduced by Koedam and colleagues43 may
be helpful in providing an objective measure of parietal volume loss
(FIGURE 3-8). However, in the presence of a typical history for PCA, the
absence of marked parietal volume loss should not exclude the diagnosis.
Hippocampal volumes are typically relatively preserved in PCA compared to
typical AD dementia, in keeping with the relative preservation of episodic
memory. It is also important to exclude vascular disease, inflammation, and
mass lesions within the posterior cortices, which can mimic neurodegeneration;
when Creutzfeldt-Jakob disease is possible, diffusion-weighted imaging (DWI)
may be very helpful, typically showing cortical ribboning in occipital lobes in the
Heidenhain variant (FIGURE 3-9).19
FIGURE 3-6
Pattern of cognitive impairment in typical Alzheimer disease (A) and posterior cortical
atrophy (B). Increasing impairment in a cognitive domain is represented by retreat of the color
in its segment toward the center of the circle. Thus, verbal and nonverbal memory are
profoundly affected in panel A but relatively preserved in panel B, while profound posterior
cortical impairment is seen in panel B.
Modified with permission from Warren JD, et al, Nat Rev Neurol.40 © 2012.

FIGURE 3-7
Typical MRI in posterior cortical atrophy. Sagittal (A) and coronal (B) MRIs show marked
parietal lobe volume loss.
Functional Imaging
In cases in which the clinical phenotype of PCA is clear and posterior atrophy
is seen on MRI, further imaging is not typically required. However, in
equivocal cases, fludeoxyglucose positron emission tomography (FDG-PET)
may be extremely valuable in demonstrating hypometabolism within the
parietooccipital cortices,44,45 which is typically more extensive than the
pattern of atrophy and may be seen earlier than structural changes are
apparent (FIGURE 3-10). While not in routine clinical use, arterial spin labeling
MRI (which provides a measure of cortical blood flow) may provide similar
information, albeit reflecting blood flow rather than metabolism.46
Molecular Imaging
As patients with PCA, by definition, have atypical disease and almost all present
with early-onset dementia, most will fall within appropriate use criteria for
amyloid PET imaging.47 Where available, amyloid PET can provide invaluable
evidence for underlying AD. However, in contrast to the striking focality both
of the symptom and structural imaging changes, amyloid deposition is usually
seen across the cortex, with amyloid PET scans from patients with PCA often
being indistinguishable from patients with more typical forms of AD.45,48 Thus,
while amyloid PET has a role in defining pathology, it is not useful in defining
AD syndromes. By contrast, tau PET scanning, which is currently only available
in a research setting, often shows very striking posterior cortical deposition of
tau pathology in PCA (FIGURE 3-11).49
Cerebrospinal Fluid
In keeping with PCA usually being underpinned by AD, CSF amyloid-β (Aβ)1-42 is
depressed and concentrations of total tau and phosphorylated tau are increased.
However, while levels of Aβ1-42 depression are similar to other forms of AD,
some evidence indicates that levels of total tau and phosphorylated tau are not
62 FEBRUARY 2019

KEY POINTS
● Fludeoxyglucose positron
emission tomography may
be extremely valuable
in demonstrating
hypometabolism within the
parietooccipital cortices.
● While amyloid positron

emission tomography has a
role in confirming the
presence or absence of
amyloid pathology, it is not
useful in distinguishing
between Alzheimer
disease syndromes.
● Tau positron emission

tomography, which is
currently only available in a
research setting, often
shows very striking posterior
cortical deposition of
tau pathology.
● Posterior cortical atrophy

due to Alzheimer disease is a
sporadic condition, and
routine testing for the
autosomal dominant forms
of the disease is not
usually indicated.
FIGURE 3-8
Visual rating scale for the posterior brain regions. In sagittal, axial, and coronal orientation,
this rating scale rates atrophy as follows: 0 = no atrophy, 1 = minimal atrophy, 2 = moderate
atrophy, and 3 = severe atrophy.
PAR = parietal lobe; PCS = posterior cingulate sulcus; POS = parietooccipital sulcus; PRE = precuneus.
Reprinted with permission from Koedam EL, et al, Eur Radiol.43 © 2011 The Authors.
as elevated as in typical AD, perhaps relating to either different intensities or

extent of neurodegeneration.50 In practice, therefore, clinicians should be aware
that tau to Aβ1-42 ratios may be less elevated in PCA than in typical AD. As with
other forms of AD, the total cell count and protein are not elevated; if these are
seen, other diagnoses should be considered.
Genetic Testing
PCA due to AD is a sporadic condition, and routine testing for the autosomal
dominant forms of the disease is not usually indicated. Testing for APOE
genotyping is not recommended as part of the diagnostic workup for any form
of AD, and this is particularly the case for PCA, in which evidence indicates

that possession of an APOE ε4 allele may

be less frequent than in typical cases.9
DIAGNOSTIC CRITERIA
Original diagnostic criteria from Mendez
and colleagues15 and Tang-Wai and
colleagues5 have been recently updated
with the 2017 international consortium
criteria (TABLE 3-1).8 These updated
criteria describe a three-level
classification. Level 1 describes the core
clinical, cognitive, and neuroimaging
features and exclusions, ie, the
clinicoradiologic syndrome. Level 2
FIGURE 3-9
distinguishes between a PCA-pure
Cortical ribboning in Heidenhain variant syndrome and, allowing for individuals
of Creutzfeldt-Jakob disease. Axial who also fulfill criteria for another
diffusion-weighted 1.5T MRI shows neurodegenerative syndrome, a PCA-plus
right occipital lobe cortical ribboning
(arrow) in a patient presenting with the
categorization. Level 3 classifies patients
Heidenhain phenotype, which can with PCA attributable to a specific
clinically resemble posterior cortical underlying disease (eg, PCA due to AD,
atrophy. PCA due to Lewy bodies, PCA due to
Reprinted with permission from Townley RA,
19
et al, Neurocase. © 2018 Information UK
corticobasal degeneration, or PCA due to
Limited. prion disease) based on the availability
of biomarkers (or histopathologic
assessment at autopsy) that can define the
underlying pathology. This classification aims also to be complementary to the
diagnostic classifications for AD, which increasingly recognize PCA as an atypical
form of AD,51,52 providing a framework that can be adapted for different purposes.
Thus, for providing appropriate support to individuals, the underlying pathology
may be less relevant than the clinical picture, while for research studies aiming to
determine the causes of phenotypic heterogeneity, it may be important to classify
patients on the basis of both syndrome and pathology.
MANAGEMENT
While much of the management of PCA is similar to that for typical AD, the
dominant visual problems encountered by most patients mean that some specific
issues require consideration.
Medical Treatment
Pharmacologic treatments for PCA should be directed to the underlying
pathologic substrate. For most patients with PCA due to AD, treatment with
acetylcholinesterase inhibitors or memantine, as would be standard treatment
for AD, is appropriate. While pivotal clinical trials for the licensing of these drugs
focused on typical amnestic AD, individual reports have shown that patients
with PCA also benefit.53
Progressive visual impairment and increasing dependence emerging in the
face of intact insight often results in significant anxiety, depression, and feelings
of guilt.32 While no controlled trials have been conducted, anecdotal evidence
suggests that patients may benefit from counseling and other psychological
64 FEBRUARY 2019

KEY POINT
● For most patients with

posterior cortical atrophy
due to Alzheimer disease,
treatment with
acetylcholinesterase
inhibitors or memantine, as
would be standard
treatment for Alzheimer
disease, is appropriate.
FIGURE 3-10
Multimodal imaging in posterior cortical atrophy (PCA). Single-participant axial images for
one control participant and five patients with posterior cortical atrophy showing cerebral
blood flow (CBF) (arterial spin labeling [ASL]), glucose metabolism (fludeoxyglucose positron
emission tomography [FDG-PET]), atrophy (structural MRI), and amyloid deposition
(florbetapir PET). Amyloid deposition varies between individuals but is distributed
throughout the cortex in all. Cerebral blood flow, hypometabolism, and atrophy are, by
contrast, all restricted to posterior cortical areas.
f = female; m = male; SUVR = standardized uptake value ratio.
Reprinted with permission from Lehmann M, et al, J Neurol Neurosurg Psychiatry.46
© 2016 British Medical Journal.
FIGURE 3-11
Tau imaging in posterior cortical atrophy. [18F]Flortaucipir positron emission tomography
(PET) imaging reveals focal parietooccipital tau pathology.
SUVR = standardized uptake value ratio.

TABLE 3-1 Core Features of the Posterior Cortical Atrophy Clinicoradiologic Syndromea,b
Clinical Features
◆ Insidious onset
◆ Gradual progression
◆ Prominent early disturbance of visual with or without other posterior cognitive functions
Cognitive Features
◆ At least three of the following must be present as early or presenting features with or
without evidence of their impact on activities of daily living
◇ Space perception deficit
◇ Simultanagnosia
◇ Object perception deficit
◇ Constructional dyspraxia
◇ Environmental agnosia
◇ Oculomotor apraxia
◇ Dressing apraxia
◇ Optic ataxia
◇ Alexia
◇ Left/right disorientation
◇ Acalculia
◇ Limb apraxia (not limb-kinetic)
◇ Apperceptive prosopagnosia
◇ Agraphia
◇ Homonymous visual field defect
◇ Finger agnosia
◆ All of the following must be evident
◇ Relatively spared anterograde memory function
◇ Relatively spared speech and nonvisual language functions
◇ Relatively spared executive functions
◇ Relatively spared behavior and personality
Neuroimaging
◆ Predominant occipitoparietal or occipitotemporal atrophy/hypometabolism/
hypoperfusion on MRI/FDG-PET/SPECT
Exclusion Criteria
◆ Evidence of a brain tumor or other mass lesion sufficient to explain the symptom
◆ Evidence of significant vascular disease including focal stroke sufficient to explain the symptoms
◆ Evidence of afferent visual cause (eg, optic nerve, chiasm, or tract)
◆ Evidence of other identifiable causes for cognitive impairment (.g, renal failure)
FDG-PET = fludeoxyglucose positron emission tomography; MRI = magnetic resonance imaging; SPECT =
single-photon emission computed tomography.
a
Reprinted from Crutch, et al, Alzheimers Dement.8 © 2017 The Authors.
b
Clinical, cognitive, and neuroimaging features are rank ordered in terms of (decreasing) frequency at first
assessment as rated by online survey participants.8
66 FEBRUARY 2019

approaches and from standard pharmacologic treatments for mood and anxiety KEY POINTS
(eg, with selective serotonin reuptake inhibitors [SSRIs]). When myoclonus
● The mainstay of
emerges and becomes problematic, small doses of levetiracetam may be helpful. management of patients
with posterior cortical
Nonpharmacologic Treatments atrophy (as with typical
In the absence of disease-modifying therapies, the mainstay of management Alzheimer disease) is the
provision of practical and
of patients with PCA (as with typical AD) is the provision of practical and
psychological support to
psychological support to affected patients and their caregivers. Even in the affected patients and
absence of specific therapies, an accurate diagnosis is a vital staging point in an their caregivers.
individual patient’s journey, not least as diagnosis is often delayed and symptoms
overlooked, misinterpreted, or ignored for many years. Most patients will have ● Most patients with
posterior cortical atrophy
stopped, or been stopped from, driving by the time a diagnosis is made, but will not be fit to drive.
determining whether patients with PCA are fit to drive is clearly of Establishing driving safety is
paramount importance. of paramount importance.
The major functional problems in PCA involve everyday skills and self-care.54
Loss of ability to read may be helped with the provision of audio books.
Technologic advances such as voice recognition on smartphones, computers, and
mobile devices can be invaluable in maintaining an individual’s independence.
Specific apps have been developed to help the reading problems in PCA, moving
text into the individual’s central vision at an appropriate speed and thus avoiding
the need to make saccadic movements from word to word (refer to the Useful
Websites section).35 When out of the home, the provision of a white cane is a
simple measure that ensures that others are aware of the patient’s potential
impairments. Within the house, measures to help with identification of objects
and navigation (eg, by putting colored tape on doorframes) or labeling specific
items may be helpful. As the disease progresses, home adaptions to minimize
stair use and help with bathing and washing may be required. Involving a
multidisciplinary team with occupational and physical therapy is often invaluable.
Practical tips for patients with PCA and their families are summarized in
TABLE 3-2. The relative rarity of PCA can lead to isolation. The development of
55
specific support groups for these individuals locally and, increasingly, nationally
and internationally can provide a valuable source of support to individuals and
their families (for more information, refer to the Useful Websites section).
FUTURE DIRECTIONS
PCA has the potential to provide invaluable insights into the factors underpinning
the development of AD generally and the factors influencing phenotypic
diversity.56 It is unknown, for example, why patients develop these symptoms
on a sporadic basis and at a considerably younger age than patients with typical
AD. The single biggest genetic study in AD confirmed that possession of an
APOE ε4 allele was a risk factor for PCA but conferred less risk than for typical
AD. This study highlighted a number of genes that may potentially influence
risk, some of which are implicated in neurodevelopment.9 A 2018 study has also
provided evidence that patients with PCA are more likely to report nonlanguage
mathematical and visuospatial learning disabilities compared to patients with
typical AD and controls.57 From a pathologic perspective, emerging evidence
shows different strains of Aβ in PCA compared to typical AD, raising the
suggestion that different forms of Aβ may propagate through different brain
networks and associate with different forms of the disease.58 These findings,
while in their infancy, may in time provide a more detailed understanding

TABLE 3-2 Home Safety Tips and Recommendations for Patients With Posterior
Cortical Atrophy and Other Dementias With Visual Dysfunctiona
General Environment
◆ Simplify the environment
◇ Remove clutter and objects no longer in use; keep pathways clear
◇ Remove unsafe furniture and accents (eg, low-height stools, chairs, or tables)
◇ Options to decrease the potential falls risk from scatter rugs and doormats:
→ Remove unsafe scatter rugs/mats
→ Install nonslip underpadding
→ Replace with rugs/mats with a rubber backing
→ Secure all edges with double-sided carpet tape (not for outdoor use)
◇ Relocate and secure trailing cords that are in high-traffic areas
◇ Ensure adequate lighting: use night-lights, install extra light fixtures
◇ Leave lights on before nightfall
◇ Diffuse bright light areas; reduce glare by covering windows with blinds, shades, or sheer
curtains to block direct bright sunlight; avoid using bare light bulbs without shades
◇ Obtain a door alarm and/or safety lock
◇ Place stickers on large glass windows or large glass doors to prevent people from
bumping or walking into to them
◆ Increase contrast
◇ Label room doors; use yellow paper with black writing
◇ Paint doorframes and light switch plates in a contrasting color to the wall
◇ Use a contrasting color dot to mark the number/button to release automatic door
◇ Use contrasting color strips (paint or tape) or tactile cue at top and bottom of stairs as well
as on the edge of each individual step (both inside and outside)
◇ Use contrasting color adhesive strips to mark pathways to important areas: bathroom,
kitchen, living room, laundry
Kitchen
◆ Mark burners and stove dials with contrasting color to make them easier to identify and to
know when elements are hot
◆ Dials at the front of the stove are more desirable than dials at the back of the stove to
avoid reaching over the elements
◆ Mark frequently used settings on the oven or other dials (eg, 350° or normal cycle for the
dishwasher) with a bumper dot or contrasting tactile marker
◆ Supervise patients while they are using the stove, and, if necessary, disconnect the stove
and other appliances when they are home alone
◆ Mark the 1-minute button on the microwave with a contrasting color bumper dot, tactile
marker, bright tape, or nail polish
◆ Place cleaning supplies away from food supplies (very important)
◆ Dispose of hazardous substances that are no longer needed and store other potentially
hazardous substances in secured storage (locked cupboard, childproof door locks)
68 FEBRUARY 2019

◆ Keep cupboard doors and drawers closed at all times and ensure everything is put away in
its proper place
◆ Problem-solve an appropriate organizational structure to the kitchen; consider having one
designated area of counter space for preferred and usual foods; trial placing frequently
used items on a contrasting mat or tray located in the same place every day to increase
independence in finding items and participating in meal preparation
◆ Store/relocate frequently used items at accessible and visible level
◆ Keep counters clear and minimize clutter
◆ Consider using appliances with automatic shutoff (eg, kettle)
◆ Use other items to optimize safety, independence, and participation in the kitchen:
◇ Elbow-length oven mitts to ensure maximum protection
◇ Knife guard aid to enable safe use and pressure when cutting
◇ Cutting board with a black side and a white side to enhance contrast while cutting
◇ Gooseneck lamp above the cutting area may also assist with vision
◇ Large-print timer
◇ Liquid measure tool to assist in pouring liquids and avoiding spills
◇ Relabel jars and canned goods using a thick black marker, white recipe card, single words,
and elastic bands
◇ Audio labeler
Eating
◆ Use brightly colored contrasting dishes and ensure they are all one solid color (no patterns
and no ridged edges)
◆ Use a dark solid-color placemat if using light-colored plates and use a light solid-color
placemat if using dark plates
◆ Light-colored food will be easier to see on a solid dark-colored dish and dark food on a
light dish
◆ Avoid patterned tablecloths
◆ Maintain a strict pattern for mealtime setup (eg, always place the same utensils, drinking
glass, and condiments in the same place for every meal)
◆ Avoid cluttering the eating area and only have necessary items within reach
◆ Use verbal directions as reminders of where items are located (eg, “your glass is on your
right” and “salt and pepper are on your left”)
◆ Use plate guards during mealtimes
Bedroom
◆ Use bright, contrasting-color fitted sheet, top sheet, pillowcases. Each should be a
different color to optimize identification and orientation to and within the bed
◆ Place a brightly colored mat on nightstand to contrast with items placed on it

Dressing
◆ Label drawers and shelves with high-contrast wording or pictures
◆ Remove clothes that are no longer being used, including permanent removal of clothes no
longer worn and temporary storage of out-of-season clothing
◆ Simplify and organize arrangement of clothing (eg, group similar items together, one
drawer for shirts and another drawer for pants)
◆ Lay out clothing for the day
◆ Minimize clothing requiring buttons and zippers and replace with elastic waists,
pull-over/on, and loose clothing
◆ Pin socks together when placing them in the laundry so they will stay matched
Bathroom
◆ Reduce clutter on bathroom floor, countertop, in drawers and cabinets.
◆ Use high-contrast nonslip bath mat and install high-contrast grab bars in the shower or
bathtub; use contrasting tactile strip on existing grab bars to differentiate from tub or
towel bar
◆ Pick up bath mat after each use and store appropriately to prevent falls
◆ If difficulty in accurately locating the toilet is noted, consider obtaining a toilet seat in a
contrasting bright color; also consider obtaining a raised toilet seat with arms and then
taping arms with a bright color that contrasts with the toilet seat
◆ Tape toilet-flushing handle in a contrasting bright color
◆ Label important areas in the bathroom: toilet, sink, bathroom door (yellow paper with
black writing).
◆ Tape sink faucet handles with brightly colored tape (use color such as red, green, blue) to
distinguish handle from the rest of the sink
◆ Keep soap in a bright container (eg, red) with contrasting color soap (eg, white)
◆ Use sign as reminder to wash hands, flush toilet, brush teeth
◆ Keep frequently used items (toothbrush, toothpaste) in small shallow basket or on a mat to
contrast items against the counter
◆ Use toothpaste that contrasts in color to the toothbrush and bristles (eg, red toothpaste on
white brush and bristles)
◆ Cover mirrors if necessary; often people with vision problems may not be able to
recognize the item as a mirror
Personal Care
◆ Ensure nail care is done by a professional; can be provided in-home
◆ Ensure appropriate footwear is used: flat, nonslip sole, enclosed toe and heel, Velcro
fasteners
70 FEBRUARY 2019

Medication Routine
◆ Supervision of medication routine is usually recommended
◆ Store medications in a secure place
◆ Remove and properly dispose of medications that are no longer needed or have expired
◆ Inquire whether the medication routine can be simplified (eg, to once a day instead of 3
times a day)
◆ Other ways to simplify a medication routine: prefilled blister packs, dosette; list of current
medications, medication schedule, medication alarms/reminders
Stairs
◆ Ensure adequate lighting on the stairs, with switches at both the top and bottom
◆ Install secure railings on one or both sides
◆ Install railing extensions beyond the top and bottom of the stairs
◆ Remove or replace unsafe flooring with a nonslip surface
◆ Contrasting-color tape or paint on the edge of each step
◆ Contrasting-color tape or paint and/or tactile strip at the top and bottom of the stairs
◆ With progression:
◇ Safety gate to prevent use of stairs
◇ Arrange living area on one level
Communication and Scheduling
◆ Use a phone with large print and high-contrast numbers as well as one-touch
programmable numbers
◆ Program emergency and frequently used numbers to the one-touch programmable
numbers and add tactile markers to increase ease of identification
◆ Set up a “memory center,” with the phone, keys, note pad, whiteboard with large writing
area, and black marker
◆ Include a paper, pen/pencil, and task lamp beside the phone for messages
◆ Place telephone on a bright contrasting-color mat
◆ Use contrasting-color tape to outline the phone cradle
◆ If possible, utilize a service that requires voice activation for phone dialing
◆ Use talking watches or clocks to indicate the time and appointments
a
Reprinted with permission from Lake A, et al, UHN Multidisciplinary Memory Clinic, University of Toronto.55

of the mechanisms underlying the development of both PCA and typical AD and
lead to the development of new and more specific treatments of these conditions.
CONCLUSION
PCA is a rare but important neurodegeneration syndrome typically underpinned
by AD. Patients with this condition are often diagnosed late or are misdiagnosed
as having a primary ocular or psychologically mediated illness. Recognition of
PCA as a distinct syndrome and determination of its underlying cause allow for
appropriate nonpharmacologic and pharmacologic treatments to be instigated
and for appropriate support to be provided for patients and families. PCA
provides a valuable paradigm for exploring the causes of phenotypic
heterogeneity in AD.
ACKNOWLEDGMENT
This work was supported by a grant from the Economic and Social Research
Council-National Institute for Health Research (ES/L001810/1).
VIDEO LEGEND
VIDEO 3-1
Visual disorientation in posterior cortical
atrophy. A 77-year-old man with posterior
cortical atrophy. The patient is asked to fixate
on the examiner’s face and to reach out and take
the examiner’s moving hand. The patient is able
to see the moving hand (which he imitates) but
has major difficulties in locating it in space.
links.lww.com/CONT/A266
© 2019 American Academy of Neurology.
USEFUL WEBSITES
POSTERIOR CORTICAL ATROPHY SUPPORT USA READ-CLEAR
Posterior Cortical Atrophy Support USA is a website Read-Clear is an app designed to help reading in
run by caregivers for and supporters of patients patients with posterior cortical atrophy and related
with posterior cortical atrophy. disorders.
pinterest.co.uk/pcasupportusa/ readclear.co.uk
RARE DEMENTIA SUPPORT

Rare Dementia Support is a UK website that
provides a rich support of information for patients
with posterior cortical atrophy and their caregivers.
raredementiasupport.org/pca
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DISCLOSURE
Continued from page 52
Alzheimer’s Society, (AS-PG-14-022), The Dunhill

Medical Trust (R337/0214), the Economic and Social
Research Council-National Institute for Health
Research (ES/L001810/1), and the Engineering and
Physical Sciences Research Council
(EP/M006093/1).

REVIEW ARTICLE
Behavioral Variant
Frontotemporal

Dementia
ONLINE
By William W. Seeley, MD
ABSTRACT
PURPOSE OF REVIEW: This article describes the clinical, anatomic, genetic,
and pathologic features of behavioral variant frontotemporal dementia
CITE AS:
(bvFTD) and discusses strategies to improve diagnostic accuracy,
CONTINUUM (MINNEAP MINN) emphasizing common pitfalls to avoid. Key aspects of management and
2019;25(1, DEMENTIA):76–100. the future of diagnosis and care for the disorder are highlighted.
Dr William Seeley, 675 Nelson RECENT FINDINGS:BvFTD is a clinical syndrome, not a disease. Patients
Rising Ln, San Francisco, CA with the syndrome share core symptoms that reflect degeneration within
94158, bill.seeley@ucsf.edu. the most consistently affected brain regions, but accompanying features
RELATIONSHIP DISCLOSURE: vary and reflect the precise topography of regional degeneration. The
Dr Seeley serves on the clinician must distinguish a bvFTD syndrome from psychiatric illness
editorial boards of Acta
Neuropathologica, Annals of
and other neurodegenerative syndromes that feature a prominent
Neurology, and NeuroImage: behavioral component. Antemortem prediction of pathologic diagnosis
Clinical and as a consultant for remains imperfect but improves with careful attention to the clinical
Biogen; Merck & Co, Inc; and
Third Rock Ventures, LLC.
details. Management should emphasize prevention of caregiver
Dr Seeley receives research/ distress, behavioral and environmental strategies, symptom-based
grant support from the Bluefield psychopharmacology, and genetic counseling.
Project to Cure FTD, the
National Institutes of Health/
National Institute on Aging SUMMARY: BvFTD is an important and challenging dementia syndrome.
(AG023501, AG019724), and the
Although disease-modifying treatments are lacking, clinicians can have a
National Institutes of Health/
National Institute of profound impact on a family coping with this disorder. Treatment trials are
Neurological Disorders and under way for some genetic forms of bvFTD. For sporadic disease, pathologic
Stroke (NS1104437, NS092474).
Dr Seeley has provided expert
heterogeneity remains a major challenge, and ongoing research seeks to
medical testimony on legal improve antemortem molecular diagnosis to facilitate therapeutic discovery.
cases related to violence in
patients with neuropsychiatric
illness.
INTRODUCTION
T
UNLABELED USE OF
PRODUCTS/INVESTIGATIONAL he behavioral variant of frontotemporal dementia (bvFTD) is a
USE DISCLOSURE: devastating neurodegenerative syndrome that most often arises in
Dr Seeley discusses the
midlife, with a mean age at onset around 58 years but a range from
unlabeled/investigational use of
medications for the treatment of the twenties to the nineties.1 Prevalence peaks in the early sixties at
behavioral variant frontotemporal about 13 per 100,000.2 The disorder belongs to a larger heterogeneous
dementia, none of which are
approved by the US Food and
class of clinical syndromes, the frontotemporal dementias, which are united by
Drug Administration. their links to underlying frontotemporal lobar degeneration (FTLD) pathology.
BvFTD, in which social and emotional functions slowly decline, is the most
© 2019 American Academy common frontotemporal dementia (FTD) syndrome, accounting for roughly 50%
of Neurology. of all FTD patients.1
76 FEBRUARY 2019

As a species, humans vary widely in their social-emotional aptitudes. KEY POINTS
Behaviors that represent a drastic change for one person may represent the
● Behavioral variant
baseline personality quirks, routine indiscretions, or stress responses of frontotemporal dementia
another. BvFTD symptoms also overlap with those seen in psychiatric diseases, (bvFTD) is an important
creating further challenges for clinicians seeking to make an early bvFTD disorder than can be
diagnosis. By the time a patient is cognitively impaired, care must be taken to difficult to recognize, in part
because of the wide
distinguish bvFTD from other neurodegenerative disorders, most often an
normative variation in
Alzheimer-type dementia, in which prominent frontal/neuropsychiatric social-emotional functions
features can arise. Attention to the clinical details, family history, neurologic and the long list of disorders
signs, neuropsychology, and brain imaging can help neurologists navigate the that affect those functions.
diagnostic landscape for patients with a prominent behavioral change in mid
● BvFTD is a syndrome, not
to late life. a disease, and clinicians who
Upon reaching a bvFTD syndromic diagnosis, the clinician must formulate a diagnose bvFTD should
pathologic differential diagnosis. The list of potential causes includes all the many generate a differential
distinct FTLD histopathologic subtypes as well as Alzheimer disease (AD) and, diagnosis.
rarely, other neurodegenerative diseases. Although only autopsy can identify the ● BvFTD presents with
specific cause, narrowing the list during a patient’s life can inform prognosis, slowly progressive decline
render some costly diagnostic tests unnecessary, influence genetic testing and in social and emotional
counseling, and guide psychopharmacologic treatment and referral to clinical functions.
trials. Indeed, the advent of molecule-specific therapies will require that the
● BvFTD core diagnostic
specific cause of a patient’s bvFTD is identified during life and early enough in features reflect
the course to make intervention desirable. degeneration of networked
structures, typically
CLINICAL AND ANATOMIC FEATURES including the anterior insula,
anterior cingulate and
The early manifestations of bvFTD are subtle, insidious, rarely reported by the adjacent medial prefrontal
patient, and often mistaken for a “midlife crisis” or depression or other psychiatric cortices, amygdala,
illness.3 Recurrent job loss and unanticipated marital discord are common. These striatum, and thalamus.
outcomes stem from bvFTD’s central features: (1) loss of motivation toward
previously valued interests and activities (ie, apathy) and (2) a loss of social grace,
resulting from deficits in response inhibition (ie, disinhibition) and compassion
(sympathy, empathy, and prosociality). Pervasive errors of omission and
commission result. Patients may abandon family duties; approach strangers
(including children) with unwanted questions or other interpersonal boundary
violations; or tactlessly comment on others’ weight, attractiveness, or position in
a social hierarchy. A spouse’s major life events (eg, cancer diagnosis, death in the
family, job loss) may be ignored or trivialized. Other common features include
repetitive and compulsive or even ritualistic behaviors, a predilection for sweets,
and relentless overeating. These behavioral features are the most critical to
diagnosis and form the heart of prevailing bvFTD clinical diagnostic criteria
(TABLE 4-1).4 Research on brain-behavior relationships in bvFTD has clarified
important aspects of human social and emotional function, ranging from
emotion reactivity and regulation to autonomic, nociceptive, reward, and error
processing. For further reading, reviews focusing on this rich literature
are available.5–8
What neurodegenerative anatomic lesion gives rise to the core bvFTD features?
The earliest9 and most consistent10 atrophy in bvFTD, regardless of the underlying
cause,11 involves the anterior cingulate cortex (pregenual and subgenual), anterior
insula (ventral [ie, frontoinsular] and dorsal), striatum, amygdala, hypothalamus,
and thalamus. These interconnected brain regions form a salience network in
humans that represents the homeostatic relevance (ie, salience) of ambient

BEHAVIORAL VARIANT FRONTOTEMPORAL DEMENTIA
internal and external stimuli so that appropriate visceral-emotional-autonomic,

behavioral, and cognitive responses can be deployed (FIGURE 4-1).12 For success in
social contexts, these diverse brain resources must be mobilized in a dynamic,
time-sensitive manner that is tuned in response to rapidly evolving conditions.
Perhaps not surprisingly, then, the system can break down in multiple distinct
ways yet still manifest as bvFTD. As in all of neurology, how the system breaks
depends on where it breaks, and where it breaks can help determine or predict the
specific underlying disease process.
TABLE 4-1 Research Criteria for Behavioral Variant Frontotemporal Dementiaa
Possible Behavioral Variant Frontotemporal Dementia (bvFTD)

Three of the following as persistent or recurrent features:
A Early behavioral disinhibition
B Early apathy or inertia
C Early loss of sympathy or empathy
D Early perseverative, stereotyped, or compulsive/ritualistic behavior
E Hyperorality and dietary changes
F Neuropsychological profile: executive/generation deficits with relative sparing of
memory and visuospatial functions
Probable bvFTD
All of the following:
A Meets criteria for possible bvFTD
B Exhibits significant functional decline (by caregiver report, Clinical Dementia Rating, or
Functional Activities Questionnaire)
C Imaging results consistent with bvFTD:
C1 Frontal and/or anterior temporal atrophy on MRI or CT
C2 Frontal and/or anterior temporal hypoperfusion or hypometabolism on PET or SPECT
bvFTD With Definite Frontotemporal Lobar Degeneration (FTLD) Pathology
All of the following:
A Meets Criterion A for probable bvFTD
B Histopathologic evidence of FTLD on biopsy or postmortem
C Presence of a pathogenic mutation known to cause FTLD
Exclusionary Criteria for bvFTD
Criteria A and B must be answered negatively for any bvFTD diagnosis. Criterion C can be
positive for possible bvFTD but must be negative for probable bvFTD:
A Pattern of deficits is better accounted for by other nondegenerative nervous system or
medical disorders
B Behavioral disturbance is better accounted for by a psychiatric diagnosis
C Biomarkers strongly indicative of Alzheimer disease or other neurodegenerative process
CT = computed tomography; MRI = magnetic resonance imaging; PET = positron emission tomography;
SPECT = single-photon emission computed tomography.
a
Modified with permission from Rascovsky K, et al, Brain.4 © 2011 The Authors.
78 FEBRUARY 2019

KEY POINTS
● Features that develop

less frequently in patients
with bvFTD reflect variable
involvement of additional
brain regions.
● Patients with bvFTD often

develop prominent motor
deficits of various types
later in the course of the
syndrome.
FIGURE 4-1
Network-patterned regional degeneration in behavioral variant frontotemporal dementia
(bvFTD). BvFTD results from several distinct neuropathologic causes. In the University of
California San Francisco Neurodegenerative Disease Brain Bank, the nine most common are
frontotemporal lobar degeneration with transactive response DNA-binding protein
43 (TDP-43)–immunoreactive inclusions (FTLD-TDP) Types A through C and unclassifiable,
Pick disease, corticobasal degeneration, progressive supranuclear palsy, atypical FTLD with
ubiquitin-immunoreactive inclusions (aFTLD-U), and Alzheimer disease. Overlap analysis
across these diverse diseases using voxel-based morphometry revealed core structures
atrophied in all nine (white shading, bottom row),11 which recapitulate the major nodes of the
salience network, defined using task-free functional MRI (fMRI) (top row).12
Top row reprinted from Seeley WW, et al, Neuroscientist.5 © 2012 SAGE Publications.
Beyond the core behavioral features, patients variably develop additional

symptoms and deficits that relate to degeneration in specific brain structures:
(1) distractibility, disorganization, mental rigidity, and other forms of executive
dysfunction (dorsolateral prefrontal cortex); (2) semantic loss, especially for
emotions and faces (right more than left anterior temporal lobe); (3) aphasia,
often manifesting as an abulic, adynamic aphasia (left anterior midcingulate
and presupplementary motor area); (4) memory loss (entorhinal-hippocampal
complex); and (5) motor impairment that may include parkinsonism (substantia
nigra, striatum), oculomotor control problems (frontal eye fields, dorsal
midbrain), or motor neuron disease (upper and lower motor neurons).
Uncommonly, but more often in inherited bvFTD, patients will develop some
combination of alexia, agraphia, acalculia, anomia, and visuospatial dysfunction
resulting from lateral posterior parietal involvement. Attention to these
additional features can be one key to making an accurate antemortem prediction
of the underlying neuropathology (TABLE 4-2).
GENETICS AND PATHOLOGY

BvFTD may result from any of the known FTLD-causing genetic mutations and
any of the myriad FTLD histopathologic subtypes as well as AD and (very rarely)

TABLE 4-2 Behavioral Variant Frontotemporal Dementia Symptom Characteristics
Symptom/Feature Anatomy Frequency Pathology Predicted

a
Apathy Medial frontal, anterior High (~80%) All
cingulate cortex
Disinhibitiona Ventral anterior insula, High (~80%) All

orbitofrontal
Repetitive/compulsive Ventral striato-pallidum High (~80%) All

behaviora
Change in eating Anterior insula, ventral High (~80%) All

behaviora striatum, hypothalamus
Loss of sympathy/ Anterior temporal, ventral Moderate (~50%) All

empathya anterior insula
Frontal-predominant Dorsolateral prefrontal Occasional (~30%) All

neuropsychological
deficitsa
Motor neuron disease Upper and lower motor Occasional (~30%) TDP-B, TDP, unclassifiable
neurons
Oculomotor control Dorsal midbrain, frontal Occasional (~25%) Progressive supranuclear

problems eye fields palsy, corticobasal
degeneration
Semantic loss for people, Anterior temporal Occasional (~20%) TDP-C>>Pick disease
emotions, words
Prominent episodic Entorhinal-hippocampal Low (<10%) TDP-A or TDP-B with

amnesia hippocampal sclerosis
Nonfluent or adynamic Left frontal operculum, Low (<10%) Corticobasal degeneration,

aphasia pre–supplementary motor progressive supranuclear
area/anterior cingulate palsy, Pick disease. or
cortex TDP-A/B
Alexia, agraphia, Lateral parietal Low (<10%) TDP-A (GRN or C9orf72),

acalculia, visuospatial TDP-B (C9orf72)
dysfunction
Onset before age 40 NA Low (<10%) aFTLD-U (FTLD-FUS) or

inherited FTLD
aFTLD-U = atypical FTLD with ubiquitin-immunoreactive inclusions; FTLD = frontotemporal lobar degeneration; FTLD-FUS = frontotemporal lobar
degeneration with fused in sarcoma–immunoreactive inclusions; NA = not applicable; TDP = frontotemporal lobar degeneration with transactive
response DNA-binding protein 43 (TDP-43)–immunoreactive inclusions; TDP-A = frontotemporal lobar degeneration with TDP-43-immunoreactive
inclusions Type A; TDP-B = frontotemporal lobar degeneration with TDP-43-immunoreactive inclusions Type B; TDP-C = frontotemporal lobar
degeneration with TDP-43-immunoreactive inclusions Type C.
a
Core criteria for behavioral variant frontotemporal dementia.4
80 FEBRUARY 2019

KEY POINT
● BvFTD is the result of a

known pathogenic variant in
15% to 20% of patients.
FIGURE 4-2
Genetic and pathologic spectrum of behavioral variant frontotemporal dementia (bvFTD).
Most patients with bvFTD show underlying frontotemporal lobar degeneration (FTLD)
pathology at autopsy. Color-coded bars within the bvFTD box depict the approximate proportion
of patients whose syndrome results from each of the neuro pathologic entities shown.
Embedded genetic causes of each pathologic diagnosis are shown in parentheses insofar as
the relevant diagnosis can also be seen in sporadic bvFTD. Conversely, for the genes not in
parentheses, the pathologic disease only results from a pathogenic variant in that gene.
3R = 3-repeat; 4R = 4-repeat; aFTLD-U = atypical frontotemporal lobar degeneration with ubiquitin-immunoreactive
inclusions; AGD = argyrophilic grain disease; BIBD = basophilic inclusion body disease; CBD = corticobasal
degeneration; CJD = Creutzfeldt-Jakob disease; CTE = chronic traumatic encephalopathy; FTLD =
frontotemporal lobar degeneration; FTLD-FUS = frontotemporal lobar degeneration with fused in
sarcoma–immunoreactive inclusions; FTLD-tau = frontotemporal lobar degeneration with tau-immunoreactive
inclusions; FTLD-TDP = frontotemporal lobar degeneration with transactive response DNA-binding protein
43 (TDP-43)–immunoreactive inclusions; FUS = fused in sarcoma; GGT = globular glial tauopathy; HDLS =
hereditary diffuse leukoencephalopathy with axonal spheroids; MST = multisystem tauopathy; ND =
neurodegenerative; NIBD = neurofilament inclusion body disease; NIFID = neuronal intermediate filament
inclusion disease; NOS = not otherwise specified; PSP = progressive supranuclear palsy.
other neurodegenerative disorders (FIGURE 4-2). For this reason, when first
gaining the impression that a patient may have a bvFTD syndrome, it is best to
keep all diagnostic possibilities in mind to guide further data collection. About
15% to 20% of bvFTD results from a mutation in a known disease-causing genetic
variant,2,13 and each of the major genes (MAPT, GRN, and C9orf72) is associated
with a slightly different bvFTD flavor.
With MAPT mutations, symptom onset typically occurs in midlife and
tends to be consistent within a given family. Presentation and tempo vary
according to the particular MAPT mutation. Most patients have a ventral
pattern of degeneration first affecting the amygdala, hippocampus, entorhinal
cortex, and temporal pole but progressing to involve the anterior insula, orbitofrontal
cortex, and ventral striatum.14 Clinical features reflect the anatomy, with prominent
memory or semantic deficits accompanying the behavioral change.
In patients with GRN mutations, age of onset is highly variable, even within
families, and occasionally mutation carriers may even escape the illness if they die of
other causes before age 75.15 The anatomic pattern is more lateralized (to the right or
left) and often spreads beyond the core bvFTD regions to involve posterior areas,

including posterior cingulate, precuneus, and lateral parietal neocortex,16 although it

remains unclear how often this posterior component is due to comorbid AD.17
Hexanucleotide repeat expansions in C9orf72 are the most common genetic
cause of bvFTD.18 Mutations have been identified even in patients without a
family history due to variable penetrance and possibly lengthening of the repeat
expansion (ie, anticipation) from one generation to the next in some families.
Here, the anatomic pattern involves core bvFTD structures but may be mild
overall19 or accentuated in the medial (especially pulvinar) thalamus20–22; less
consistent cerebellar atrophy has also been reported.22 Prominent psychiatric
features (eg, delusions, hallucinations, even fuguelike nonepileptic spells) may
be seen in the symptomatic23 and presymptomatic phases,24 but the cause of these
symptoms remains unclear.24 Motor neuron disease may emerge with, before, or
after the bvFTD syndrome, or not at all, in patients with C9orf72 expansions.
Despite these general statements about the genetic forms of bvFTD, considerable
variation exists within each genetic subgroup. Less common genetic causes of bvFTD
include pathogenic variants in TBK1, TIA1, TARDBP, FUS, CHMP2B, and VCP.
The list of genetic causes of bvFTD is long, but the list of pathologic substrates
is longer (FIGURE 4-2). FTLD pathology is divided into three major molecular classes
based on the protein composition of the neuronal and glial inclusions, which may
contain tau (FTLD-tau, about 40% of cases), transactive response DNA-binding
protein 43 (TDP-43) (FTLD-TDP, about 50% of cases), or fused in sarcoma
(FTLD-FUS, about 10% of cases). Each major molecular class includes a few major
and several minor histopathologic subtypes, defined based on the morphology and
distribution of the neuronal and glial inclusions. In sporadic bvFTD, the most
common pathologic substrates are Pick disease, FTLD-TDP (Type B more
common than Type A), and corticobasal degeneration.11 When bvFTD is due to a
mutation, predicting pathology is more straightforward. MAPT mutations result
in a mutation-specific tauopathy. GRN mutations are universally accompanied
by FTLD-TDP, Type A. C9orf72 expansions are also linked to FTLD-TDP, but
the subtype is more variable; Type B is most frequent, but some patients show
Type A or a pattern too sparse, blended, or atypical to classify. Clinical features
that can help predict pathology in bvFTD are shown in TABLE 4-2.
DIAGNOSIS
BvFTD is best diagnosed by using a systematic, stepwise approach (FIGURE 4-3)
to prevent treatable or reversible conditions from being overlooked. A bvFTD
diagnosis communicates a serious prognosis for the patient and potential genetic
risk to family members, such that it is best to achieve high confidence before
rendering the diagnosis.
Step 1: Identify and Refine the Syndrome

As with most neurologic disorders, obtaining the clinical history is the most
essential step toward making a correct bvFTD syndromic diagnosis. Verifying a
gradual and progressive behavior change helps reduce the odds of overlooking a
non-neurodegenerative bvFTD mimic (refer to Step 2). If the patient comes to
the visit unaccompanied reporting executive dysfunction or even social errors,
the correct syndromic diagnosis is rarely bvFTD.
To refine the anatomy of the syndrome, careful chronicling can suggest
whether the bvFTD syndrome began with (1) disinhibition, overeating,
compulsivity, and loss of disgust, reflecting a more ventral subtype involving
82 FEBRUARY 2019

KEY POINTS
● Expansions in C9orf72 are

the most common genetic
cause of bvFTD and are
commonly accompanied by
motor neuron disease.
● BvFTD results from a

diverse array of
neuropathologic entities,
most of which are classified
as frontotemporal lobar
degeneration.
● Accurate bvFTD diagnosis

requires a methodical
stepwise approach that
relies heavily on the
clinical history.
FIGURE 4-3
A stepwise approach to behavioral variant frontotemporal dementia (bvFTD) diagnosis.
FTLD-FUS = frontotemporal lobar degeneration with fused in sarcoma–immunoreactive inclusions; FTLD-tau =
frontotemporal lobar degeneration with tau-immunoreactive inclusions; FTLD-TDP = frontotemporal lobar
degeneration with transactive response DNA-binding protein 43 (TDP-43)–immunoreactive inclusions; CSF =
cerebrospinal fluid; PET = positron emission tomography.
ventral anterior insula, pregenual and subgenual anterior cingulate, ventral

striatum, amygdala, and orbitofrontal areas (CASE 4-1); (2) apathy, impulsivity,
and executive dysfunction, reflecting a more dorsal subtype involving dorsal
anterior insula, anterior midcingulate, and dorsolateral/opercular prefrontal
structures (CASE 4-2); or (3) loss of sympathy/empathy and agnosia for
person-specific semantic knowledge, reflecting focal anterior temporal lobe
degeneration. Recognizing these anatomic variations and others can be useful in
formulating the neuropathologic differential diagnosis (refer to Step 4).
Family history taking should seek out not only bvFTD but also motor neuron
disease, myopathy, bone disease (including Paget disease or bone cysts), and any
form of dementia or psychiatric illness, keeping in mind that bvFTD
misdiagnosis was even more common in preceding generations.
Useful neurologic signs include those that indicate emerging motor neuron
disease (eg, muscle atrophy, fasciculations, focal weakness, or spasticity)
or elements of a corticobasal syndrome (asymmetric bradykinesia-rigidity-
dystonia) or progressive supranuclear palsy-Richardson syndrome (slowed
saccades or vertical gaze restriction, axial rigidity, and gait instability).
Neuropsychological evaluation will usually show an executive-predominant
pattern but may be normal or reveal unexpected episodic memory impairment.
If a patient lacks the classic behavioral profile, detection of severe amnesia should
raise concern about the possibility of underlying AD. In the presence of a classic
bvFTD syndrome, however, severe amnesia may be a clue to FTLD-associated
hippocampal sclerosis pathology (refer to the section on common myths and pitfalls).

CASE 4-1 A 51-year-old woman presented for evaluation of 4 years of behavioral

symptoms that were affecting her work performance and home life. She
was a business executive and had been passed over for promotions at
work because her boardroom conduct had become less polished. She
arrived exactly 5 minutes before each meeting and openly criticized
others for being even seconds late. She interjected political views not
related to the topic at hand. She told higher-ranking coworkers to “pipe
down” and belittled the clothing or body habitus of support staff
members. She became preoccupied with sugary coffee drinks,
consuming two to three large beverages per day, and began collecting
antique statuettes. Her husband discovered spending in excess of
$15,000 on these and other collectibles, which she had been stockpiling
in the family basement. She refused to drive her daughters to their
basketball games, explaining that “their teams stink anyway” and
presented her husband with a partly used cigar (found on the street) for
Father’s Day. She had no family history of dementia or related illness.
Neurologic examination revealed a healthy-appearing woman with a
distant, yet sometimes jocular, affect who often spoke over the examiner
or stood up to inspect framed credentials. Neuropsychological testing
was normal, including tests of executive function. MRI showed right-
predominant anterior insula, anterior cingulate, rostromedial prefrontal,
and temporopolar atrophy (FIGURE 4-4).
The patient was diagnosed with behavioral variant frontotemporal
dementia (bvFTD) and treated with escitalopram, which attenuated her
overeating and collecting behaviors. She died after 12 years of symptoms,
and autopsy revealed Pick disease, a subtype of frontotemporal lobar
degeneration with tau-immunoreactive inclusions (FTLD-tau) (FIGURE 4-4).
COMMENT This case provides a canonical presentation of bvFTD due to one of its most
frequent neuropathologic causes. The disinhibited, socially inappropriate,
and insensitive presentation reflects the patient’s more ventral atrophy
pattern involving the ventral anterior insula, orbitofrontal cortex, subgenual
anterior cingulate cortex, ventral striatum, and anterior temporal lobe. Other
FTLD subtypes that commonly present with a ventral pattern include FTLD
with transactive response DNA-binding protein 43 (TDP-43)–immunoreactive
inclusions (FTLD-TDP), Type B or unclassifiable (with or without a C9orf72
expansion), atypical FTLD with ubiquitin-immunoreactive inclusions
(aFTLD-U, a subtype of FTLD with fused in sarcoma–immunoreactive
inclusions [FTLD-FUS]), and FTLD-tau due to a MAPT pathogenic variant.
84 FEBRUARY 2019

FIGURE 4-4
Imaging and pathology of the patient in CASE 4-1. A, Coronal and sagittal MRIs show a typical
behavioral variant frontotemporal dementia pattern with right worse than left atrophy
involving the anterior insula, anterior cingulate, anterior temporal lobes, amygdala, and
ventral striatum. B, Gross inspection of the brain at autopsy revealed the same pattern.
Note the remarkable sparing of more dorsal frontal and striatal structures. Microscopic
pathology shows ballooned neurons (arrowhead) in layer 5 (C, shown in anterior cingulate
cortex) and Pick bodies, which are round, circumscribed neuronal cytoplasmic inclusions
that stain positively for 3-repeat tau (D). Scale bars represent 100 microns in C and
10 microns in D.
H&E = hematoxylin and eosin; RD3 = 3-repeat tau.

Step 2: Consider Non-neurodegenerative Behavioral Variant

Frontotemporal Dementia Imitators
When a patient presents to a dementia specialist with a referring diagnosis of
bvFTD, the underlying cause is usually neurodegenerative. In primary care
or general neurology practice, however, non-neurodegenerative causes should
receive serious consideration and be evaluated before a specialist referral. Metabolic,
nutritional, endocrine, infectious, autoimmune, neoplastic, and toxicologic causes
should be entertained in every patient with a dementia syndrome and screened
for whenever suspicion is nonzero. The most common non-neurodegenerative
causes of a bvFTD-like syndrome are discussed further here.
PRIMARY PSYCHIATRIC DISEASE. A reported long-standing history of psychiatric

illness requiring psychopharmacologic treatment should prompt an in-depth
CASE 4-2 A 62-year-old man presented for evaluation of a 3-year history of new
behavioral symptoms. He had become less hard-driving in his work as an
attorney, accepting fewer cases and taking longer to close them.
Although he had always been a diligent gardener, he left the yard
unattended despite his wife’s encouragement. He became less
systematic when attempting to repair broken household fixtures or plan
even short trips. His emotional range diminished; he remained agreeable,
almost malleable, and warm toward his wife, but his conversations with
her lacked depth. Spontaneous speech slowly diminished but was
otherwise intact. He often repeated questions or asked for clarification
about recent events.
On examination, motor function was spared. His Mini-Mental State
Examination (MMSE) score was 21/30. Neuropsychological testing
revealed executive deficits, especially in processing speed, generativity,
and response switching, as well as poor delayed verbal recall and spared
visuospatial function. MRI revealed severe left-predominant medial and
dorsolateral frontal atrophy with conspicuous sparing of the anterior
temporal lobe and posterior brain regions but marked left hippocampal
atrophy (FIGURE 4-5). He died 8 years after symptom onset, and autopsy
revealed frontotemporal lobar degeneration with transactive response
DNA-binding protein 43 (TDP-43)–immunoreactive inclusions (FTLD-TDP),
Type A, with hippocampal sclerosis (FIGURE 4-5).
COMMENT This case highlights a more dorsal “apathetic-dysexecutive” presentation

of behavioral variant frontotemporal dementia (bvFTD) and serves as a
reminder that disinhibition and loss of caring, although common in
behavioral variant frontotemporal dementia, are not universal features. A
more dorsal presentation is often due to FTLD-TDP, Type A, or corticobasal
degeneration, although other FTLD subtypes and Alzheimer disease merit
consideration. In this case, the profound verbal memory deficit and
hippocampal atrophy suggested hippocampal sclerosis, which is more
commonly seen in FTLD-TDP.
86 FEBRUARY 2019

psychiatric history and give the clinician great pause before diagnosing bvFTD.
Careful scrutiny of the presenting symptoms is key; apathy must be
distinguished from anhedonia, disinhibition from mania, compulsive behaviors
from anxious obsessive-compulsiveness, and loss of empathy from lifelong
autism spectrum or personality disorder.25 Primary psychiatric disease
may change or worsen in midlife in response to new stressors or comorbid
medical or neurologic illness. In such cases, careful adjustment of the
psychopharmacologic regimen, preferably led by the treating psychiatrist,
may reveal a nonprogressive trajectory.26 On the other hand, unheralded
midlife psychosis, compulsivity, and manialike episodes are uncommon and
should arouse suspicion for bvFTD or other neurologic disorders. The
interpretation of psychiatric symptoms should also factor into the family history,
as patients with inherited FTD may have a higher rate of psychiatric diagnosis
FIGURE 4-5
Imaging and pathology of the patient in CASE 4-2. A, Coronal MRIs show a more dorsal left
worse than right atrophy pattern involving the superior frontal gyri, anterior and midcingulate
cortex, dorsal striatum, and hippocampus. B, Gross inspection of the brain at autopsy
revealed a similar pattern with conspicuous sparing of anterior temporal lobes. C,
Microscopic pathology shows frontotemporal lobar degeneration with transactive response
DNA-binding protein 43 (TDP-43)–immunoreactive inclusions, Type A, with numerous
TDP-43–immunoreactive short, thin neuropil threads; small round or crescentic neuronal
cytoplasmic inclusions, and occasional neuronal intranuclear inclusions (inset). Scale bar
in C represents 50 microns.

during the presymptomatic phase. Whether this phenomenology represents

prodromal neurodegeneration, abnormal brain development, bona fide
psychiatric illness, or a mix of these factors remains uncertain, but asymptomatic
carriers of bvFTD-causing mutations (especially C9orf72) often show subtle
volume reduction in bvFTD-related brain regions compared to controls and their
noncarrier siblings.24,27
BEHAVIORAL VARIANT FRONTOTEMPORAL DEMENTIA PHENOCOPY. In the

mid-2000s, Hodges and colleagues28 called attention to a “bvFTD phenocopy”
syndrome. Patients with this syndrome met prevailing formal research criteria
for bvFTD29 but lacked clinical progression over long follow-up intervals. Brain
imaging showed no, or mild nonspecific, changes, and tests of executive and
other cognitive functions were often normal or mildly abnormal but stable.
Today, we understand this group to include at least two major subgroups. First,
and most relevant to this section, is a group of patients who indeed manifest
social behaviors falling at, or even well below, the lower limits of normal. The
onset and progression of these behaviors, however, is unclear, often because the
patient lacks a reliable informant or has a new spouse or partner. The dynamic of
recognizing poor social skills in a partner after marriage can, in some instances,
lead spouses to seek a medical explanation when, in fact, the unwanted behaviors
represent lifelong eccentricities, a personality disorder, or an undiagnosed
high-functioning autism spectrum disorder. Gathering input from additional
family members, friends, or coworkers can help clarify the temporal features.
The second phenocopy subtype is a very slowly progressive bvFTD in which
there is often prominent psychiatric symptomatology, minimal or focal thalamic
atrophy, and a C9orf72 expansion.30
CEREBROVASCULAR DISEASE. Patients with slowly accrued multifocal subfrontal

infarcts may develop a seemingly gradual behavior-predominant dementia.
Cognitive slowing is often prominent, and executive dysfunction outpaces social
behavioral change. Strategic insular, striatal, or medial thalamic infarction may
also produce a bvFTD-like syndrome, but the onset is abrupt or may seem
subacute if there are barriers to detection.
SUBSTANCE ABUSE. Downward-spiraling work performance and evasive,

suspicious, emotionally distant behavior toward loved ones can reflect an
occult substance abuse disorder, often abuse of alcohol or opioid analgesic
medications. Indicated studies include toxicology and brain MRI to rule out
neurologic sequelae.
FRONTOTEMPORAL BRAIN SAGGING SYNDROME. Perhaps the least common

disorder that imitates bvFTD is also the best mimic. Rare patients with intracranial
hypotension develop clinical features that strongly overlap with bvFTD,31 even
when postural headache is minimal or absent (CASE 4-3). Brain MRI reveals sagging
of brain contents into the foramen magnum, presumably creating tension on long
tract pathways connecting frontal-insular-temporal cortical areas with subcortical
and brainstem structures. These features are often associated with diffuse meningeal
gadolinium enhancement. Although rare, this cause of the bvFTD syndrome is
critical to detect since it can be partly or totally reversed with an intervention to
patch the site of CSF leakage.
88 FEBRUARY 2019

Step 3: Scrutinize the Brain Atrophy Pattern KEY POINTS
MRI features were added to the revised research criteria for bvFTD with
● Both neurodegenerative
two intentions in mind: (1) avoid the non-neurodegenerative causes outlined and non-neurodegenerative
above and (2) reduce the likelihood of a non-FTLD neurodegenerative disease. causes should be
Patients can meet “possible bvFTD” criteria based on clinical features alone, considered in all patients
but “probable bvFTD” requires a supportive MRI scan. What does “supportive” with bvFTD.
look like? When reviewing a brain MRI in a patient with possible bvFTD,
● Structural MRI and,
the clinician must answer several key questions. Does evidence suggest increasingly, molecular
cerebrovascular disease or other nondegenerative focal lesion sufficient to biomarkers play a key role in
account for the clinical syndrome? If not, does the presence of cortical thinning, predicting pathology in
sulcal widening, subcortical atrophy, and ventricular enlargement suggest a patients with a bvFTD
syndrome.
neurodegenerative disorder? Is the cortical atrophy pattern anterior, posterior, or
both? An anterior-predominant pattern is sufficient to reach a probable bvFTD
diagnosis because it usually suggests underlying FTLD pathology. This anterior
pattern almost always includes the anterior insula and anterior cingulate cortices,11
but which additional structures are affected: frontal, temporal, parietal, limbic,
subcortical, or brainstem? Answers to these questions can assist in formulation of
the pathologic differential diagnosis (TABLE 4-2 and Step 4 below).
Step 4: Formulate the Pathologic Differential Diagnosis

Once the clinician rules out non-neurodegenerative causes of a bvFTD-like
syndrome, it is time to generate a prioritized list of the most likely
neuropathologic diagnoses. As shown in TABLE 4-2, several clinical features
strongly increase the likelihood of one pathologic diagnosis over others. Of these
features, only the genetic associations (and not all of those) have proven
themselves invariant. During early clinical stages, anchoring clinical features
such as motor neuron disease or a supranuclear gaze palsy are typically absent,
and prioritizing the differential diagnosis relies on looser clinicoanatomic
subtype–based associations. For example, severe asymmetric (usually
nondominant) temporal lobe atrophy predicts underlying FTLD-TDP, Type C
or, less often, Pick disease. Dramatic “knife-edge” frontal and insular atrophy
predicts Pick disease (CASE 4-1) or, less often, FTLD-TDP, Type A. Midbrain
atrophy can herald the emergence of progressive supranuclear palsy syndromic
features, and focal thalamic atrophy can suggest C9orf72 expansion even when
the family history is unremarkable. A ventral frontal pattern accompanied by
paper-thin anterior caudate nuclei suggests FTLD-FUS (aFTLD-U subtype),
especially in a patient with a symptom onset before 50 years of age. Patients with
prominent dorsal frontoparietal atrophy, with or without prominent memory
loss, should raise concern for underlying AD (CASE 4-4).
Step 5: Consider Molecular Biomarkers to Rule Out Alzheimer Disease

Distinguishing bvFTD due to FTLD from a behavioral syndrome due to
pathologic AD can be challenging in clinically atypical patients but has important
management implications. Although still imperfect, clinically available
biomarkers can sensitively detect AD-related molecular changes. A normal CSF
amyloid-β1-42 to phosphorylated tau ratio or negative amyloid imaging with, for
example, florbetapir positron emission tomography (PET), greatly reduces the
likelihood that AD is the cause of any FTD-like syndrome. These tests are most
useful in young patients, however, because incidental CSF and amyloid PET
biomarker abnormalities become more common with age, such that 25% to 40%

of asymptomatic individuals test positively after 70 years of age.32 Therefore,

in this age group, a positive test cannot confirm that a patient’s bvFTD is due to
AD. In patients aged 45 to 60, however, the risk of false positives is much lower,
and a positive biomarker usually means that the bvFTD-like syndrome is due to
AD. Health insurance rarely covers these tests, so it is important to have a frank
discussion with caregivers regarding costs and benefits.
COMMON BEHAVIORAL VARIANT FRONTOTEMPORAL DEMENTIA

MYTHS AND PITFALLS
Despite growing awareness of bvFTD among primary care physicians and
general neurologists, misdiagnosis remains common. Some diagnostic errors can
be traced back to the following common misconceptions.
The Memory Loss Is Too Severe; It Must Be Alzheimer Disease

This myth arises from the fact that amnesia is not a defining feature of bvFTD,
but even patients who meet probable bvFTD criteria may show severe memory
CASE 4-3 A 50-year-old man presented with a 1-year history of behavioral

symptoms. He had been an upstanding and even-tempered grocery store
manager but had begun to speak rudely to his wife, berating her for minor
mistakes. He threw her neatly organized paperwork on the floor and
laughed when she responded tearfully. He touched her publicly in ways
that made her uncomfortable and told off-color jokes to his daughter’s
teenage friends. He spent significant savings on pornography, which he
watched in front of others, including children. He was forced to retire
because of repeated complaints from his employees to store ownership.
He ate gummy bears compulsively yet had lost 13.6 kg (30 lb) over 2 years.
He exhibited repetitive motor behaviors such as foot tapping and head
scratching and made repeated trips to the bathroom. He forgot recent
conversations and had occasional nonpostural headaches. His medical
history was notable for a significant childhood head trauma.
On examination, he violated interpersonal boundaries, exhibited
utilization behavior, and spoke out of turn in a hypophonic voice. He had
square-wave jerks and a postural tremor predominantly affecting his
trunk and right hand. His Mini-Mental State Examination (MMSE) score
was 26/30. He showed prominent deficits in verbal memory and
generativity but otherwise normal language and visuospatial function.
Brain MRI revealed a normal pattern of cortical thickness but distortion
of brainstem structures, forward displacement of the third ventricle, a
prominent pituitary, enlarged venous sinuses, the appearance of cerebellar
tonsillar herniation, and diffuse pachymeningeal enhancement, all
consistent with intracranial hypotension (FIGURE 4-6). An MRI myelogram of
the whole spine showed a rim of extradural contrast in the upper thoracic
canal (T2 through T6, above the level of the lumbar puncture). Targeted
blood patching resulted in only short-lived benefits. After the fourth blood
patch, his behavior improved significantly and remained stable for 2 years.
90 FEBRUARY 2019

loss due to hippocampal sclerosis, in which CA1 and subicular pyramidal neurons
are almost completely destroyed. FTLD-related hippocampal sclerosis is usually
seen in the context of underlying FTLD-TDP and is distinct from hippocampal
sclerosis of aging,33 a TDP-43–related disease typically seen in patients older than
80 years of age. For more information on hippocampal sclerosis, refer to the
article “Hippocampal Sclerosis, Argyrophilic Grain Disease, and Primary
Age-Related Tauopathy” by Gregory A. Jicha, MD, PhD, and Peter T. Nelson, MD,
PhD,34 in this issue of Continuum. In older patients with bvFTD due to underlying
FTLD, comorbid AD neuropathologic changes and other common age-related
conditions may also mislead clinicians away from the FTLD diagnosis.35
The MRI Is Normal; It Cannot Be Behavioral Variant

Frontotemporal Dementia
As preceding sections imply, a normal MRI should not lead clinicians to limit
their differential diagnosis to non-neurodegenerative etiologies. In patients with
C9orf72 expansions, sporadic FTLD-TDP (Type B or unclassifiable), or even
FIGURE 4-6
Imaging of the patient in CASE 4-3. A, Sagittal T1-weighted MRI shows sagging of brainstem
and diencephalon toward the foramen magnum, with crowding of cerebellar tonsils. B, Axial
T1-weighted MRI highlights crowding of the midbrain. Postcontrast T1-weighted images (not
shown) revealed diffuse pachymeningeal enhancement.
Treatable causes of dementia are essential to rule out, and this case COMMENT
illustrates a behavioral variant frontotemporal dementia–like syndrome for
which an MRI scan can make the diagnosis. Although treatment is invasive
and not always effective, the small existing literature suggests that
persistent treatment may be critical to long-term symptom relief, at least in
some patients.31

CASE 4-4 A 55-year-old man presented for evaluation of a 3-year history of

behavioral and cognitive symptoms. He was an accountant but could no
longer retain his clients. Tax forms were filed late, and he mixed up
appointments because of double bookings and missed emails. Papers
piled up on his desk, including stacks of unopened envelopes. He
became despondent, prone to angry outbursts, and clingy, following his
wife around the house and watching her speak on the telephone. He
approached strangers, often telling distasteful jokes or bursting into song
in midsentence. Other times, he would retreat from social gatherings to
watch television. He ate whenever food was present and often took food
from family members’ plates. Both of his parents had developed an
amnestic dementia in their late seventies.
On examination, his affect was flat, and he fidgeted impulsively.
Imitative, stimulus-bound behaviors took the form of motor mirroring and
echolalia. Spoken language was tangential with circumlocution. He could
not calculate 25 + 33 without paper. Praxis was normal. When asked
about a recent major world event, he could not name the key participants
but recognized their names among multiple-choice arrays. He had mild
hypomimia, but the remainder of the general neurologic examination was
normal. Neuropsychological testing revealed a Mini-Mental State
Examination (MMSE) score of 22/30; he lost points for orientation,
spelling world backward, and three-item delayed recall (0/3). He was
unable to complete a modified trail-making task and made 26 stimulus-
bound errors on the Stroop color-naming test. Verbal and category
fluency were impaired. Verbal learning was poor, and free recall
was absent after 10 minutes, unaided by recognition prompts.
Visuoconstructive and visuoperceptive tests were normal. MRI showed
mild to moderate dorsolateral frontal greater than lateral parietal
atrophy (FIGURE 4-7).
The clinical syndrome was characterized as dysexecutive-amnestic
with elements of behavioral variant frontotemporal dementia (bvFTD)
but with suspicion for underlying Alzheimer disease (AD). Amyloid
imaging with florbetapir positron emission tomography (PET) showed
widespread tracer uptake. Clinical genetic testing revealed two copies of
the APOE ε4 allele. Over time, amnesia and posterior cortical deficits
blossomed. Treatment with donepezil made him somewhat less
distractible but had no influence on disruptive, agitated behaviors, which
made him difficult to manage at a residential care facility. Treatment with
antipsychotic drugs made him calmer but apathetic and parkinsonian. He
died after 10 years of symptoms, and autopsy showed advanced AD
(FIGURE 4-6).
92 FEBRUARY 2019

FIGURE 4-7
Imaging and pathology of the patient in CASE 4-4. Coronal MRIs (A) show a dorsal frontal
atrophy pattern as well as mild posterior cingulate and lateral parietal atrophy (not shown).
Gross inspection of the brain at autopsy (B) showed similar, although more severe, findings.
Microscopic pathology showed abundant diffuse and neuritic amyloid plaques and mild
cerebral amyloid angiopathy (C, as shown in middle frontal gyrus) accompanied by severe
tau-immunoreactive neurofibrillary tangle and neuropil thread pathology (D, as shown
using CP-13 antibody, inferior frontal gyrus). Scale bars represent 500 microns in C and
100 microns in D.
a-beta = amyloid-β; p-tau = phosphorylated tau.
This case illustrates a presentation of early-onset AD that may be mistaken COMMENT

for bvFTD. Although the patient had early behavioral symptoms, many of
them, including irritability, agitation, and low mood, are more typical of
Alzheimer-type dementia than bvFTD. Molecular imaging was particularly
helpful because of the patient’s young age.

early progressive supranuclear palsy pathology, the brain MRI may be so bland as
to be startling. Careful review may reveal a focal pattern of medial thalamic or
midbrain atrophy that may or may not blossom into a more widespread
cingulate-insular pattern in the years to come. Some patients with C9orf72
expansions have a long-term stable trajectory of slowly or minimally progressive
behavior change, even after presenting to a dementia clinic. In others without a
mutation, the anchoring clue may be the emergence of subtle motor neuron
disease or eye signs, such as square-wave jerks or slowed saccades, that suggest
an incipient supranuclear ophthalmoparesis.
Executive Frontal Functions Are the Worst Cognitive Deficit; It Must Be

Behavioral Variant Frontotemporal Dementia
Executive functions are often the worst cognitive deficit in bvFTD, but they
are rarely the worst deficit overall, being overshadowed by social-emotional
dysfunction in most patients. Middle-aged patients with an executive-
predominant deficit profile and a dorsolateral frontal atrophy pattern are
commonly seen in dementia centers, often with a referring diagnosis of bvFTD.
In most, the correct clinical diagnosis will be early-onset Alzheimer-type dementia
(CASE 4-4). Meticulous assessment will reveal that executive dysfunction is
(or will soon be) part of a larger pattern that includes other neocortical cognitive
domains such as language (particularly lexical retrieval), visuospatial function,
calculations, and praxis. Emotional changes may be prominent but tend toward
anxiety, irritability, and even impulsivity, while social warmth, decorum, and
connectedness with loved ones are broadly preserved. Occasionally a patient with
underlying AD will present with a more typical bvFTD syndrome. Often in such
patients the caregiver will confess that the patient has always been “the life of the
party,” having a loose, disinhibited personal style that has been, one imagines,
amplified by the emergence of a disease that would have otherwise presented
differently. Some patients with AD may also show more prominent frontal-
behavioral features due to comorbid vascular subfrontal leukoencephalopathy
stemming from arteriolosclerosis or cerebral amyloid angiopathy.
MANAGEMENT
The years leading up to a patient’s bvFTD diagnosis are often the most stressful
period in the lifetime of a spouse and other family members. Marital strife,
financial chaos or even ruin, and estrangement from friends and family are
common and may create resentment toward the patient that persists even after a
neurologic diagnosis has been made. Caregiver emotional responses to a bvFTD
diagnosis are often mixed. The diagnosis creates enormous grief because of the
prognosis: progression to death within 5 to 7 years.36 On the other hand,
caregivers are often relieved—eventually—to know that a disease accounts for
the patient’s behaviors and that those behaviors are not just a new and permanent
normal. Death typically results from motor impairment (parkinsonism, motor
neuron disease, or both) leading to aspiration pneumonia, so caregivers should
be advised to look out for emerging motor features. The patient’s emotional
response to the diagnosis is characteristically bland or concrete.
Caring for patients and families with bvFTD is challenging but rewarding. At a
dementia specialty clinic, model care involves a multidisciplinary team that
includes a physician (most often a neurologist, psychiatrist, or geriatrician), nurse,
neuropsychologist, social worker, genetic counselor, and a seasoned pharmacist.
94 FEBRUARY 2019

For the community practice neurologist, adding even one or two of these disciplines KEY POINTS
(but as many as feasible) to the care team can greatly enhance care quality.
● Occasionally, patients
with bvFTD have severe
Caregiver Support/Behavioral Management early memory loss or a
With bvFTD, the major treatment imperative is to provide spouses and other normal MRI.
caregivers with information, emotional support, strategies for behavioral
● Executive dysfunction is
management, and access to community resources. Without these tools, caregiver
common in bvFTD but also in
burnout is almost inevitable and can have major adverse consequences, including other disorders and should
poor health outcomes, for both caregiver and patient.37 Lay language not be used as an indicator
informational materials are available via books and websites (refer to the Useful of bvFTD unless
Websites section). Support groups can be helpful, especially if focused on accompanied by signature
social-emotional features.
non-Alzheimer dementias. Day-to-day caregiver-patient interactions should focus
on redirecting attention away from unwanted preoccupations and activities in a ● Model care for bvFTD
nonconfrontational manner.38 Harmless compulsions within the home involves contributions from
environment (weed-pulling, recycling, sorting, ordering) need not be discouraged a multidisciplinary team that
supports both patient and
and can even provide caregiver relief. Unwelcome compulsive behaviors can be caregiver.
replaced by innocuous alternatives such as a squeeze ball (to replace touching
strangers) or a lollipop (to diminish repetitive, stereotyped vocalizations).38 ● BvFTD caregivers are at
Challenging the patient’s newly ordered priorities or false beliefs is generally high risk for burnout.
unproductive. Patient access to financial resources should be controlled and
● Nonpharmacologic
monitored or removed based on the context. Problematic public behaviors can approaches are often the
often be defused by providing those involved with a business card–sized best way to manage
explanation that the patient has a brain disorder that affects behavior. Dietary troublesome behavioral
or monetary rewards for desired behaviors (showering, grooming) can be symptoms in bvFTD.
effective in some patients.38 Adult day programs that offer a structured ● Pharmacologic
environment for several consecutive hours can provide valuable caregiver management of bvFTD
respite if the staff is trained to manage behavioral symptoms in dementia. should target specific
Caregivers should be encouraged to exercise and engage in other forms of stress symptoms, such as
overeating, compulsivity,
management, prioritize their own sleep, and maintain social contacts and
severe agitation, or
personal interests or hobbies as much as possible. Early consideration of psychosis.
end-of-life care and advance directives is warranted, although by the time
patients are diagnosed with bvFTD, they rarely retain the capacity to make or ● Selective serotonin
even guide these decisions. reuptake inhibitors are
first-line therapy for
overeating and compulsivity
Psychopharmacologic Treatment symptoms in bvFTD.
No disease-modifying therapies are available for patients with bvFTD.
Therefore, drug treatment should focus on the most disruptive or targetable
behaviors and be rooted in the neurochemical deficits observed in bvFTD.
Overeating and, to a lesser extent, compulsivity may respond to selective
serotonin reuptake inhibitors (SSRIs)39; citalopram or escitalopram are often
used because of their low side effect profiles. Patients with an apathy-
predominant form of bvFTD may show subtly increased energy/engagement
in response to venlafaxine given its activating (ie, noradrenergic) properties.
Social disinhibition is notoriously difficult to treat with drugs. When patients
become agitated and confront other nursing home residents in a way that
threatens resident or staff safety (or the patient’s status at the facility),
atypical antipsychotic drugs such as quetiapine or risperidone can be used
in low incremental doses but with extreme caution given the risk of cardiac
complications, including sudden death. Less commonly, patients with bvFTD
develop frank psychosis, which may also respond to these medications.

Distinguishing bvFTD due to FTLD from a frontal/behavioral variant of AD

has important implications for psychopharmacology. Whereas patients with
underlying AD may show modest cognitive or even behavioral benefit from
acetylcholinesterase inhibitors, patients with bvFTD due to FTLD have shown no
benefit40 and may even become agitated or irritable in response to these drugs.41,42
Memantine showed no benefit in a randomized controlled trial for FTD (including
bvFTD and semantic variant primary progressive aphasia)43 but may decrease
caregiver distress in patients with underlying AD, including those with a behavioral/
executive presentation. It should be noted, however, that the previous memantine
trial for FTD was not powered to assess the bvFTD subgroup, and no clinical trial
has specifically recruited behavioral/executive forms of AD.
FAMILY CONSIDERATIONS AND GENETIC COUNSELING

Because bvFTD represents a monogenic, autosomal dominant inherited disease
in 15% to 20% of patients,13 families are often uneasy about and eager to discuss
heritability implications. Clinical testing is available for the major known genetic
causes and can help guide next steps in family counseling. Negative results from
existing clinical tests provide only partial reassurance, especially if a worrisome
family history is present, since there may be additional FTD-related genes
awaiting discovery. If a genetic cause is identified in the patient (ie, proband),
genetic testing of at-risk asymptomatic family members should be considered only
for adults and only with appropriate genetic counseling in place. Such counseling
can help at-risk individuals think through the psychological and family-planning
consequences of knowing their own genetic status. If an at-risk individual tests
positive for a known FTD pathogenic variant but wishes to start a family,
preimplantation diagnosis followed by in vitro fertilization has become an option,
although it remains uncommonly used in the United States for this indication.
FRONTIERS
Advancing clinical and basic science efforts promise to improve care for patients
with bvFTD. A few among many horizons related to diagnosis and treatment are
outlined here.
Diagnosis
Even once all patients with underlying AD within a bvFTD cohort can be
identified, a need will remain for better prediction of the underlying FTLD
pathologic diagnosis. FTLD is a rich and diverse category, and treatment trials
will seek to target the specific molecular mechanisms related to tau, TDP-43, and
FUS. Research-based PET imaging for the tau protein shows great promise for
detecting the neurofibrillary pathology of AD,44 but, to date, these approaches
have proven neither sensitive nor specific enough for use in FTLD-tau
diagnosis.45,46 Further work is needed to identify new tau PET ligands and to
develop approaches for imaging TDP-43 aggregates. Nonetheless, the sensitivity
of existing tau PET ligands to Alzheimer-type neurofibrillary tau pathology may
prove useful in older patients by clarifying whether a positive amyloid PET
means that the patient’s bvFTD syndrome is likely due to AD.
Treatment
Great optimism and excitement is emerging within the FTD patient, caregiver,
and researcher communities about the potential for new therapies.47 Several
96 FEBRUARY 2019

approaches are in or nearing the clinical trials phase. For FTLD-tau, candidate KEY POINT
strategies include stabilization or immunologic clearance of pathologic tau
● Acetylcholinesterase
and therapeutic reduction of total tau, among others. For FTLD-TDP, the inhibitors have shown no
major treatment targets relate to the genetic forms caused by pathogenic benefit in bvFTD and may
variants in GRN or C9orf72. For GRN-FTD, researchers are pursuing ways worsen behavioral
to normalize circulating progranulin protein levels, which are reduced symptoms.
due to haploinsufficiency; obviate lysosomal dysfunction; and dampen
neuroinflammation. For C9orf72-FTD, one major approach proposed is to use
antisense oligonucleotides to diminish toxicity resulting from repeat RNA
transcripts and the dipeptide repeat protein products of repeat-associated
unconventional translation.48
CONCLUSION
The human social brain, so wondrous in its capacities, remains a delicate
frontier that slowly erodes in patients with bvFTD. Clinicians can play a major
role in accurately diagnosing and treating bvFTD and caring for the patient
and family. Ongoing research promises to clarify molecular mechanisms,
raising hope for improved patient-centered diagnosis and disease-modifying
treatment.
ACKNOWLEDGMENTS
The author would like to thank his colleagues at the University of California,
San Francisco Memory and Aging Center, especially Georges Nasaan, MD;
David Perry, MD; Robin Ketelle, RN, MS; and Bruce Miller, MD, for discussion
related to this manuscript. Special thanks go to University of California, San
Francisco FTD study participants and their families for contributing to
neurodegeneration research.
USEFUL WEBSITES
ALZHEIMER’S ASSOCIATION CLINICALTRIALS.GOV
The Alzheimer’s Association website describes the ClinicalTrials.gov lists clinical trials of medications
types of frontotemporal dementia (including for frontotemporal dementia and their status.
behavioral variant frontotemporal dementia and clinicaltrials.gov/ct2/results?cond=Frontotemporal+
primary progressive aphasia) and the key Dementia&term=&cntry=&state=&city=&dist=?
differences between frontotemporal dementia and
Alzheimer disease and provides telephone numbers NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS
for support for patients and caregivers. AND STROKE FRONTOTEMPORAL DEMENTIA
alz.org/alzheimers-dementia/what-is-dementia/ INFORMATION PAGE
types-of-dementia/frontotemporal-dementia The National Institute of Neurological Disorders and
Stroke frontotemporal dementia information page
THE ASSOCIATION FOR FRONTOTEMPORAL provides a definition of the disease and links to
DEGENERATION clinical trials, patient organizations, and
The Association for Frontotemporal Degeneration publications.
website explains the difference between ninds.nih.gov/Disorders/All-Disorders/
frontotemporal degeneration and Alzheimer Frontotemporal-Dementia-Information-Page
disease and provides resources for living with
frontotemporal degeneration and information on UNIVERSITY OF CALIFORNIA SAN FRANCISCO
research and clinical trials. MEMORY AND AGING CENTER
theaftd.org/what-is-ftd/disease-overview/ The UCSF Memory and Aging Center
website provides information on the forms of
frontotemporal dementia; medications used
to treat it; resources for patients, caregivers,
and providers; and research trials.
memory.ucsf.edu/frontotemporal-dementia

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100 FEBRUARY 2019

Primary Progressive REVIEW ARTICLE

Aphasias and Apraxia C O N T I N U UM A U D I O
I NT E R V I E W A V A I L AB L E
ONLINE
of Speech 
VIDEO CONTENT
By Hugo Botha, MBChB; Keith A. Josephs, MD, MST, MSc A V AI L A B L E O N L I N E
ABSTRACT
PURPOSE OF REVIEW: This article reviews two of the primary progressive
aphasias (PPAs), disorders characterized by the early and predominant
impairment of language, and primary progressive apraxia of speech, a
degenerative motor speech disorder that is closely related to PPA. An
outline of the history and controversy surrounding how these disorders are
classified is provided before the article focuses on each disorder’s clinical
and imaging features.
RECENT FINDINGS:Over the past decade, the classification of degenerative

speech and language disorders has been refined. Clinical, imaging, and
pathologic evidence suggests that primary progressive apraxia of speech is
a distinct degenerative disorder. Furthermore, multiple lines of evidence
have highlighted issues with nonfluent/agrammatic variant PPA, which
complicates the diagnosis, prognosis, and study of this disorder. Semantic
variant PPA, while not without controversy, remains one of the most CITE AS:
well-defined disorders, with good clinicopathologic correlation. CONTINUUM (MINNEAP MINN)
2019;25(1, DEMENTIA):101–127.
SUMMARY: Accurate classification and diagnosis of these degenerative Address correspondence to

speech and language disorders is crucial in clinical practice and ongoing Dr Keith A. Josephs, Department
of Neurology, Mayo Clinic, 200
research efforts. For nonfluent/agrammatic variant PPA, the authors
First St SW, Rochester, MN,
suggest emphasizing agrammatism as the core inclusion criterion and 55905, Josephs.Keith@mayo.edu.
taking care not to include patients with isolated or predominant apraxia
of speech. Isolated apraxia of speech can be the manifestation of a Dr Botha receives research/
degenerative disease and, based on the different prognosis, should be grant support from the
recognized as distinct from PPA. Finally, it is important to recognize that National Institutes of Health
(R01 DC012519-06). Dr Josephs
some patients with semantic dementia, despite sharing the same receives research/grant
pathologic associations, may not meet criteria for PPA. support from the National
Institutes of Health
(R01 AG37491, R01NS89757,
R01 DC14942).
INTRODUCTION
UNLABELED USE OF
P
rimary progressive aphasia (PPA) refers to a group of PRODUCTS/INVESTIGATIONAL
neurodegenerative diseases characterized by early and prominent USE DISCLOSURE:
Drs Botha and Josephs report
language impairment occurring in the relative absence of cognitive no disclosures.
impairment, behavioral disturbance, or motor symptoms.1 Although
this label was coined in the 1980s and was important in the recognition
of PPA as a clinical entity distinct from Alzheimer disease dementia,2 the © 2019 American Academy
concept of progressive language impairment as the initial manifestation of a of Neurology.

PRIMARY PROGRESSIVE APHASIAS
TABLE 5-1 Root Criteria for a Diagnosis of Primary Progressive Aphasiaa
Inclusion: Criteria 1–3 Must Be Answered Positively

1 Most prominent clinical feature is difficulty with language
2 These deficits are the principal cause of impaired daily living activities
3 Aphasia should be the most prominent deficit at symptom onset and for the initial phase of
the disease
Exclusion: Criteria 1–4 Must Be Answered Negatively for a Primary Progressive Aphasia
Diagnosis
1 Pattern of deficits is better accounted for by other nondegenerative nervous system or
medical disorders
2 Cognitive disturbance is better accounted for by a psychiatric diagnosis
3 Prominent initial episodic memory, visual memory, and visuoperceptual impairments
4 Prominent, initial behavioral disturbance
a
Reprinted with permission from Gorno-Tempini ML, et al, Neurology.1 © 2011 American Academy
of Neurology.
TABLE 5-2 Criteria for Variants of Primary Progressive Aphasiaa
Nonfluent/Agrammatic Variant Logopenic Variant Primary Semantic Variant Primary

Primary Progressive Aphasia Progressive Aphasia Progressive Aphasia
Core features At least one of the following: Both of the following core Both of the following core
features must be present: features must be present:
Agrammatism in language
production Impaired single-word Impaired confrontation
retrieval in spontaneous naming
Effortful, halting speech with speech and naming
inconsistent speech sound Impaired single-word
errors (apraxia of speech) Impaired repetition of comprehension
sentences and phrases
Supportive features At least two of the following: At least three of the following: At least three of the following:
Impaired comprehension of Speech (phonologic) errors Impaired object knowledge,

syntactically complex in spontaneous speech and particularly for low-frequency
sentences naming or low-familiarity items
Spared single-word Spared single-word Surface dyslexia or dysgraphia

comprehension comprehension and object
knowledge Spared repetition
Spared object knowledge
Spared motor speech Spared speech production
(grammar and motor speech)
Absence of frank
agrammatism
a
Modified with permission from Gorno-Tempini ML, et al, Neurology.1 © 2011 American Academy of Neurology.
102 FEBRUARY 2019

degenerative disease dates back to the work of Arnold Pick3 more than a KEY POINTS
century ago. The past decade has seen considerable advances in our
● Primary progressive
understanding of the neurobiological mechanisms underlying language and aphasia refers to a group of
disorders affecting language, with PPA playing an important role in expanding neurodegenerative diseases
the simplistic models based on stroke and other focal insults.4 Three canonical characterized by early and
variants of PPA are recognized, of which two (nonfluent/agrammatic prominent language
impairment occurring in the
variant PPA and semantic variant PPA) are classified as frontotemporal
relative absence of
dementia syndromes because of their propensity to affect the frontal and cognitive impairment,
temporal lobes and their association with frontotemporal lobar degeneration behavioral disturbance, or
pathology, while the other (logopenic variant PPA) is most commonly motor symptoms.
viewed as an atypical variant of Alzheimer disease. For more information
● Three canonical variants
on logopenic variant PPA, refer to the article “Early-onset Alzheimer Disease of primary progressive
and Its Variants” by Mario F. Mendez, MD, PhD, FAAN,5 in this issue of aphasia (PPA) are
Continuum. recognized, of which two
In parallel to advances in the study of language, much has been learned about (nonfluent/agrammatic
variant PPA and semantic
the mechanisms underlying speech and the disorders affecting it. Apraxia of variant PPA) are classified as
speech is one such speech disorder and is thought to result from impaired frontotemporal dementia
planning and programming of the movements required for speech production.6 syndromes while the other
Since its initial description in the 1960s, it has become increasingly recognized as (logopenic variant PPA) is
most commonly viewed as
an important feature of neurodegenerative diseases.7 Only recently, however, an atypical variant of
has it been recognized that it may be the initial manifestation of a degenerative Alzheimer disease.
disease termed primary progressive apraxia of speech.8
This article discusses nonfluent/agrammatic variant PPA, semantic variant ● Apraxia of speech is a
motor speech disorder
PPA, and primary progressive apraxia of speech. These disorders are first placed
thought to result from
within a broader context by discussing the classification of degenerative speech impaired planning and
and language disorders. An understanding of classification schemes is crucial programming of the
to interpreting the literature, which has important implications for ongoing movements required for
research (eg, clinical trial enrollment and assessment of external validity) and speech production.
patient care (eg, treatment decisions and prognostication). Each disorder is then ● The most widely
discussed in detail, with unclassified or mixed cases briefly reviewed. A accepted current
simplified approach to the diagnosis and management of degenerative speech classification scheme and
and language disorders is then presented. diagnostic criteria for
primary progressive aphasia
consists of two stages. First,
CLASSIFICATION AND CONTROVERSY a root diagnosis of primary
The most widely accepted current classification scheme and diagnostic criteria progressive aphasia is
for PPA consist of two stages.1 First, in keeping with PPA being viewed as a considered. Second, criteria
for the three main variants
distinct clinical disorder targeting language, a root diagnosis of PPA is considered
are considered, each with a
(TABLE 5-1). In simplified terms, this requires that language dysfunction is set of mandatory and
the primary cause of difficulty in the initial phase of the illness and that no supportive features.
prominent findings (eg, amnesia, behavioral disturbance) indicate that an
alternative diagnosis is more likely. Thus, a patient presenting with progressive
aphasia accompanied from the start by prominent asymmetric motor
impairment would not qualify for a diagnosis of PPA and may instead be
diagnosed with corticobasal syndrome. Second, criteria for the three main
variants are considered, each with a set of mandatory core features and
supportive features (TABLE 5-2). In other words, only patients who have met
the root criteria (ie, have aphasia in the absence of more prominent cognitive,
behavioral, or motor disturbances) are considered for a subtype diagnosis.
Despite many advantages of these new criteria, they have not been without
controversy.

In the case of nonfluent/agrammatic variant PPA, the criteria require only one
of the core features, which results in an inherent heterogeneity: some patients
will have agrammatism and no apraxia of speech, some will have nonagrammatic
aphasia and apraxia of speech, and some will have both agrammatism and
apraxia of speech. More important, if the two-step process is not followed,
patients with isolated apraxia of speech or another motor speech disorder that
may mimic it may erroneously be diagnosed with nonfluent/agrammatic variant
PPA. This amounts to conflating language and speech function and dysfunction
despite distinct underlying neurobiological mechanisms. But while motor speech
disorders such as dysarthria and apraxia of speech often co-occur with aphasia,
these are clearly not language impairments that would, on their own, qualify a
patient for a diagnosis of PPA. Practical implications also exist for patients, given
the differences in management and prognosis discussed later in this article.9,10
The primary source of confusion and controversy with semantic variant PPA
has been its relation to semantic dementia, which predates the description of
semantic variant PPA. Semantic dementia, as evidenced by earlier consensus
criteria for frontotemporal dementia, was thought to result from disruption of
semantic memory in a way that results in deficits regardless of the modality by
TABLE 5-3 Features of Apraxia of Speecha
◆ Slow overall speech rateb

◆ Lengthened intersegment durations (between sounds, syllables, words, or phrases; possibly
filled, including intrusive schwa)b
◆ Increased sound distortions or distorted sound substitutions with increased utterance
length or increased syllable/word articulatory complexity
◆ Syllable segmentation within words >1 syllableb
◆ Sound distortionsb
◆ Syllable segmentation across words in phrases/sentencesb
◆ Audible or visible articulatory groping; speech initiation difficulty; false starts/restartsc
◆ Lengthened vowel and/or consonant segmentsb
◆ Distorted sound substitutions
◆ Deliberate, slowly sequenced, segmented and/or distorted (including distorted substitutions)
speech sequential motion rates in comparison with speech alternating motion ratesc
◆ Increased sound distortions or distorted substitutions with increased speech rate
◆ Distorted sound additions (not including intrusive schwa)
◆ Sound or syllable repetition
◆ Sound prolongations (beyond lengthened segments)c
◆ Inaccurate (off-target in place or manner) speech alternating motion rates (as in rapid
repetition of puh, puh, puh)c
◆ Reduced words per speech breath group relative to maximum vowel duration
a
Modified with permission from Josephs KA, et al, Brain.8 © 2012 The Authors.
b
Can also be present in spastic dysarthria.
c
Can also be present in aphasia.
104 FEBRUARY 2019

which it is tested (eg, verbal, nonverbal). In contrast, semantic variant PPA is KEY POINTS
suspected of resulting from relatively restricted involvement of the verbal
● While motor speech
aspects of semantic memory. While some researchers have simply replaced the disorders such as dysarthria
term semantic dementia with semantic variant PPA, others have continued to draw and apraxia of speech often
the distinction between predominantly verbal semantic difficulties versus more co-occur with aphasia,
widespread semantic difficulties. With disease progression, this distinction these are clearly not
language impairments that
becomes less relevant as all aspects of semantic memory are affected, but patients
would, on their own, qualify
who present with primarily nonverbal semantic deficits (usually from right- a patient for a diagnosis of
sided greater than left-sided involvement) will not meet root criteria for PPA. primary progressive aphasia.
Therefore, this article discusses semantic dementia more broadly, albeit
while focusing on the language-predominant presentation. ● The relative dominance of
phonetic impairment (sound
While not the focus of this article, criteria for logopenic variant PPA have level errors, such as
also been problematic, primarily because of the overlap with working memory distorted substitutions or
deficits in early-onset Alzheimer disease11 and the inclusion of impaired additions) or prosodic
repetition as a mandatory criterion.4,12 Finally, it has become evident that the impairment (such as slow
rate or segmented speech)
current criteria result in a large proportion of PPA cases being unclassifiable.13 is the primary source of
Changes have been proposed to address this, but some cases will likely remain heterogeneity in apraxia
unclassifiable.12,14 Unclassified and unclassifiable PPA are briefly discussed in of speech.
this article after primary progressive apraxia of speech, nonfluent/agrammatic
● Primary progressive
variant PPA, and semantic variant PPA are discussed.
apraxia of speech refers to
cases in which apraxia of
PRIMARY PROGRESSIVE APRAXIA OF SPEECH speech is the sole initial
Apraxia of speech can be defined in simple terms as a “neurological speech manifestation of a
neurodegenerative disease.
disorder that reflects an impaired capacity to plan or program sensorimotor
commands necessary for directing movements that result in phonetically and
prosodically normal speech.”6 This definition also captures the fact that the
relative dominance of phonetic impairment (sound level errors, such as distorted
substitutions or additions) or prosodic impairment (such as slow rate or
segmented speech) is the primary source of heterogeneity in the disorder,
although others exist (TABLE 5-3). This has led to the recognition of subtypes
of apraxia of speech: phonetic (formerly Type 1), prosodic (formerly Type 2),
and mixed (formerly Type 3).10,15
As mentioned previously, while several case reports and retrospective studies
documented the occurrence of apraxia of speech as the initial manifestation of a
degenerative disease,7,8 prospective characterization of apraxia of speech as the
sole manifestation of a neurodegenerative disease occurred within the past
decade. Operational definitions for primary progressive apraxia of speech
continue to be refined and, much like the criteria for PPA, require that features of
other degenerative disorders are not present (TABLE 5-4).
Epidemiology
No studies have formally evaluated the prevalence of primary progressive
apraxia of speech, but based on the proportion of patients with primary
progressive apraxia of speech included in observational studies relative to
disorders for which prevalence has been established, it has been estimated to
be approximately 4.4 per 100,000.16 Age of onset varies considerably, ranging
from the late forties to early eighties, although it is older than age 65 in about
two-thirds of cases. It appears to affect men and women approximately
equally, and no demographic, socioeconomic, or environmental risk factors
are known.

Clinical Presentation
Patients typically present with complaints pertaining to articulating words (eg,
“I know what I want to say but can’t get the words out”) or their overall rate
of speech (CASE 5-1). It is crucial to ask about writing or typing, as preservation
of these forms of communication is often striking despite severe speech
impairment. In fact, many patients continue to work and may rely on assistive
devices despite having little meaningful speech output, in contrast to PPA, in
which these devices are rarely useful. Given the fact that apraxia of speech may
occur early in other degenerative diseases, it is crucial to ask the patient and
family members about cognitive and other symptoms, such as decline in gross or
fine motor skill, changes in gait, and behavioral disturbance. When patients
present later in the course of the illness, features of other degenerative disorders
may accompany severe apraxia of speech, which tends to remain the
predominant symptom. It can be almost impossible to ascertain, after the fact,
whether such patients indeed had primary progressive apraxia of speech that
evolved into a hybrid syndrome (eg, with features similar or identical to those of
corticobasal syndrome or Richardson syndrome) or if the apraxia of speech was
merely one of many abnormalities early in the course of the disorder. However, it
is worth noting that cases in which apraxia of speech dominates over aphasia
appear to have clinical and imaging features that are more like those seen in
TABLE 5-4 Criteria for a Diagnosis of Primary Progressive Apraxia of Speech
Inclusion
◆ Insidious onset and progressive worsening of speech disturbance
◆ Apraxia of speech is the only or dominant speech disturbance at the time of testing
◆ Dysarthria can be present but must be less severe than apraxia of speech
◆ Any evidence of aphasia is considered equivocal
Exclusion
◆ Pattern of deficits is better accounted for by other nondegenerative nervous system or
medical disorders
◆ Cognitive disturbance is better accounted for by a psychiatric diagnosis
◆ Unequivocal evidence for aphasia on detailed language/neuropsychological testing (ie, the
patient may meet root criteria for primary progressive aphasia)
◆ Dysarthria deemed to be more severe than apraxia of speech
◆ Prominent initial episodic memory, visual memory, and visuoperceptual impairments (ie, the
patient may meet criteria for typical or atypical Alzheimer dementia)
◆ Prominent initial behavioral disturbance (ie, the patient may meet criteria for behavioral
variant frontotemporal dementia)
◆ Prominent initial parkinsonism, falls, or eye movement abnormalities (ie, the patient may
meet criteria for progressive supranuclear palsy)
◆ Prominent initial ideomotor apraxia, parkinsonism, dystonia, or other asymmetric motor and
cognitive features excluding speech/language (ie, the patient may meet criteria for
corticobasal syndrome)
◆ Prominent upper and/or lower motor neuron abnormalities (ie, the patient may meet criteria
for motor neuron disease)
106 FEBRUARY 2019

primary progressive apraxia of speech than, for example, nonfluent/agrammatic KEY POINTS
variant PPA.10 Whether these cases should be viewed as a separate entity or a
● In primary progressive
subtype of nonfluent/agrammatic variant PPA has been a source of controversy. apraxia of speech, it is
crucial to ask about writing
Cognitive Examination or typing, as preservation
Patients with primary progressive apraxia of speech typically score well within of these forms of
communication is often
the normal range on bedside cognitive testing and may continue to do so in the
striking despite severe
later disease stages, provided written responses are allowed.8,9 On formal speech impairment.
neuropsychological testing, patients may score in the impaired range on tests that
are dependent on the rate and accuracy of speech, such as lexical or semantic ● Cases in which apraxia of
fluency.8 A discrepancy often exists between tests that allow for written speech dominates over
aphasia appear to have
responses compared to tests in which oral responses are required. Similarly, some clinical and imaging features
patients are motorically slow and so may underperform on certain tests, such as that are more like those seen
the Trail Making Test.8 in primary progressive
apraxia of speech than
nonfluent/agrammatic
Speech and Language Examination variant primary progressive
Referral to a speech and language pathologist is warranted for multiple reasons. aphasia.
First, the referral can be important diagnostically since patients often present
when apraxia of speech is mild and difficult to appreciate. Apraxia of speech is ● Patients with primary
progressive apraxia of
also a heterogeneous disorder with features that overlap with dysarthria and
speech typically score well
aphasia (TABLE 5-3). Spastic and ataxic dysarthria are especially difficult to within the normal range on
differentiate from apraxia of speech in some cases. These are, however, not bedside cognitive testing
typically accompanied by the trial-and-error articulatory attempts, groping, and and may continue to do so in
the later disease stages,
distorted substitutions seen in apraxia of speech. When the predominant features
provided written responses
are prosodic, rather than articulatory, patients are often diagnosed with a are allowed.
functional speech disorder by inexperienced clinicians. Second, referral allows
for more thorough language testing, which is often nontrivial in these patients ● The most helpful parts of
because of the speech difficulties, necessitating specialized batteries to rule out, the speech examination for
primary progressive apraxia
or rule in, any concomitant aphasia. Finally, more than any of the aphasia of speech are those that
syndromes, apraxia of speech may be amenable to speech therapy. demand the production of
The most helpful parts of the speech examination are those that demand motorically complex
the production of motorically complex utterances. An adequate sample of utterances: conversational
or narrative speech,
conversational or narrative speech should be obtained, which also allows the alternating motion rates,
clinician to assess grammar. It is helpful to obtain a written response to the same sequential motor rates, and
question or stimulus for comparison. As for more focused examination of repetition of increasingly
speech mechanisms, assessment of alternating motion rates, sequential motor complex words and
sentences.
rates, and repetition of increasingly complex words and sentences are most
helpful (TABLE 5-5).6 ● About two-thirds of
patients with primary
Neurologic Examination progressive apraxia of
About two-thirds of patients have a coexisting nonverbal oral apraxia, which can speech have a coexisting
nonverbal oral apraxia,
be assessed at the bedside by asking patients to perform simple movements such which can be assessed at
as smacking their lips, clicking their tongue, coughing, or blowing.17 When the bedside by asking the
present in a patient with a progressive but subtle speech impairment, this patient to perform simple
nonverbal oral apraxia raises the probability that the patient may have apraxia of movements such as
smacking their lips, clicking
speech. Care should be taken to differentiate between apractic errors and errors their tongue, coughing,
resulting from comprehension or semantic deficits. In the case of apraxia, or blowing.
patients may show groping, imprecise execution of the correct movement, or
complete inability to complete a simple task such as coughing (often to the
frustration and disbelief of the patient), whereas deft execution of the incorrect

movement, lack of task engagement, or perseveration suggests nonapractic

errors. These may be seen in semantic variant PPA, logopenic variant PPA, and
other dementia syndromes.
Subtle parkinsonian signs, such as rigidity with contralateral activation, mildly
slowed finger tapping, or reduced spontaneous movements, may be present 2
to 3 years into the illness. Around the same time, mild difficulties with limb
praxis can be seen in roughly one-third of participants, typically involving
complex transitive instructions (eg, “pretend to start and drive a car”).8
Neuroimaging
Primary progressive apraxia of speech appears to result from dysfunction of
and damage to a distributed set of cortical and subcortical regions that are
closely linked to the planning, production, and monitoring of speech, with
sparing of language regions such as the inferior frontal gyrus and lateral temporal
regions.8,10,14 Gray and white matter atrophy of the motor, premotor, and
CASE 5-1 A 70-year-old woman presented with a 5-year history of “stumbling over
words” and slowed speech. She had no cognitive symptoms and denied
language difficulties, such as with word finding, spelling, reading,
following conversations, or putting together a sentence. Over time, her
disease progressed to the point that she had minimal intelligible verbal
output and relied on written forms of communication. No clear diagnosis
had been reached despite several evaluations.
On examination, she scored 26/30 on the Montreal Cognitive
Assessment (MoCA). No abnormalities were seen on bedside testing of
frontal lobe function, limb praxis, or higher-order visual processing. Her
speech output was slow and segmented, with frequent distortions and
groping, consistent with severe apraxia of speech (VIDEO 5-1, links.lww.
com/CONT/A263). She had no difficulty naming, reading, writing, or
following instructions, although poor intelligibility complicated testing.
When allowed to respond in writing, she performed well. She had no
evidence for agrammatism on written picture description, review of
emails, or dedicated testing with the Northwestern Anagram Test (a test
of grammar). She was slightly bradykinetic on motor testing but had
normal extraocular movements and no postural instability or gait
changes. Neuropsychological testing was normal accounting for slowed
and distorted speech, which negatively impacted tests of verbal and
semantic fluency, and slightly slowed performance on the Trail Making Test.
A clinical diagnosis of primary progressive apraxia of speech was made.
Brain MRI did not reveal atrophy beyond that expected for her age
(FIGURE 5-1A). A fludeoxyglucose positron emission tomography (FDG-PET)
scan was performed and revealed hypometabolism of the supplementary
and premotor areas bilaterally, with no involvement of inferior frontal
(Broca) or posterior temporal (Wernicke) areas (FIGURE 5-1B).
108 FEBRUARY 2019

supplementary motor areas bilaterally has been reported at a group level, but
it is worth noting that this may be hard to appreciate, and fairly asymmetric,
on the individual level. Subcortical structures, including the striatum and
midbrain, may also be involved. Although hypometabolism on fludeoxyglucose
positron emission tomography (FDG-PET) typically occurs in these same areas,
abnormalities may be more noticeable on the individual level using this modality
compared to MRI (FIGURE 5-2). With progression, patients with primary
progressive apraxia of speech often show midbrain atrophy, in contrast to
nonfluent/agrammatic variant PPA without apraxia of speech.10
Genetics
While case reports exist of known genetic mutations presenting with prominent
and early apraxia of speech, the majority of these patients had coexisting
behavioral, motor, cognitive, or language impairment. A 2015 evaluation of a
large, prospectively recruited cohort of patients with primary progressive
FIGURE 5-1
MRI and fludeoxyglucose positron emission tomography (FDG-PET) findings of the patient in
CASE 5-1. A, Coronal T1-weighted MRI shows a relative lack of atrophy. B, The stereotactic
surface projection z-score map of the patient’s FDG-PET shows focal hypometabolism of the
supplementary motor and dorsolateral premotor areas. (Black/dark blue represent normal
uptake; green/yellow/red represent worsening degrees of hypometabolism.)
This case highlights several characteristic features of primary progressive apraxia COMMENT
of speech. This patient’s problems were primarily phonetic, which tend to be
easier to appreciate than predominantly prosodic symptoms. Despite being
5 years into the illness, her only difficulty was with speech. In fact, she found an
electronic communicative device incredibly helpful, which greatly aided her
independence. However, if her speech problem had not been recognized, she
may have been diagnosed with aphasia because of impaired verbal responses.
The subtle parkinsonism was expected at this stage. The very restricted
involvement on FDG-PET was consistent with her isolated motor speech disorder.

apraxia of speech and PPA did not document any mutations in the three genes
most commonly associated with frontotemporal lobar degeneration pathology
(MAPT, GRN, C9orf72) in patients with primary progressive apraxia of speech.18
While one in four patients reported a family history of neurodegenerative disease,
a history of multiple affected first-degree relatives was found in only 5%, with the
majority of cases occurring after 60 years of age. As such, a diagnosis of primary
progressive apraxia of speech appears to confer a relatively low risk of an
underlying genetic mutation compared to other disorders associated with tau,
especially in comparison to behavioral variant frontotemporal dementia (bvFTD).
Prognosis
All patients with primary progressive apraxia of speech appear to develop
parkinsonian signs, usually with axial greater than appendicular rigidity, and all
patients develop worsening of their apraxia of speech.9 Approximately 40% of
patients develop a progressive supranuclear palsy (PSP)/corticobasal
syndrome–like disorder, which has been termed progressive supranuclear
palsy–apraxia of speech, approximately 5 years into their illness. This is
characterized by slowing of saccades or frank supranuclear gaze palsy, ideomotor
apraxia that may be asymmetric, falls, and a frontal lobe syndrome of
neuropsychological impairment. Dysphagia, urinary incontinence, dysarthria
(spastic more than hypokinetic), and aphasia with agrammatism are often
accompanying features in these patients. In the remaining 60% of patients,
worsening apraxia of speech remains the primary issue, although mild cognitive
impairment and aphasia may be present. It does not appear that aphasia
worsens to the point of overtaking apraxia of speech unless accompanied by
more general cognitive and motor decline, at which point patients may be most
appropriately labeled as having an alternative clinical diagnosis (eg, PSP or
corticobasal syndrome).
Neuropathology
The overwhelming majority of autopsied cases of primary progressive apraxia of
speech reported in the literature were found to have an underlying 4-repeat
tauopathy, with corticobasal degeneration pathology being the most common.
TABLE 5-5 Helpful Aspects of the Bedside Speech and Language Examination
Obtained as Part of Language Examination

◆ Conversational or narrative speech sample
◆ Conversational or narrative writing sample
◆ Sentence repetition
Focused Speech Examination
◆ Speech alternating motion rates (rapid repetition of puh, tuh, and kuh sounds individually)
◆ Speech sequential motion rates (rapid repetition of puh-tuh-kuh sequence)
◆ Repetition of graded-in-complexity words (eg, cat, catnip, catapult, catastrophe, specific,
with each word repeated 3 times)
◆ Nonverbal oral praxis assessment
110 FEBRUARY 2019

FIGURE 5-2
Surface projections of typical patterns of hypometabolism in primary progressive apraxia of
speech (A) and dominant apraxia of speech with coexisting agrammatic aphasia (B).
Isolated case reports of patients with a primary progressive apraxia of

speech–like syndrome but with underlying Pick disease (3-repeat tau) or even
nontau have been reported, but whether these patients truly had isolated apraxia
of speech at onset is unclear.
NONFLUENT/AGRAMMATIC VARIANT PRIMARY PROGRESSIVE APHASIA

Nonfluent/agrammatic variant PPA may be the most heterogeneous of PPA
subtypes, in large part because of variable interpretations of the criteria. First,
patients with isolated apraxia of speech may be included if the root PPA criteria
are not applied. Even more uncertainty exists when it comes to cases in which
apraxia of speech is the predominant source of impairment but unequivocal
evidence for aphasia is present. Impaired grammar, despite the name of the
disorder, is also not required by the criteria. Some have argued that this should be
a core feature,12,14 whereas others have proclaimed that neither agrammatism nor
apraxia of speech is present in the majority of cases.19 This may seem confusing at
first but results from emphasis being placed on a loss of fluency and telegraphic
verbal output rather than grammar. Variable interpretations of fluency have
also plagued this disorder, with some interpreting the frequent word-finding
pauses seen in PPA as a loss of fluency and others viewing fluency as synonymous
with rate and accuracy of speech. However, if neither agrammatism nor apraxia
of speech is present, the differentiation between this and logopenic variant
PPA becomes very difficult (TABLE 5-2). It is no surprise that this variant has
the weakest association with any one neuropathologic entity.
This article focuses on cases in which agrammatism is present. In the authors’
opinion, PPA cases that appear nonfluent but without agrammatism are best
labeled unclassified, assuming they do not meet criteria for logopenic variant
PPA, as discussed later in this article. Even with this prerequisite, some
heterogeneity still exists, resulting from the presence/absence of apraxia of

speech. Given the importance of apraxia of speech from a diagnostic and

therapeutic standpoint, the authors view nonfluent/agrammatic variant PPA as
consisting of two subgroups: those with apraxia of speech and agrammatic
aphasia, which is by far the most common, and those with agrammatic aphasia in
the absence of apraxia of speech. Where such data exist, this article highlights
clinical and imaging features with reference to these two subgroups.
Epidemiology
Based on the relative proportion of cases included in clinical and autopsy series,
the prevalence of nonfluent/agrammatic variant PPA has been estimated to be
0.5 to 3.9 per 100,000 people.20 Although the age of onset varies greatly,
including patients diagnosed in their eighties, the average age of onset appears to
be around 60. Men and women appear to be at equal risk and, although no
socioeconomic, demographic, or environmental risk factors have been validated,
a higher proportion of patients with degenerative speech and language disorders
CASE 5-2 A 68-year-old woman presented with a 2-year history of word-finding

difficulty, reduced verbal output, and word choice errors. Specifically,
her family noticed frequent reversal of yes and no and shorter sentences
overall, at times with words left out. She had no cognitive or motor
complaints, which was corroborated by her family.
Assessment (MoCA), primarily losing points on language subtests.
Bedside testing of frontal lobe function was normal. She was moderately
aphasic, with impaired comprehension of complex instructions, reduced
category and action fluency, agrammatic verbal and written output, and
impaired performance on the Northwestern Anagram Test (a test of
grammar) (VIDEO 5-2, links.lww.com/CONT/A264). Minimal abnormalities
were noted on repetition and naming, and she had no loss of word or
object knowledge. During conversational speech and verbal portions of
the language examination, she had a normal rate and prosody and no
distorted substitutions or articulatory errors. On dedicated motor speech
examination, vowel prolongation did not reveal any phonatory or
resonance abnormalities, and her speech sequential and alternating
motion rates were both normal. In other words, she showed no features
to suggest apraxia of speech or dysarthria. She had no evidence of
ideomotor apraxia and no parkinsonism, extraocular movement
abnormalities, or changes in her gait. The rest of her examination was
normal. A clinical diagnosis of nonfluent/agrammatic variant primary
progressive aphasia (PPA) was made.
Her MRI showed left frontal periopercular and insular atrophy (FIGURE 5-3A).
A fludeoxyglucose positron emission tomography (FDG-PET) scan was
performed and revealed hypometabolism of the inferior frontal and
medial prefrontal regions on the left (FIGURE 5-3B).
112 FEBRUARY 2019

appear to be teachers than is seen in Alzheimer disease or the population in
general.21 The majority of nonfluent/agrammatic variant PPA cases have
coexisting apraxia of speech, with estimates ranging from 56% to 86%,
depending largely on whether cases in which apraxia of speech dominates
over aphasia are included despite not meeting core PPA criteria.10,14,22
While some patients or informants may volunteer examples of impaired
grammar or syntax (eg, “sometimes I drop words” or “he uses words out of
order”), focused questioning is often necessary to reveal early problems. In
general, it is difficult to obtain a history of impaired comprehension of
grammatically complex sentences, and thus, the focus is usually on language
output. Serial samples of written language, such as emails or letters, may reveal
issues before they are evident in verbal output. Patients and family members may
notice reversal of binary terms, such as yes and no or him and her (CASE 5-2).
FIGURE 5-3
Imaging of the patient in CASE 5-2. A, Coronal T1-weighted MRI shows medial and lateral
prefrontal, insular, and inferior frontal atrophy on the left. B, The stereotactic surface
projection z-score map of the patient’s fludeoxyglucose positron emission tomography
(FDG-PET) scan shows focal hypometabolism involving the left inferior frontal and medial
prefrontal regions. (Black/dark blue represent normal uptake; green/yellow/red represent
worsening degrees of hypometabolism.)
This patient had no apraxia of speech, illustrating one end of the COMMENT
nonfluent/agrammatic variant PPA spectrum. Many patients with
nonfluent/agrammatic variant PPA will have some apraxia of speech, just
as many patients with predominant apraxia of speech will have some
agrammatism. It is easy to classify patients with only one of these disorders
and much harder when both are present to about the same degree. Also
note, in contrast to CASE 5-1, hypometabolism here is present anterior to the
supplementary motor area, in keeping with the lack of apraxia of speech in
this case, and clear involvement of the inferior frontal region is seen, in
keeping with her agrammatism.

If apraxia of speech is present, the initial symptoms may overlap with those
discussed for primary progressive apraxia of speech. As mentioned previously,
the diagnostic classification of cases in which the dominant feature is apraxia of
speech but clear agrammatism is present is controversial. If the root PPA criteria
were applied strictly, these cases would not qualify for a diagnosis of PPA as
speech, rather than language, is the primary cause of clinical impairment.
Furthermore, cross-sectional clinical and imaging studies have documented
differences between “dominant apraxia of speech” and “dominant aphasia”
cases.10,14 However, longitudinal data and autopsy-confirmed studies are
lacking, and, as such, most research programs have continued to include cases in
which apraxia of speech dominates in the nonfluent/agrammatic variant PPA
category.1,23 In the authors’ experience, cases of nonfluent/agrammatic variant
PPA with apraxia of speech have a different disease course than “pure”
agrammatic cases, but it is less clear whether dominant apraxia of speech cases
evolve differently from dominant agrammatic cases.
It is not uncommon for family members to mention that the patient has become
quieter or less talkative, and during the interview it can be very difficult to get more
than a few words from the patient in response to questions. However, it is
important to note that a lack of spontaneous verbal output or the reliance on short
answers does not imply impaired grammar or syntax. Abulia can be seen in many
neurodegenerative diseases and may be limited to speech early in some cases. This
may represent a distinct entity, which some have argued should be recognized as
a subtype of PPA reminiscent of Luria’s dynamic aphasia,24 but in the authors’
opinion, these patients should not be diagnosed with nonfluent/agrammatic
variant PPA unless unequivocal evidence for agrammatism is present. Psychomotor
slowing is common, and symptoms pertaining to fine motor movements (eg,
writing) or motoric slowing in general (eg, slowed gait) may be present.
Speech and Language Examination

Examining for apraxia of speech is similar to the examination described for
primary progressive apraxia of speech. It is important to establish if apraxia of
speech is present and how severe it is, since that may limit the rest of the
examination. When assessing language ability, it is important to bear in mind
that aphasia typically involves all aspects of language to varying degrees, and
thus the PPA classification depends on the relative impairment. Naming and
word-finding difficulties are common to all PPA variants,25 although patients
with nonfluent/agrammatic variant PPA should recognize the target word if
provided. Typically, patients with nonfluent/agrammatic variant PPA are not
significantly impaired on testing of repetition, word meaning, semantic
association, or writing and reading of irregularly spelled words. However, with
sufficiently challenging tests, some impairment in these areas may be revealed.
These should be overshadowed by impairments in grammar and syntax for this
diagnosis to be considered. That being said, assessing grammatical ability can be
challenging, and no single test appears to have optimal sensitivity. It is crucial to
obtain a good sample of conversational speech, such as asking patients to explain
their occupation or a sport. For example, when asked to explain baseball, one
patient responded: “Uh…baseball…it’s a…you have…there’s three strikes and
you’re out. Uh…pitchers line up against batters. They throw…they throw the
strikes. Uh…the score…uh…the…first base…second base, shortstop is a…third
base and there’s fielders. Right field, left field, center field, and left field.”
114 FEBRUARY 2019

It is also helpful to review samples of written language, such as emails, as they KEY POINTS
frequently contain errors involving word order or functional morphemes (eg,
● Gray and white matter
incorrect use of suffixes meant to convey verbal inflections or plurality or atrophy of the motor,
omission of conjunctions), in addition to spelling errors seen in all PPA variants. premotor, and
Verbal picture description is revealing in some patients, although it is important supplementary motor areas
to specify that full sentences are expected. Written language output may be more bilaterally has been
reported in primary
sensitive, and obtaining a written picture description is advised (FIGURE 5-4).
progressive apraxia of
Referral to a speech and language pathologist is advised for more detailed testing speech at group level, but it
and discussion of treatment options. Tests focused more explicitly on grammar, is worth noting that this may
such as the Northwestern Anagram Test, can be considered.26 be fairly asymmetric at the
single patient level.
Cognitive Examination ● Approximately 40% of

Patients with nonfluent/agrammatic variant PPA often score in the abnormal patients with primary
range on screening tests such as the Mini-Mental State Examination (MMSE) or progressive apraxia of
speech develop a
Montreal Cognitive Assessment (MoCA). Reduced spontaneous verbal output progressive supranuclear
coupled with agrammatism can also complicate cognitive testing, along with palsy/corticobasal
psychomotor slowing and apraxia of speech, if present. Patients may show mild syndrome–like disorder,
evidence of frontal lobe dysfunction in the form of perseveration, impulsivity, which has been termed
progressive supranuclear
and attentional deficits. On neuropsychological testing, patients may be impaired palsy–apraxia of speech,
on problem-solving tasks and typically struggle with encoding more than recall approximately 5 years into
on episodic memory tasks.27 Action or verbal fluency appears to be more their illness.
impaired than letter or category fluency. Poor planning during visuospatial tasks
● The overwhelming
may be seen.
majority of autopsied cases
of primary progressive
Neurologic Examination apraxia of speech reported
in the literature were found
The rest of the neurologic examination is typically unrevealing, although mild
to have an underlying
ideomotor apraxia and parkinsonism are possible. Increased reflexes or the 4-repeat tauopathy, with
emergence of pathologic reflexes (eg, Babinski sign or frontal release signs) may corticobasal degeneration
be seen. If neurologic abnormalities are found asymmetrically, it suggests that pathology being the most
corticobasal syndrome may develop over time. Although rare, some patients common.
present with nonfluent/agrammatic variant PPA and develop a pyramidal ● While some patients or
informants may volunteer
examples of impaired
grammar or syntax, focused
questioning is often
necessary to reveal
early problems.
● When assessing language

ability, it is important to
bear in mind that aphasia
typically involves all aspects
of language to varying
degrees, and thus the
primary progressive aphasia
classification depends on
the relative impairment.
FIGURE 5-4
Example of agrammatism in written picture description.

syndrome, such as amyotrophic lateral sclerosis; therefore, close examination

for fasciculations and atrophy is warranted.
Neuroimaging
The anterior portions of the language network appear to be most vulnerable in
nonfluent/agrammatic variant PPA. The dominant inferior frontal lobe,
including Broca areas 44 and 45, is almost always involved. Other dominant
anterior opercular and perisylvian areas are often involved, including the
anterior insula and superior temporal gyrus. When apraxia of speech is present,
the dorsolateral premotor cortex, motor cortex proper, and supplementary
motor areas may be involved (FIGURE 5-5).
Genetics
Although up to one-third of patients with PPA may report a family history of
neurodegenerative disease, mutations are rarer than those seen in bvFTD.18,20
Cases with features of nonfluent/agrammatic variant PPA have been reported as
resulting from mutations in each of the three main frontotemporal lobar
degeneration genes (MAPT, GRN, and C9orf72), although at least some of these
had associated behavioral, cognitive, or motor symptoms early in the disease
course.28 Prospectively recruited PPA cohorts suggest mutations are a rare cause
of sporadic nonfluent/agrammatic variant PPA.20
Prognosis
The heterogeneity inherent in nonfluent/agrammatic variant PPA and variable
interpretations of the criteria have complicated the study of the prognosis and
natural history of the disorder. Patients may progress along several different
FIGURE 5-5
Surface projections of typical patterns of hypometabolism in nonfluent/agrammatic variant
primary progressive aphasia (A) and semantic variant primary progressive aphasia (B).
116 FEBRUARY 2019

trajectories. Some develop more behavioral abnormalities and may later meet KEY POINTS
criteria for bvFTD. These patients may be more at risk of coexisting motor neuron
● When evaluating patients
disease. Others develop features of corticobasal syndrome or PSP. This appears for nonfluent/agrammatic
to be more common in those with apraxia of speech, and the relative prominence variant primary progressive
of articulatory or prosodic difficulty may be predictive of the rate of worsening aphasia, it is helpful to
aphasia or parkinsonism, respectively.29 Median survival appears to be around review samples of written
language, such as emails, as
7 years,20 although this varies greatly, at least in part because of the variety of
they frequently contain
underlying pathologic processes. In the authors’ experience, cases of nonfluent/ errors involving word order
agrammatic variant PPA without apraxia of speech have a less favorable prognosis. or functional morphemes.
Neuropathology ● The rest of the neurologic

As alluded to previously, nonfluent/agrammatic variant PPA variant lacks the examination is typically
unrevealing in nonfluent/
tight clinicopathologic association seen in the other variants. In fact, it appears agrammatic variant primary
that the disorder can be associated with 3-repeat tau (Pick disease), 4-repeat progressive aphasia,
tau (corticobasal degeneration or PSP pathology), transactive response although mild ideomotor
DNA-binding protein 43 (TDP-43), and, in cases where agrammatism is not apraxia and parkinsonism
are possible.
emphasized, even Alzheimer disease.28 However, the subset of nonfluent/
agrammatic variant PPA cases with apraxia of speech is more likely to have ● The anterior portions of
underlying 4-repeat tau.22 Similarly, coexisting motor neuron disease would be the language network
predictive of underlying TDP-43 pathology. appear to be most
vulnerable in nonfluent/
agrammatic variant primary
SEMANTIC VARIANT PRIMARY PROGRESSIVE APHASIA/SEMANTIC progressive aphasia,
DEMENTIA including Broca areas
First described more than a century ago,3 semantic dementia has continued to 44 and 45.
fascinate behavioral neurologists in the 21st century. Warrington30 postulated ● The subset of nonfluent/
that the syndrome results from a breakdown in semantic memory, the amodal agrammatic variant primary
and time-independent knowledge store, in contrast to the episodic memory progressive aphasia cases
system, which is involved with recall of specific events or experiences. This with apraxia of speech are
more likely to have
has remained the leading hypothesis, as the later stages of the disease are underlying 4-repeat tau.
characterized by a severely eroded knowledge base, regardless of the modality
used to probe it (eg, verbal versus nonverbal), with relatively spared episodic ● Semantic dementia
and autobiographical memory. However, as mentioned previously, most patients results from a breakdown in
semantic memory, the
do present with language-related symptoms, and these patients usually meet
amodal and time-
criteria for PPA, thus this subset has been subsumed under the PPA criteria. The independent knowledge
authors feel it is important to discuss the approximately 30% or so of patients store, in contrast to the
who do not meet PPA criteria and who often present with predominant right episodic memory system,
temporal disease.31 This article uses the term semantic dementia to refer to the which is involved with recall
of specific events or
broader syndrome, including those who do not meet criteria for PPA, and uses experiences.
semantic variant PPA when referring to the subset of patients who present with
predominant language difficulty. ● About 70% of cases of
semantic dementia have
predominant left-sided
Epidemiology involvement (ie, would be
Dedicated prevalence studies in semantic dementia are lacking, but it is estimated viewed as semantic variant
that it accounts for one-fourth to one-third of frontotemporal dementia cases.32,33 primary progressive
Based on frontotemporal dementia prevalence estimates of 10 to 22 per 100,000 aphasia), while the
remaining 30% present
people, that would suggest a prevalence of 2.5 to 7.3 per 100,000 for semantic with predominant right-
dementia.32,34 sided involvement.
The average age of onset in semantic dementia appears to be around 60,
although it is worth noting that about one-fourth of cases may present after the
age of 70.35 About 70% of cases have predominant left-sided involvement (ie,

would be viewed as semantic variant PPA), while the remaining 30% present
with predominant right-sided involvement.35,36 As mentioned previously, a
higher number of teachers is seen among patients with degenerative speech and
language disorders, but beyond that, no socioeconomic, demographic, or
environmental risk factors for semantic dementia are known.
Most commonly, patients with semantic variant PPA present with language-
or memory-based symptoms, such as word-retrieval difficulties or trouble
remembering words. Nouns are typically most difficult, which may result in
circumlocution (eg, saying device for moving around in place of car), the use of a
more general or category label (eg, animal for dog), or the use of nonspecific filler
words (eg, thing or place). However, it is not uncommon for patients to be
relatively blind to the extent of their impairment. Perhaps more than any of the
other syndromes discussed in this article, the diagnosis of semantic dementia
often hinges on focused history taking, including from collateral sources, and
dedicated bedside cognitive testing. Specifically asking family members about a
history of loss of word meaning is crucial and often results in striking examples
(such as the patient not knowing what asparagus is). The same is true of
right-sided semantic dementia, which may present later, typically with
associative agnosias such as prosopagnosia (loss of face knowledge and hence
recognition). Patients are unlikely to volunteer examples of misidentification of
acquaintances or the complete lack of recognition of family members. Yet, when
asked, a history of not recognizing a best friend or repeatedly introducing
themselves to a brother-in-law may be revealed.
An overlap exists between right-sided semantic dementia and right
temporal predominant bvFTD,37 and, unsurprisingly, patients with
right-sided semantic dementia are more likely to have behavioral disturbances
than those with semantic variant PPA.36 That being said, behavioral
symptoms are more common in semantic variant PPA than in any of the other
PPA variants.25
Cognitive Examination
Patients with semantic dementia may struggle on some aspects of general
bedside screening tests, especially if they require naming, but early on, most
patients perform well. Similarly, most patients do not have evidence of frontal
lobe dysfunction. The most helpful tests tend to be those specifically targeted
toward semantic dementia. Testing for a breakdown of semantic memory can be
broadly split into verbal and nonverbal measures, although most involve some
degree of both. Verbal testing, which is most helpful in semantic variant PPA, is
discussed later in this article; the focus here is on nonverbal tests, which tend
to be more helpful in right-sided semantic dementia.
Testing for prosopagnosia is usually done by showing pictures of celebrities or
other famous people and asking the patient to either identify the famous face
among distractors or to provide some information to prove that they have
correctly recognized the person. This is not a naming test, although patients will
likely name the people they recognize. When faces are not recognized, it is often
helpful to probe further. For example, if a patient fails to recognize Michael
Jordan (“I think he is a movie star or singer”), it can be helpful to ask who, in fact,
Michael Jordan is. In more advanced cases, a dense loss of person knowledge is
118 FEBRUARY 2019

seen, often accompanied by loss of knowledge about historically important KEY POINTS
events, such as World War II or the Civil War.
● Nouns are typically most
Another helpful set of bedside tests involves matching pictures, sounds, or difficult for patients with
smells without requiring any explicit verbal response. For example, the patient semantic variant primary
may be played a sound and shown four pictures to choose from, or the patient progressive aphasia,
may be shown a stimulus picture (eg, a strawberry) and asked to choose the best which may result in
circumlocution, the use of a
fit from other pictures (eg, cream, butter, and salt). Many of these tests are
more general or category
possible at the bedside, although formal neuropsychological tests are available label, or the use of
that follow the same design. In general, one would expect concepts at the edge of nonspecific filler words.
semantic space to be affected first, which translates to a failure to identify less
familiar objects and people first. ● Testing for prosopagnosia
is usually done by showing
One important thing to note when reviewing neuropsychological testing on patients pictures of
patients with semantic dementia is how pervasive the effect of loss of word celebrities or other famous
knowledge can be. Remembering a word list can be hard if the words are not people and asking them to
recognized, for example. In general, patients with semantic dementia have spared either identify the famous
face among distractors or to
episodic memory, but it may require modification of the battery to show this. provide some information
to prove that they have
Speech and Language Examination correctly recognized the
The most prominent feature on language testing in semantic variant PPA is person.
anomia, which is often severe. However, anomia in itself does not differentiate
● Whereas patients with
semantic variant PPA from the other subtypes. Instead, loss of word meaning nonfluent/agrammatic
must be demonstrated if it was not evident on history. This can be explored variant or logopenic variant
during the naming task by first providing a verbal cue and then providing a list of primary progressive aphasia
typically benefit greatly
possible words to choose from for unnamed items. Whereas patients with
from cueing on unnamed
nonfluent/agrammatic variant PPA or logopenic variant PPA typically benefit items, patients with
greatly from this, patients with semantic variant PPA often fail to choose the semantic variant primary
correct word from a small list. Further probing can involve asking them what the progressive aphasia often
correct word refers to. For example, one patient could not name a scorpion, fail to choose the correct
word from a small list.
did not benefit from a verbal cue, and chose a different word when presented
with choices. Asked to define the word scorpion she said it was “a plaything for ● A supportive, albeit not
kids.” Verbal batteries are available that follow the same design as the nonverbal specific, feature of semantic
batteries discussed previously, in which the patient is provided with a word variant primary progressive
aphasia is trouble with
and asked to match it to another related word or to one of a number of pictures. reading (surface dyslexia)
A supportive, albeit not specific, feature is trouble with reading (surface and writing {surface
dyslexia) and writing (surface dysgraphia) of irregularly spelled words such as dysgraphia) of irregularly
yacht, colonel, and debt (CASE 5-3 and FIGURE 5-5). These words do not follow the spelled words, such as
yacht, colonel, and debt.
typical lexical-phonetic rules and require the recognition of the entire word to be
pronounced or written correctly. Patients may write them phonetically (eg, det
for debt) and regularize them during reading (co-lo-nel) (FIGURE 5-7).
Speech, grammar, and repetition are typically spared, and sentence
comprehension tends to be better than single-word comprehension since the
context may provide sufficient clues as to what is required. Patients with
right-sided semantic dementia will likely show mild deficits on language-related
semantic memory tests early on, just as patients with semantic variant PPA may
show deficits on nonverbal tests, such as recognition of famous faces.
Neurologic Examination
The remaining parts of the neurologic examination are usually unremarkable in
semantic dementia. In a small subset of patients, features of motor neuron
disease emerge during the illness, so a close motor examination is still warranted.

Ideomotor apraxia, parkinsonism, oculomotor abnormalities, and gait changes

should, however, prompt a reevaluation of the diagnosis.
Neuroimaging
Focal anterior temporal pole involvement is characteristic of semantic dementia
(FIGURE 5-5).32 While usually bilateral, with the left side being more involved in
semantic variant PPA and the right side more involved in right-sided semantic
dementia, some patients have involvement of only one side. This is especially
common early in the disease course. Atrophy tends to be more severe and hence
CASE 5-3 A 68-year-old right-handed man presented with a history of word-

retrieval difficulty. According to his wife, the difficulty had been
gradually progressing over the past 2 years, although the patient felt it
had only been present for 6 months. He felt that he could not “figure
out how to answer questions” because he could not “get the words”
and that reading was more laborious. His wife noticed that he had
become less specific in his language, substituting device for many
inanimate objects and friend for anyone outside his nuclear family. She
also brought up examples of common words he did not comprehend,
such as button.
On examination, he scored 26/30 on the Mini-Mental State
Examination (MMSE) and performed well on bedside tests of frontal
lobe function. He was able to recognize famous faces, although he
could not name them. He had no speech abnormalities. Detailed
language testing (VIDEO 5-3, links.lww.com/CONT/A265) revealed
marked difficulty with naming, with only moderate improvement after
cueing. He did not appear to recognize some objects and had a hard
time matching pictures based on their semantic association (eg,
matching a bicycle with a bicycle helmet rather than a football or
motorcycle helmet). He had difficulty reading irregular words, and his
picture description contained numerous nonspecific words such as
device and thing. Grammar, repetition, and sentence comprehension
were unaffected. Neuropsychological testing was notable for mild
verbal memory impairment but no impairment on testing of visual
memory. He was clinically diagnosed with semantic variant primary
progressive aphasia.
His brain MRI showed severe medial, inferior, and anterior
temporal atrophy on the left (FIGURE 5-6A). A fludeoxyglucose positron
emission tomography (FDG-PET) scan was done and demonstrated left
anterior temporal hypometabolism, most severe in the temporal pole
and amygdala, and orbitofrontal hypometabolism (FIGURE 5-6B).
120 FEBRUARY 2019

easier to appreciate in semantic dementia than in other PPA subtypes. Medial and
lateral anterior temporal structures are involved, including the middle and inferior
temporal gyri, fusiform gyri, and amygdala, with widening of the collateral
sulci. While the Papez circuit is involved in semantic dementia, the mammillary
bodies and the body and tail of the hippocampus are typically spared, in keeping
with the spared episodic memory seen in the disorder.38 This may be helpful in
differentiating it from other disorders affecting the medial temporal lobe, such as
hippocampal sclerosis. FDG-PET is almost always abnormal by the time patients
present for evaluation and can be considered in cases in which the diagnosis is unclear.
FIGURE 5-6
Imaging of the patient in CASE 5-3. A, Coronal T1-weighted MRI shows severe medial, inferior,
and anterior temporal atrophy on the left as well as left insular and left frontal atrophy. B, The
stereotactic surface projection z-score map of the patient’s fludeoxyglucose positron emission
tomography (FDG-PET) scan shows left anterior temporal hypometabolism, most severe in the
polar and medial temporal areas, as well as left inferior temporal and orbitofrontal
hypometabolism. (Black/dark blue represent normal uptake; green/yellow/red represent
worsening degrees of hypometabolism.)
This case is representative of the left temporal predominant form of semantic COMMENT
dementia (or semantic variant primary progressive aphasia). The patient had no
evidence of right temporal involvement on testing (he had no prosopagnosia
but rather trouble with naming) or imaging, although he had trouble on semantic
association tasks in which a verbal response was not explicitly required, in
keeping with a breakdown of semantic memory. The pattern of severe
temporal polar atrophy is almost exclusively seen in this disorder.

FIGURE 5-7
Example of surface dysgraphia when writing to dictation.
Prognosis
Median survival is longer than is typically associated with frontotemporal lobar
degeneration pathology, on the order of 10 to 13 years.35 Education, occupation,
gender, and age at presentation do not appear to impact survival.35 Over time,
both temporal lobes become severely atrophic and the aforementioned left and
right dominant syndromes merge. However, it appears that right-sided cases
progress with more orbitofrontal involvement, and hence more behavioral
disturbance, than left-sided cases.36 The small subset of patients with coexisting
motor neuron disease naturally have a far shorter disease course.
Genetics
Semantic dementia appears to be the frontotemporal dementia syndrome with
the lowest risk of an underlying genetic cause. A history of early-onset dementia
in first-degree family members is unusual, and documented cases of genetic
mutations associated with semantic dementia are considered rare.32,35 Despite
this rarity, cases of semantic dementia due to mutations in each of the three
major frontotemporal dementia genes have been published.
Neuropathology
The majority (>80%) of semantic dementia cases are associated with the
accumulation of TDP-43 Type C, making it is one of the frontotemporal
dementia syndromes with the highest pathologic predictive value. The
remaining cases are due to TDP-43 Type A or Type B, a tauopathy (typically
Pick disease), or Alzheimer disease.
MIXED AND UNCLASSIFIED PRIMARY PROGRESSIVE APHASIA

The current consensus criteria for PPA leave a number of cases unclassified.13,14
However, as with most tools in medicine, criteria have to balance specificity,
sensitivity, and practicality, thus some cases will always be unclassifiable.
Some patients do not meet criteria for a PPA subtype because the cases are too
mild (eg, cases of isolated anomia). Over time, these patients may progress to
meet criteria for semantic variant PPA or logopenic variant PPA, so this is not
particularly problematic. Other cases are too severe, rendering them difficult to
test and characterize. These cases are likely to remain unclassified. Even so,
the presence of certain features (eg, apraxia of speech) may still influence
122 FEBRUARY 2019

management and can still be predictive of the underlying pathology. Some KEY POINTS
cases, however, appear to be unclassifiable throughout the entire disease
● Focal anterior temporal
course (ie, not because they are too mild or too severe). Some of these pole involvement is
represent truly mixed cases, meeting major criteria for more than one characteristic of semantic
subtype, and likely have multiple pathologies. For example, the presence of dementia.
loss of word meaning and apraxia of speech suggests both TDP-43 and
● Semantic dementia
4-repeat tau.39 Other cases may not be mixed but are distinct enough that
appears to be the
some researchers have suggested additional PPA subtypes to capture them frontotemporal dementia
(eg, primary progressive speech abulia24). syndrome with the lowest
risk of an underlying
CLINICAL APPROACH TO DEGENERATIVE SPEECH AND genetic cause.
LANGUAGE DISORDERS ● The majority (>80%) of

Given the variable interpretations of the consensus criteria for PPA and the semantic dementia cases
controversy surrounding primary progressive apraxia of speech, the approach are associated with the
to patients will vary significantly from center to center. An approach that is accumulation of TDP-43
Type C.
consistent with the discussion of the disorders in this article is outlined in
FIGURE 5-8. While it may seem complicated at first, the approach rests on a ● Even in unclassified or
few simple questions that can be answered with the tests outlined previously. mixed cases of primary
Accurate and consistent classification in the research setting will improve progressive aphasia, the
presence of certain features
external validity and clinical trial enrollment. It is also important in the clinical
(eg, apraxia of speech) may
setting, given the distinct prognoses discussed previously, the varying degrees still influence management
of genetic risks between diagnoses, and the different approaches to treating and can still be predictive of
speech and language disorders. the underlying pathology.
The first crucial branching point involves establishing whether the patient has
a predominantly speech-based or a predominantly language-based disorder.
Within speech-based disorders, the next step is establishing whether apraxia of
speech is present and, if so, whether it is the only feature or not (TABLE 5-3 and
TABLE 5-4). This branch allows for the identification of primary progressive
apraxia of speech, cases of apraxia of speech dominating over aphasia, and
apraxia of speech embedded within a nonaphasic syndrome.
If language is the primary problem, the next step is to establish whether the
core criteria for PPA are met (TABLE 5-1). This allows the differentiation of the
PPA syndromes from aphasia embedded within a broader cognitive syndrome,
such as dysexecutive Alzheimer disease or other causes of aphasic dementia.
Within the PPA branch, the patient is then classified as having a specific subtype
(TABLE 5-2), mixed subtype, or unclassified subtype.
The last branch in the approach allows for the inclusion of right temporal
predominant semantic dementia cases. It is worth noting that some would simply
include these as a PPA. Given the pathologic similarity, this is not a point of
major contention.
MANAGEMENT OF SPEECH AND LANGUAGE DISORDERS

No medications have been shown to be beneficial in degenerative apraxia of
speech or aphasia, although clinical trials targeting the underlying proteinopathies
in these disorders are under way. Medications may play a role in the nonspeech-
and nonlanguage-associated features, such as symptomatic management of
behavioral disturbances, but the approach here is no different from treating
abnormal behaviors in bvFTD.
The lack of pharmacologic options should not dissuade the physician or
patient from seeking therapeutic options, however. Speech therapy can be

FIGURE 5-8
Approach to the patient with a suspected degenerative speech or language disorder.
1
Note that some would suggest including these patients in the nonfluent/agrammatic variant primary
progressive aphasia group, which may be appropriate provided agrammatism is present.
2
For example, apraxia of speech may be embedded in a corticobasal syndrome phenotype.
3
For example, progressive spastic-flaccid dysarthria may suggest motor neuron disease.
4
The patient may have an aphasic dementia due to any number of etiologies, for example.
5
Note that some would suggest including these patients in the semantic variant primary progressive aphasia group.
6
Some patients present with language symptoms but, in fact, have visual or working memory dysfunction.
agPPA = nonfluent/agrammatic variant primary progressive aphasia; DAOS = dominant apraxia of speech;
lvPPA = logopenic variant primary progressive aphasia; PPA = primary progressive aphasia; PPAOS = primary
progressive apraxia of speech; PPA-U = unclassified primary progressive aphasia; rSD = right temporal
semantic dementia; svPPA = semantic variant primary progressive aphasia.
124 FEBRUARY 2019

particularly helpful in cases of isolated or predominant apraxia of speech, as can KEY POINT
assistive communicative devices. Similarly, the associated motor impairment
● The lack of
can benefit from occupational and speech therapy. This underscores once more pharmacologic options to
the importance of identifying these disorders. For language impairment, some treat speech and language
patients benefit from therapy, while most family members benefit from disorders should not
strategies to maximize communicative effectiveness. As mentioned previously, dissuade the physician or
patient from seeking
referral to a speech and language pathologist is highly recommended when a
therapeutic options, and
degenerative speech and language disorder is considered. referral to a speech and
language pathologist is
highly recommended when
CONCLUSION a degenerative speech
and language disorder
This article has focused on degenerative speech and language disorders that are
is considered.
typically viewed as part of frontotemporal dementia. While considerable
controversy remains over the way these disorders are classified, considerable
progress has been made in our understanding of them over the past decade. In
the approach this article outlines, apraxia of speech is viewed as distinct from
aphasia and, when occurring in isolation, is viewed as a distinct degenerative
syndrome. The criteria for the two PPA variants discussed (nonfluent/
agrammatic and semantic) have significant shortcomings, and the authors
advocate for a focus on agrammatism with regard to the nonfluent/agrammatic
variant and an expanded view be taken of the semantic variant, incorporating
aphasic and nonaphasic presentations within the broader category of semantic
dementia. The authors are optimistic that trials of disease-modifying therapies
will be expanded to these disorders over the next decade, although these will
have to be grounded on consistent and evidence-based classification schemes and
improved biomarkers for the underlying pathologies.
VIDEO LEGENDS
VIDEO 5-1 VIDEO 5-3
Speech examination in a woman with primary Language examination in a man with semantic
progressive apraxia of speech. Video shows a variant primary progressive aphasia. Video shows a
70-year-old woman with primary progressive apraxia 68-year-old man with semantic variant primary
of speech. Speech alternating motion rates are slow progressive aphasia. During picture description the
but reasonably accurate. When combining sounds patient uses a nonspecific word in several
during speech sequential motion rates, a slow rate instances, such as something for wine, flower thing
is required for accurate enunciation. During word for kite, over there for dock, and something for
sand. When reading irregular words, he regularizes
repetition, evidence of groping, distortions, and
the word in several instances (surface dyslexia).
substitutions is seen. This patient had minimal During object naming, he first calls a screwdriver a
intelligible verbal output during picture description pen, and, even after holding it, he cannot name it.
but tested normally on all language measures when He does not benefit from a phonetic cue and
written responses were allowed (not shown on video). appears not to recognize the object.
links.lww.com/CONT/A270 links.lww.com/CONT/A272
© 2019 American Academy of Neurology © 2019 American Academy of Neurology
VIDEO 5-2
Language examination in a woman with nonfluent/
agrammatic variant primary progressive aphasia.
Video shows a 68-year-old woman with nonfluent/
agrammatic variant primary progressive aphasia.
Agrammatic and telegraphic speech is evident in
response to a simple question (“Why are you here?”)
and during picture description. Specifically, the first
sentence in her response is clearly agrammatic:
“Well, I not say the words.” She also omits and and
incorrectly uses is when she describes the couple
as: “The mother dad is picnicking.” Also, notice the
presumed omission during the final sentence: “The
radio is probably music.”
© 2019 American Academy of Neurology

ACKNOWLEDGMENT
This work was supported by grants from the National Institutes of Health
(R01 AG37491, R01NS89757, R01 DC14942).
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REVIEW ARTICLE

Lewy Body Dementias
C O N T I N UU M A UD I O By Melissa J. Armstrong, MD, MSc, FAAN
ONLINE
 ABSTRACT
S U P P L E M E N T AL D I G I T A L
PURPOSE OF REVIEW: This
article describes current diagnostic criteria relating
CONTENT (SDC)
A VA I L A B L E O N L I N E to the diagnosis of Lewy body dementia, highlights diagnostic
controversies, and reviews treatment approaches.
RECENT FINDINGS:Clinical diagnostic criteria for both Parkinson disease and

dementia with Lewy bodies have been recently updated. These criteria
CITE AS:
result in overlap between individuals diagnosed with Parkinson disease
CONTINUUM (MINNEAP MINN) and those with dementia with Lewy bodies. Although clinical features and
2019;25(1, DEMENTIA):128–146. symptomatic treatment overlap, differences remain in epidemiology and
expected progression. The high prevalence of cognitive impairment in
Dr Melissa J. Armstrong, Parkinson disease supports regular screening for cognitive changes and
Department of Neurology, counseling patients and families regarding what to expect. Treatment for
University of Florida College of Lewy body dementia involves avoiding medications that may cause or
Medicine, McKnight Brain
Institute, L3-100 MBI, PO Box exacerbate symptoms; prescribing pharmacologic agents to address
100236, Gainesville, FL 32610, bothersome cognitive, behavioral, movement, and other nonmotor
melissa.armstrong@neurology.
ufl.edu.
symptoms; recommending physical exercise and therapy; and providing
education, counseling, caregiver support, and palliative care.
Dr Armstrong serves on the
SUMMARY: Lewy body dementia includes both dementia with Lewy bodies
evidence review board of
Neurology journals and as a and Parkinson disease dementia, overlapping clinicopathologic entities
guideline consultant for the with differences relating to diagnosis and expected progression. Treatment
American Academy of Neurology
and has received personal is symptomatic and thus largely overlapping for the two conditions.
engagements from
the American Academy of
Neurology and Medscape CME. INTRODUCTION
L
Continued on page 146 ewy body dementia is an umbrella term that includes the clinical
diagnoses of both Parkinson disease (PD) dementia and dementia with
UNLABELED USE OF
PRODUCTS/INVESTIGATIONAL Lewy bodies (DLB), making it the second most common degenerative
USE DISCLOSURE: dementia after Alzheimer disease (AD).1 The nomenclature includes
Dr Armstrong discusses the
unlabeled/investigational use of
the following:
biomarkers for the diagnosis of
dementia with Lewy bodies and u Lewy body dementia: An umbrella term for a clinical diagnosis of either PD dementia or DLB
the unlabeled/investigational
use of donepezil, galantamine, u Parkinson disease dementia: Dementia occurring in the context of an established
and memantine for cognitive diagnosis of PD
symptoms in Lewy body
dementia; clozapine and u Dementia with Lewy bodies: Dementia associated with some combination of fluctuating
quetiapine for psychosis in Lewy cognition, recurrent visual hallucinations, rapid eye movement (REM) sleep behavior
body dementia; and disorder (RBD), and parkinsonism starting with or after the dementia diagnosis
clonazepam and melatonin for
rapid eye movement sleep u Lewy body disease: A pathologic diagnosis based on the identification of Lewy body
behavior disorder. pathology on postmortem examination
© 2019 American Academy The clinical diagnoses of PD dementia and DLB are distinct from Lewy
of Neurology. body disease, a pathologic diagnosis assigned when Lewy bodies (neuronal
128 FEBRUARY 2019

α-synuclein inclusions) and neuronal loss are identified on postmortem KEY POINTS
examination, independent of clinical presentation. Lewy body disease has
● Lewy body dementia is an
multiple types, including brainstem predominant, transitional (limbic), and diffuse umbrella term that includes
(neocortical) forms, associated with increasing degrees of pathologic burden. the clinical diagnoses of
While this categorization seems straightforward on the surface, physicians, both Parkinson disease
scientists, patients, and families alike can be confused by the nuanced dementia and dementia with
Lewy bodies.
distinctions between Lewy body terms. More than one patient and family have
announced with concern that they have had the wrong diagnosis for years, ● According to current
labeled with PD only to find that what they really have is “Lewy body.” Such diagnostic criteria from the
commonly encountered confusion underscores the importance of precision in Dementia With Lewy Bodies
how clinical and pathologic terms are used and clarity when explaining Consortium, probable
dementia with Lewy bodies
overlapping vocabulary to patients and families. is diagnosed in the context
The situation is made more challenging by ongoing updates in the clinical of a dementia consistent
diagnostic criteria for both PD and DLB that impact how these diseases are with the dementia with Lewy
identified and diagnosed. Historically, the presence of dementia within the first bodies phenotype and
either two or more core
year of the onset of parkinsonian symptoms was an exclusion criterion for the clinical features or the
diagnosis of idiopathic PD and considered more suggestive of an alternative presence of one core
diagnosis such as DLB. In 2015, however, the International Parkinson and clinical feature and at least
Movement Disorder Society released new clinical diagnostic criteria for PD that one indicative biomarker.
dispensed with the 1-year rule.2,3 If applying the new criteria, physicians assign
a diagnosis of PD to individuals meeting criteria regardless of cognitive status,
with the option to qualify patients with the distinction “PD, dementia with
Lewy bodies subtype.”2,3 The rationale for this change included overlapping
prodromal, clinical, and pathologic findings between individuals diagnosed
with PD, PD dementia, or DLB.
This change was met with dismay by members of the Lewy Body Dementia
Association Scientific Advisory Council, who argued to maintain DLB as a
distinct diagnostic entity for reasons including (1) patients with DLB may have
little or no parkinsonism, (2) some clinical and pathologic differences exist
between patients with DLB and those with PD/PD dementia, and (3) the
maintenance of distinct diagnoses has value for driving research and educating
the lay community.4 Arguments were well reasoned on both sides,4,5 and the new
PD criteria and subsequently published updated DLB criteria6 are both currently
used in clinical and research settings. For the purposes of this article, the classic
distinction separating DLB from PD dementia will be maintained for discussions
of the two entities, with a shared treatment section at the end. The division
between DLB and PD dementia is also present in the Diagnostic and Statistical
Manual of Mental Disorders, Fifth Edition (DSM-5) classification system, in which
neurocognitive disorder with Lewy bodies and neurocognitive disorder due to
PD are separate diagnoses.7
DEMENTIA WITH LEWY BODIES

Revised clinical diagnostic criteria for DLB were published in 2017.6 Major
updates to the previous criteria included separation of clinical features and
biomarkers, removal of the suggestive feature category, elevation of RBD to a
core clinical feature based on interim evidence, and demotion of antipsychotic
(neuroleptic) hypersensitivity to a supportive feature based on declining
frequency in clinical practice. Probable DLB is diagnosed in the context of a
dementia consistent with the DLB phenotype and either two or more core clinical
features or the presence of one core clinical feature and at least one indicative

LEWY BODY DEMENTIAS
biomarker (TABLE 6-1). Possible DLB is diagnosed in the context of a dementia

consistent with the DLB phenotype and either one core clinical feature or one
or more indicative biomarkers.
Epidemiology
In a 2014 systematic review and meta-analysis, the incidence of DLB was 3.8%
of new dementia diagnoses, with prevalence estimates suggesting that DLB
accounts for 4.2% of dementia diagnoses in community settings and 7.5% of
diagnoses in secondary care.8 These numbers likely underestimate the true
prevalence of DLB, as it is suggested that one in three cases may be missed9 and
misdiagnosis as AD is common.9,10 Advances in DLB diagnostic criteria improve
diagnosis,8 but the impact of the newest criteria is not yet known.
TABLE 6-1 Fourth Consensus Criteria for the Clinical Diagnosis of Dementia With
Lewy Bodiesa
Required Criterion
◆ Dementia, often with early and prominent deficits in attention, executive function, and
visuoperceptual ability; prominent or persistent memory impairment tends to occur
with progression.
Probable Dementia With Lewy Bodies
◆ Presence of two or more core clinical features (with or without indicative biomarker)
◆ One core clinical feature plus at least one indicative biomarker
Possible Dementia With Lewy Bodies
◆ Presence of one core clinical feature (no indicative biomarker)
◆ Presence of one or more indicative biomarkers but no core clinical features
Core Clinical Features
◆ Fluctuating cognition with pronounced variations in attention and alertness
◆ Recurrent visual hallucinations
◆ Rapid eye movement (REM) sleep behavior disorder (may precede other symptoms)
◆ Parkinsonism (defined as one or more spontaneous cardinal features: bradykinesia, rest
tremor, rigidity)b
130 FEBRUARY 2019

Clinical Diagnosis
As with any presentation for cognitive impairment, a thorough history is critical
in the diagnostic evaluation of patients who may have DLB. Clinicians should
query the onset of symptoms, cognitive weaknesses (eg, visuoperceptual errors,
short-term memory problems), pattern of progression, and functional
limitations (CASE 6-1). As dementia is a required criterion for DLB, the history
must establish that cognitive changes are impacting function sufficiently to meet
the dementia threshold. Core and supportive features of DLB (TABLE 6-1) are
largely ascertained through the history. Probing for evidence of cognitive
fluctuations is particularly important. While supportive features do not have a
role in formal diagnosis, the presence of symptoms such as postural instability,
repeated falls, excessive daytime sleepiness, transient episodes of
Supportive Clinical Features

◆ Severe sensitivity to antipsychotic agents
◆ Postural instability
◆ Repeated falls
◆ Syncope or other transient episodes of unresponsiveness
◆ Severe autonomic dysfunction (eg, constipation, orthostatic hypotension, urinary
incontinence)
◆ Hypersomnia/excessive daytime sleepiness
◆ Hyposmia
◆ Hallucinations in nonvisual modalities
◆ Systematized delusions
◆ Apathy, anxiety, and depression
Indicative Biomarkers
◆ Reduced basal ganglia dopamine transporter uptake (SPECT or PET)
◆ Abnormal (low uptake) iodine 123-MIBG myocardial scintigraphy
◆ Confirmation of REM sleep without atonia on polysomnography
Supportive Biomarkers
◆ Relative preservation of medial temporal lobe structures on CT/MRI
◆ Generalized low uptake on SPECT/PET perfusion/metabolism scan with reduced occipital
activity and/or the cingulate island sign on FDG-PET imaging
◆ Prominent posterior slow-wave activity on EEG with periodic fluctuations in the pre-alpha/
theta range
CT = computed tomography; EEG = electroencephalogram; FDG-PET = fludeoxyglucose positron emission

tomography; MIBG = metaiodobenzylguanidine; MRI = magnetic resonance imaging; PET = positron
emission tomography; SPECT = single-photon emission computed tomography.
a
Modified with permission from McKeith IG, et al, Neurology.6 © 2017 The Authors.
b
The parkinsonism in dementia with Lewy bodies occurs after or concurrent with dementia onset. If
parkinsonism is the only core clinical feature and appears only in the context of severe dementia, dementia
with Lewy bodies is less likely.

LEWY BODY DEMENTIAS
CASE 6-1 A 70-year-old woman presented with her husband and daughter because
of cognitive symptoms. Her husband reported that the patient had
worked as a librarian without any difficulties and retired 5 years earlier.
Two years before this presentation, she fell, broke her hip, and required
a surgical repair. She was delirious and experienced hallucinations
postoperatively and required an extended hospitalization because of
cognitive changes before transfer to rehabilitation. Her family felt that
she never fully recovered after the fall and hospitalization. Her husband
took over the family finances and started managing her medications,
appointments, and most meal preparation. While her hallucinations
lessened after hospital discharge, she continued to sometimes see
children in the room with her when no one was there. She also described
the sensation that someone was with her although the room was empty.
She had good days and bad days cognitively. Her family reported that
sometimes they saw her staring off into space and had to make an effort to
get her attention.
On examination, her Montreal Cognitive Assessment (MoCA) score was
19/30, with points lost on trails (-1), cube drawing (-1), clock hands (-1),
digits backward (-1), subtraction (-1), phonemic fluency (-1), abstraction
(-1), delayed recall (-3, improving by 2 with cueing), and date (-1).
Her speech was soft. She had mild rigidity at the neck and in both arms
and mild to moderate bradykinesia bilaterally with finger taps, opening
and closing of the hands, pronation-supination arm movements, and heel
taps. She walked slowly with decreased stride length and limited arm
swing. She took 5 steps to maintain her balance on the pull test but did not
require the examiner to catch her. An MRI of the brain revealed mild to
moderate global atrophy and mild chronic ischemic changes.
COMMENT This case describes a typical presentation of dementia with Lewy bodies
(DLB). Research suggests that individuals who have experienced delirium
have an increased risk of subsequent development of DLB. The MoCA is
used for cognitive screening rather than diagnosis but is consistent with a
diagnosis of dementia in this patient. Her weaknesses were particularly in
executive function, visuospatial tasks, concentration, and memory retrieval,
a pattern common in DLB. Particularly given her previous high functioning as
a librarian, her decline and functional impairments are consistent with a
diagnosis of dementia. She meets criteria for probable DLB given the
dementia, fluctuating cognition, visual hallucinations, and parkinsonism. The
transient episodes of decreased responsiveness are common in DLB and
may be mistaken for seizures. It is uncertain whether the fall resulting in
hospitalization 2 years earlier was related to an early symptom of her DLB or
mechanical contributors.
132 FEBRUARY 2019

unresponsiveness, and autonomic dysfunction are valuable in further supporting KEY POINTS
a suspicion of DLB.
Examination of an individual for whom DLB is in the differential diagnosis ● In dementia with Lewy
bodies, visual processing,
should include orthostatic vital signs to investigate autonomic dysfunction. attention, and executive
Cognitive screening is typically performed with either the Montreal Cognitive functioning are typically
Assessment (MoCA) or the Mini-Mental State Examination (MMSE). The MoCA more impaired than memory
is generally favored over the MMSE for screening in DLB given wider domain and naming.
coverage (eg, more executive and visuospatial tasks) and fewer ceiling and
● Individuals with a history
floor effects.11 Evaluation for parkinsonism includes observation for tremor, of rapid eye movement
assessment of rigidity, bradykinesia testing, and evaluation of gait and postural sleep behavior disorder are
stability. Myoclonus is sometimes seen in patients with DLB but is also observed 6 times more likely to have
autopsy-confirmed
in other dementia syndromes.
dementia with Lewy
bodies than other
Diagnostic Evaluation neurodegenerative
Diagnosis of DLB is possible based on the history and physical examination dementias.
alone, but further testing can be helpful in establishing the diagnosis. Formal
neuropsychological assessment can determine the severity of cognitive changes
and the pattern of deficits, both of which help in the assessment of DLB. It is
recommended that neuropsychological testing cover the full range of cognitive
domains impacted in DLB, in which visual processing, attention, and executive
functioning are typically more impaired than memory and naming.6
The updated criteria for DLB outline diagnostic evaluations serving as indirect
biomarkers (TABLE 6-1).6 Direct imaging of α-synuclein pathology is not yet
available. The recommended studies are most helpful for patients in whom
diagnostic uncertainty exists (CASE 6-2). Research suggests that dopamine
transporter imaging can be helpful in clarifying the diagnosis in individuals
identified as having possible DLB.12 Low dopamine transporter uptake in the
basal ganglia (FIGURE 6-1) is consistent with the presence of a parkinsonian
syndrome but cannot be used to distinguish between parkinsonian conditions
(eg, PD, DLB, multiple-system atrophy, progressive supranuclear palsy, and
some cases of frontotemporal dementia). Thus, dopamine transporter imaging is
most useful in differentiating DLB from conditions without usual parkinsonism,
such as AD.
It is now established that patients formally diagnosed with idiopathic RBD have
a markedly increased risk of developing a synuclein-related neurodegeneration,
with over 75% of individuals with idiopathic RBD diagnosed with a
neurodegenerative disease after 10 years of follow-up.13 Whereas RBD is rarely
associated with AD pathology, it is commonly associated with Lewy body
disease, particularly if RBD preceded other neurodegenerative symptoms,14
and individuals with a history of RBD are 6 times more likely to have
autopsy-confirmed DLB than other neurodegenerative dementias.15
[123I]Metaiodobenzylguanidine (MIBG) myocardial scintigraphy, where
available, quantifies postganglionic sympathetic cardiac innervation, which is
more likely to be reduced in Lewy body disease than in AD. Interpretation must
occur in the context of medications that may impact testing (eg, tricyclic
antidepressants and labetalol) and confounding diagnoses (eg, diabetes mellitus,
peripheral neuropathies, and cardiac disease).6
Occipital hypometabolism on fludeoxyglucose positron emission tomography
(FDG-PET) (FIGURE 6-2) correlates with the expected pathology in DLB, but it
does not have sufficient sensitivity and specificity to qualify as an indicative

LEWY BODY DEMENTIAS
CASE 6-2 A 73-year-old man presented with memory complaints. His wife, who
accompanied him, was frustrated that he never remembered what she
asked him to do, such as take out the garbage or pick up certain items at
the grocery store. He also frequently repeated the same questions. His
family recently asked him to stop driving after he drove too close to a
parked car and scraped the sides of both vehicles. He also drove a riding
mower so close to a ledge on their property that it went over the ledge
with just enough warning for him to scramble off. He was mildly slower
than he used to be, but his wife thought this was similar to their friends of
the same age. They had slept in separate beds for years because he kept
her awake at night by yelling out in his sleep or hitting her while dreaming,
a few times resulting in bruising.
On examination, his Montreal Cognitive Assessment (MoCA) score was
14/30, with points lost on trails (-1), cube drawing (-1), clock numbers
and hands (-2), confrontation naming (-1, describing the rhinoceros as a
hippopotamus), digits backward (-1), subtraction (-2), phonemic fluency
(-1), abstraction (-2), delayed recall (-5, improving by 3 with cueing), and
date (-1), with a point given for a 12th-grade educational level.
He had no rigidity on examiner assessment and minimal slowing with
hand tasks. He had a mildly hunched posture and mildly slow gait speed
but normal stride length and postural stability. Dopamine transporter
single-photon emission computed tomography (SPECT) showed
symmetrically decreased dopamine binding, consistent with a
parkinsonian process.
COMMENT By history, this patient had both amnestic and visuoperceptual concerns.
While the amnestic symptoms prompted inclusion of Alzheimer disease in
the differential diagnosis, the prominent visuospatial symptoms and the
pattern of domain involvement on the MoCA suggested the possibility
of an alternative diagnosis. The history suggested possible rapid eye
movement (REM) sleep behavior disorder (RBD), particularly given the
history of bed partner injury. Validated RBD screening questionnaires could
be used to assess this further. RBD can occur years before other
symptoms, suggesting a neurodegenerative process. Without a clear
history of cognitive fluctuations or visual hallucinations or evidence of
definite parkinsonism on examination, this patient met criteria for possible
dementia with Lewy bodies (DLB). The positive dopamine transporter
SPECT scan changed the diagnosis from possible to probable DLB. This is
an example of how imaging can be used to increase diagnostic confidence.
Polysomnographic confirmation of REM sleep without atonia would also
change the diagnosis from possible to probable DLB, but it is currently
unknown how relying on paired clinical features and biomarkers (ie,
parkinsonism and reduced dopamine transporter uptake or clinical RBD
and REM sleep without atonia on polysomnography) impact criteria
performance. The fact that the patient met criteria for probable DLB did
not exclude the possibility that he also had Alzheimer disease pathology,
as the two diseases commonly co-occur.
134 FEBRUARY 2019

FIGURE 6-1
Dopamine transporter single-photon emission computed tomography (SPECT) images in
parkinsonian syndromes. This series of dopamine transporter SPECT images shows a range
of results ranging from normal to markedly abnormal. Tracer uptake is often symmetrically
reduced in dementia with Lewy bodies, but this finding is also seen in other parkinsonian
conditions.
biomarker.6 The presence of the cingulate island sign on FDG-PET (reflecting

relative preservation of posterior or midcingulate metabolism compared to
surrounding structures) (FIGURE 6-2) is described in DLB, but research is
ongoing regarding how to optimize accurate assessment.6,16 Quantitative EEG
demonstrating prominent posterior slow-wave activity with periodic
fluctuations in the pre-alpha/theta range may also distinguish individuals with
DLB from those with AD and thus is currently categorized in the supportive
biomarker category.6
The final supportive biomarker is the finding of relative preservation of
medial temporal lobe structures on either CT or MRI (FIGURE 6-3).6 Atrophy of
medial temporal lobe structures is common in AD, thus its absence is
suggestive of an alternative diagnosis, such as DLB. It is notable, however, that the
presence of medial temporal atrophy does not exclude the possibility of DLB.
Mixed-pathology cases with AD and Lewy body changes are common. Clinically,
individuals with probable DLB and a CSF biomarker profile consistent with AD
have worse memory performance, more frequent hallucinations, and higher rates
FIGURE 6-2
Fludeoxyglucose positron emission tomography (FDG-PET) findings in dementia with Lewy
bodies (z score). A, Occipital and parietal hypometabolism demonstrated on the FDG-PET
scans of patients with dementia with Lewy bodies. B, Axial FDG-PET images demonstrate
the cingulate island sign (preservation of posterior cingulate metabolism relative to cuneus
and precuneus) (arrow) in a patient with dementia with Lewy bodies and the absence of
this finding in a patient with Alzheimer disease (C).

LEWY BODY DEMENTIAS
KEY POINTS of nursing home placement and

mortality than individuals who do
● Parkinson disease
psychosis includes a broad
not have such a CSF profile.17
range of experiences, Pathologically, recent findings
including hallucinations in suggest that while the presence
various modalities, sense of and severity of AD pathology may
presence or passage,
predict a faster disease course,
illusions, and delusions.
α-synuclein burden is the primary
● The American Academy driver, with a synergistic or
of Neurology Parkinson
FIGURE 6-3
additive effect from the
disease quality concomitant tau and amyloid-β
Coronal MRIs in dementia with Lewy bodies versus
measurement set includes a
measure identifying the
Alzheimer disease. Relative preservation of pathology.18 Given these findings,
medial temporal lobe structures on T1-weighted AD biomarkers may play a future
percentage of patients with
imaging of a patient with dementia with Lewy
Parkinson disease who were
bodies (A) in contrast to bilateral medial temporal
role for predicting prognosis for
assessed for cognitive patients with DLB, but their
lobe atrophy in a person with Alzheimer disease (B).
dysfunction in the past
12 months using a
presence cannot be used to exclude
recommended screening a DLB diagnosis.
tool or neuropsychological
assessment. PARKINSON DISEASE DEMENTIA
PD dementia is diagnosed in the context of an established diagnosis of PD and
consists of identifying a profile of cognitive and behavioral changes consistent
with PD and excluding other potential contributors (TABLE 6-219,20). While the
criteria for PD dementia highlight well-formed visual hallucinations (the most
common hallucination type in PD dementia), PD psychosis includes a broad
range of experiences, including hallucinations in various modalities, sense of
presence or passage, illusions, and delusions (TABLE 6-3).21 Presence
hallucinations, passage hallucinations, and illusions are classified as “minor”
hallucinatory phenomena and are common in patients with PD.19 PD psychosis is
associated with PD dementia but also occurs in patients with PD not meeting
criteria for dementia, in whom it is a risk factor for subsequent PD
dementia development.22
Epidemiology
The point prevalence of PD dementia is estimated to be around 25% to 30% of
patients with PD.22 Dementia frequency increases with disease duration and with
age. Most individuals with PD have cognitive impairment by 15 years of disease
duration, either PD dementia (48%) or mild cognitive impairment (MCI)
(36%).23 In individuals with PD surviving to 20 years of disease, the prevalence
of PD dementia increases to 83%, with most individuals showing evidence of
dementia before death.24
Clinical Diagnosis
The approach to diagnosing PD dementia is unique in that the epidemiologic data
suggest that in the context of a PD diagnosis, the development of some degree
of cognitive impairment is almost inevitable. Because of this, the American
Academy of Neurology (AAN) PD quality measurement set includes a measure
identifying the percentage of patients with PD who were assessed for cognitive
dysfunction in the past 12 months using a recommended screening tool or
neuropsychological assessment.25 The measurement set details seven cognitive
screening tools considered appropriate for use based on other assessments.
136 FEBRUARY 2019

Criteria for the Diagnosis of Parkinson Disease Dementiaa TABLE 6-2
Core (Required) Features/Criteria (for Both Probable and Possible Parkinson Disease
Dementia)
◆ Parkinson disease diagnosis (according to Queen Square Brain Bank criteria20)
◆ Dementia developing within context of established Parkinson disease with impairment in
more than one cognitive domainb
Probable Parkinson Disease Dementia
◆ Typical cognitive profile with impairment in at least two of four cognitive domains: attention,
executive function, visuospatial reasoning, and memory (usually improves with cueing)
◆ Presence of at least one supportive behavioral feature
◆ No features to suggest alternative pathology (eg, probable vascular dementia, delirium due
to systemic disease or drug intoxication, major depression)
◆ No features that make the diagnosis less certain (timing of motor and cognitive symptoms
unknown, abnormality that could impact cognition even if not suspected to be cause of
dementia, [eg, vascular changes on imaging])
Possible Parkinson Disease Dementia
◆ Atypical cognitive profile in one or more domains (eg, prominent fluent aphasia, memory
deficits not improving with cueing)
◆ Behavioral symptoms may or may not be present
◆ No features to suggest alternative pathology (eg, probable vascular dementia, delirium due
to systemic disease or drug intoxication, major depression)
Cognitive Features
◆ Impaired attention +/– fluctuations
◆ Impaired executive function, bradyphrenia
◆ Impaired visuospatial function
◆ Memory: impaired free recall of recent events and learning new material, usually improving
with cueing; recognition typically better than free recall
◆ Language: largely preserved, but word-finding difficulties and impaired complex sentence
comprehension may be present
Behavioral Features
◆ Apathy
◆ Depression, anxiety
◆ Hallucinations (usually visual and consisting of complex, formed visions of people, animals,
or objects)
◆ Delusions (usually paranoid)
◆ Excessive daytime sleepiness
a
Modified with permission from Emre M, et al, Mov Disord.19 © 2007 Movement Disorder Society.
b
As with dementia in general, cognitive changes should represent a change from baseline, have insidious
onset and gradual progression, and be associated with functional impairment relating to cognition (not
motor or autonomic symptoms).

LEWY BODY DEMENTIAS
A more recent International Parkinson and Movement Disorder Society task

force identified only three global screening scales recommended without caveats
for use in PD: the MoCA, Dementia Rating Scale-Second Edition (DRS-2), and
Parkinson’s Disease-Cognitive Rating Scale (PD-CRS).26
Parkinson Disease Mild Cognitive Impairment

With routine screening of individuals with PD by querying for subjective
cognitive complaints and performing formal cognitive screening assessments,
clinicians will identify individuals with PD demonstrating a range of cognitive
dysfunction. The concept of MCI, initially proposed in the context of individuals
with amnestic concerns, was later also defined within the context of PD. Formal
diagnostic criteria for PD-MCI were published in 2012 (TABLE 6-4).27 As with
MCI in other contexts, individuals with PD-MCI can progress, remain stable,
or revert to normal cognition.22 Individuals with PD-MCI have an increased risk
of progression to PD dementia,22,28 although estimated conversion rates vary
by cohort (eg, relating to age, disease duration) and criteria used. Given the
expected progression of PD to include dementia over time, PD-MCI likely
reflects a transitional state for many individuals meeting criteria (CASE 6-3), but
its role in predicting the trajectory for individual patients requires further study.
The diagnosis of PD-MCI should prompt clinicians to identify potentially
modifiable risk factors for cognitive impairment (eg, sleep apnea, medication
effects), perform serial evaluations to monitor for changes in cognitive status,
assess functional capabilities, and counsel patients and families to discuss
long-term planning topics (eg, advance directives, driving safety, finances, and
estate planning). These approaches reflect recommendations from the AAN MCI
guideline update29 (SDC APPENDIX, links.lww.com/CONT/A261) that also have
relevance within the context of PD-MCI.
Diagnostic Evaluation
If individuals have established PD and develop dementia in a pattern consistent
with PD dementia, additional testing may not be required. Neuropsychological
TABLE 6-3 Types of Psychosis in Parkinson Disease
Hallucination
◆ Abnormal perception without a physical stimulus
◆ Can occur in any sensory modality (visual, auditory, tactile, olfactory, gustatory)
◆ May be simple or complex
Sense of Presence
◆ Experience that someone is present when no one is actually there
Sense of Passage
◆ Fleeting, vague images in one’s peripheral vision
Illusion
◆ Misperceptions of real stimuli (often visual)
Delusion
◆ False, fixed, idiosyncratic belief that is maintained despite evidence to the contrary
138 FEBRUARY 2019

testing can be helpful to establish a baseline, investigate cognitive impairment in
individuals in whom screening may be less accurate (eg, in the context of either
high or low educational attainment), or answer specific clinical questions (eg,
pertaining to risk for deep brain stimulation or assessing atypical features). If
atypical features are seen in the history, examination, or neuropsychological
testing, the workup can include evaluations for overlapping processes, such as
structural MRI to investigate the degree of vascular burden or the appearance of
medial temporal lobe structures. Comorbid pathology is common in Lewy body
diseases, with recent research demonstrating that most individuals with Lewy
body dementia (both DLB and PD dementia) had two or three concomitant
pathologies, particularly AD.30 Thus, similar to DLB, diagnostic testing results
consistent with AD or other diagnoses do not exclude PD dementia but rather
suggest comorbid diseases.
NATURAL HISTORY
While the clinical and pathologic features of DLB and PD dementia overlap, the
presentation and course are commonly different. In individuals with DLB,
parkinsonian symptoms develop on average 2 years after the onset of dementia.15
Motor symptoms are often milder in DLB than in PD but may respond less well to
medication. Median survival of patients with clinically diagnosed DLB was only
3.72 years (95% confidence interval, 3.33 to 4.14) in a 2017 naturalistic cohort.31
This is in contrast to individuals with PD dementia, who had PD symptoms for an
average of 10.9 (standard deviation 5.5) years before dementia in the Sydney
Multicenter Study.24 Given the longer disease duration and motor progression,
individuals with PD dementia have greater motor disability, more frequent
motor fluctuations, higher medication burden, and more invasive treatment
histories (eg, deep brain stimulation) than those with DLB. After PD dementia
diagnosis, median survival in the Sydney Multicenter Study was 54 months.24
The few studies examining cause of death in Lewy body dementia combine DLB
and PD dementia. In a 2016 study, dementia was described as a contributor to
death 71% of the time, followed by circulatory (45%) and respiratory (38%)
contributors,32 consistent with reports that pneumonia is the most common
cause of death in PD dementia (25%).24
Criteria for the Diagnosis of Parkinson Disease Mild Cognitive Impairmenta TABLE 6-4
◆ Parkinson disease diagnosis (according to United Kingdom Brain Bank criteria20)

◆ Gradual cognitive decline either described by subjective report from the patient or
informant or observed by the clinician
◆ Cognitive impairment based on testingb
◆ No functional impairment relating to cognition (subtle difficulties on complex tasks
permitted)
◆ No other explanation for the cognitive decline (eg, delirium, major depression)
a
Data from Litvan I, et al, Mov Disord.27
b
Testing should reflect cognitive performance and not comorbidities such as motor impairment or severe
anxiety. Patients can be diagnosed as Parkinson disease mild cognitive impairment (PD-MCI) Level I based on
an abbreviated or screening assessment or PD-MCI Level II based on a comprehensive neuropsychological
assessment. Formal criteria for these designations are provided in the published criteria.

LEWY BODY DEMENTIAS
CASE 6-3 A 68-year-old man with a 10-year history of Parkinson disease (PD)
presented for a follow-up visit. He was a successful trial lawyer at the
time of PD diagnosis, but when he was 64 years of age, he reported
increasing difficulty in the courtroom. He described having trouble giving
closing statements spontaneously and an increased reliance on notes. His
Montreal Cognitive Assessment (MoCA) at that time was 27/30, with
points lost for a subtle error on cube copying, the phonemic fluency task,
and delayed recall (improving with cueing). He retired 1 year later
because of a combination of these difficulties, moderate dysarthria, and
motor fluctuations making the timing of court appearances more
challenging.
At this follow-up visit, he reported difficulty reading books because he
could not keep track of the plots. His wife had taken over the family
finances after noticing that it was taking him longer to balance the
checkbook and that he had paid a large bill twice. She also noticed that
he was no longer able to fix things around the house; he would take
electronic things apart and forget how to put them back together. Along
with these changes, he was sleeping more during the day and appeared
increasingly depressed. Neuropsychological testing showed significant
declines in attention, executive, and memory retrieval tasks compared to
estimated premorbid levels.
COMMENT It is likely that this patient had PD mild cognitive impairment (PD-MCI) at the
age of 64 when he noticed an impact of cognitive changes at work. If his
MoCA score of 27/30 is considered sufficient for screening positive for
cognitive impairment using an abbreviated scale, he met criteria for
PD-MCI level I. The commonly recommended cutoff for cognitive
impairment on the MoCA is 26, but recommended cutoffs in PD vary. Given
his high-functioning baseline and the fact that the points lost were
consistent with the domains typically involved in PD-MCI, the MoCA was
probably capturing true early cognitive impairment. The subsequent
progression of cognitive decline and increasing functional impairments
suggested the later development of dementia, further supported by the
neuropsychological testing results and development of behavioral
features. The etiology of behavioral changes in PD and PD-related
cognitive impairment is often multifactorial, reflecting both neurochemical
changes and “reactive” considerations in which patients sleep more
because of trouble concentrating on tasks and become depressed
because of decreasing functional abilities.
140 FEBRUARY 2019

TREATMENT KEY POINTS
Treatment for Lewy body dementia is currently symptomatic only. Strategies
● The diagnosis of
for treating DLB and PD dementia thus overlap, although no medications are Parkinson disease-mild
approved by the US Food and Drug Administration (FDA) specifically for cognitive impairment should
the treatment of DLB. As described in the AAN dementia management prompt clinicians to identify
measurement set update,33 treating individuals with Lewy body dementia and potentially modifiable risk
factors for cognitive
their families should include querying safety concerns and driving safety,
impairment, perform serial
assessing pain, screening for and managing behavioral and psychiatric evaluations to monitor for
symptoms, discussing pharmacologic and nonpharmacologic treatment changes in cognitive status,
approaches, encouraging advance care planning, and providing palliative care assess functional
capabilities, and counsel
counseling and caregiver education and support.
patients and families to
discuss long-term planning
Pharmacologic Approaches topics.
The first step in successfully treating an individual with Lewy body dementia is
to identify medications the patient is taking that could contribute to symptoms or ● In a 2016 study examining
cause of death in Lewy body
are best avoided in older adults with dementia. This includes benzodiazepines, dementia, dementia was
anticholinergic/antimuscarinic medications (eg, for genitourinary symptoms), described as a contributor
antipsychotic drugs, and tricyclic antidepressants.34 Antipsychotic use is of to death 71% of the time,
particular concern in individuals with DLB given the risk of hypersensitivity followed by circulatory
(45%) and respiratory (38%)
reactions (eg, sudden deterioration, severe parkinsonism, and mental status contributors, consistent
changes ranging from worsened confusion to unresponsiveness). Appropriate with reports that pneumonia
prescribing of this medication class is discussed further below. Particularly in is the most common cause
the context of PD dementia, the potential contribution of antiparkinsonian of death in Parkinson
disease dementia (25%).
medications should be assessed. Anticholinergic medications used to treat tremor
(eg, trihexyphenidyl, benztropine), dopamine agonists, and amantadine are ● Treating individuals with
associated with worsened cognition and psychosis. Gradual cessation of these Lewy body dementia and
medications can result in cognitive-behavioral improvement. their families should include
Cognitive symptoms in Lewy body dementia are treated with cholinesterase querying safety concerns
and driving safety, assessing
inhibitors, with use supported by multiple systematic reviews and meta- pain, screening for and
analyses.35,36 Rivastigmine is the only cholinesterase inhibitor FDA approved managing behavioral and
for use in PD dementia (TABLE 6-5). While not systematically reported in the psychiatric symptoms,
literature, a dramatic response to initiation of cholinesterase inhibitors in a discussing pharmacologic
and nonpharmacologic
subset of individuals with Lewy body dementia is observed in clinical settings. treatment approaches,
Gastrointestinal symptoms are the most common adverse event, but cholinesterase encouraging advance care
inhibitors can also worsen tremor in individuals with parkinsonism. Less planning, and providing
evidence exists for memantine efficacy in Lewy body dementia, but it is generally palliative care counseling
and caregiver education
well tolerated and may be used either as single or adjunctive therapy.6,35,36 and support.
Behavioral symptoms observed in individuals with Lewy body dementia
include psychosis, depression, anxiety, and apathy. Evidence suggests that ● The first step in
cholinesterase inhibitors improve behavioral symptoms for some patients.35,36 successfully treating an
individual with Lewy body
Using these agents to address multiple symptoms can be a prudent initial
dementia is to identify
approach. Nonbothersome hallucinations and delusions may not require medications that could
treatment. Pimavanserin was approved by the FDA for PD psychosis in 2016 contribute to symptoms or
based on a single randomized controlled trial,37 and it is the only approved are best avoided in older
treatment for this indication (TABLE 6-5). FDA labeling includes a boxed adults with dementia.
warning stating, “Elderly patients with dementia-related psychosis treated

with antipsychotic drugs are at an increased risk of death” and cautioning that
pimavanserin is only approved for hallucinations and delusions associated with
PD psychosis.38 An additional warning cautions to avoid use if patients have
risk factors (including use of other drugs) for prolonged QT interval. While

LEWY BODY DEMENTIAS
TABLE 6-5 Medications Commonly Used for Cognition and Psychosis in Lewy
Body Dementia
FDA
Indication/Drug Approved?a Dose Common Adverse Eventsb
Cognition
Rivastigmine patch Yes 4.6 mg, 9.5 mg, or Gastrointestinal (decreased appetite, diarrhea, nausea,
13.3 mg patch per vomiting), urinary tract infections, falls
24 hours (transdermal)
Rivastigmine oral Yes 1.5 mg, 3 mg, 4.5 mg, Endocrine (weight loss), gastrointestinal (abdominal pain,
or 6 mg 2 times a day diarrhea, indigestion, loss of appetite, nausea, vomiting),
(oral) neurologic (asthenia, dizziness, headache, tremor)
Donepezil No 5 mg or 10 mg in the Cardiovascular (hypertension, syncope), endocrine (weight

morning (oral) loss), hematologic (contusion, ecchymosis),
musculoskeletal (cramps, increased creatine kinase level),
neurologic (asthenia, dizziness, headache, insomnia,
somnolence), psychiatric (depression, dream disorder),
renal (urinary incontinence), other (fatigue)
Galantamine No 4 mg, 8 mg, or 12 mg Gastrointestinal (decreased appetite, diarrhea, nausea,

2 times a day (oral) vomiting), neurologic (dizziness, headache)
Memantine No Immediate release: Gastrointestinal (constipation, diarrhea, vomiting),

5 mg or 10 mg tablets, neurologic (confusion, dizziness, headache)
titrating to 10 mg
2 times a day (oral)
Extended release:
7 mg, 14 mg, 21 mg, or
28 mg once a day (oral)
Psychosis
Pimavanserinc Yes 17 mg or 34 mg once Cardiovascular (peripheral edema), gastrointestinal

daily (oral) (nausea), neurologic (confusional state)
Clozapinec,d No Typical dosing 6.25– Cardiovascular (hypotension, syncope, tachycardia),

50 mg nightly (oral) endocrine (sweating, weight gain), gastrointestinal
(constipation, excessive salivation, nausea, xerostomia),
neurologic (dizziness, headache, sedation, somnolence,
tremor, vertigo), ophthalmic (visual disturbance), other
(fever)
Quetiapinec No Regular-release typical Cardiovascular (orthostatic hypotension, tachycardia),

dosing: 25–150 mg once endocrine (increased serum cholesterol and triglycerides,
daily (oral) weight gain), gastrointestinal (abdominal pain, constipation,
increased appetite, indigestion, xerostomia), hepatic
(increased liver enzymes), musculoskeletal (backache),
neurologic (asthenia, dizziness, extrapyramidal symptoms,
headache, insomnia, lethargy, somnolence, tremor),
psychiatric (agitation), respiratory (nasal congestion,
pharyngitis), other (fatigue, pain)
FDA = US Food and Drug Administration.

a
For use in Parkinson disease; no drug is FDA approved for use in dementia with Lewy bodies.
b
Adverse effects in adult populations as reported in Micromedex (accessed 1/29/2018).
c
All antipsychotic agents have a boxed warning regarding increased risk of death in patients with dementia-related psychosis.
d
Available only under a restricted distribution program (the Clozapine Risk Evaluation and Mitigation Strategy [REMS] Program) through which
blood counts are monitored given risk of agranulocytosis.
142 FEBRUARY 2019

high-level efficacy data are lacking,36 quetiapine and clozapine are also KEY POINTS
commonly used to treat psychosis in the context of PD and Lewy body dementia
● Cognitive symptoms in
as these are safer than alternative antipsychotics. Clozapine has a higher level Lewy body dementia are
of evidence for use for PD psychosis than quetiapine but requires regular blood treated with cholinesterase
count monitoring for evidence of agranulocytosis.39 Quetiapine is simpler to inhibitors, with use
prescribe but is associated with increased mortality in individuals with PD.40 supported by multiple
systematic reviews and
In rare cases, clinicians, patients, and families may be forced to consider
meta-analyses.
antipsychotics with a riskier safety profile given psychosis severity and lack of
response to other strategies. In these circumstances, shared decision making ● Pimavanserin was
takes on an increasingly important role as potential risks and benefits are approved by the US Food
weighed.41 All antipsychotic agents have a boxed warning regarding increased and Drug Administration for
Parkinson disease psychosis
risk of death in patients with dementia-related psychosis. High-level evidence in 2016 based on a single
for specific agents for the treatment of depression, anxiety, and apathy in Lewy randomized controlled trial,
body dementia is lacking,36 and treatment usually follows best practices for the and it is the only approved
treatment of these conditions in older adults in general. treatment for this indication.
While high-level efficacy
Treatment of motor symptoms in Lewy body dementia is largely achieved data are lacking, quetiapine
through levodopa preparation monotherapy given the risks of exacerbating and clozapine are also
cognitive-behavioral symptoms with other antiparkinsonian medications. Some commonly used to treat
parkinsonian motor features, such as gait and balance dysfunction, are usually psychosis in the context of
Parkinson disease and Lewy
unresponsive to levodopa and are best treated with nonpharmacologic body dementia as these are
approaches. safer than alternative
A myriad of other symptoms in Lewy body dementia can benefit from antipsychotics. All
pharmacologic treatment, including RBD, orthostasis, constipation, and antipsychotic agents have a
boxed warning regarding
sialorrhea. Melatonin is the first-line treatment for RBD in the context of Lewy
increased risk of death in
body dementia, but clonazepam is often cautiously tried if melatonin is not patients with dementia-
sufficiently helpful.42 Orthostatic hypotension is addressed by weaning related psychosis.
contributing medications (eg, dopamine agonists and antihypertensive
treatment, if able), nonpharmacologic strategies, and prescription approaches ● Melatonin is first-line
treatment for rapid eye
(eg, midodrine, fludrocortisone, droxidopa). Constipation is treated with movement sleep behavior
increased water intake, dietary changes, and various over-the-counter and disorder in the context of
prescription therapies not specific to PD. Sialorrhea is treated with botulinum Lewy body dementia, but
toxin injections, glycopyrrolate, ipratropium bromide sublingual spray, and clonazepam is often
cautiously tried if melatonin
atropine sublingual drops.43 Pharmacologic interventions are guided by the is not sufficiently helpful.
symptoms most prominently impacting quality of life, with patients and
caregivers weighing the potential benefits and risks. ● Physical therapy,
occupational therapy, and
speech-language pathology
Nonpharmacologic Approaches
assessments (addressing
Nonpharmacologic approaches are an important aspect of treating individuals both speech and
with Lewy body dementia. While few studies have investigated the impact of swallowing) are important
exercise for individuals with Lewy body dementia,44 exercise and physical interdisciplinary
considerations for care of
activity are recommended in this context given increasing evidence of benefit for
patients with Lewy body
individuals with PD, including long-term benefits.45 Physical therapy, dementia. Therapy sessions
occupational therapy, and speech-language pathology assessments (addressing will usually include both
both speech and swallowing) are also important interdisciplinary considerations patients and caregivers to
for care. Therapy sessions will usually include both patients and caregivers to compensate for patients’
cognitive limitations and
compensate for cognitive limitations of patients and to teach caregiver-specific also to teach caregiver-
skills (eg, assistance in transfers and fall reduction). Swallow assessments are specific skills (eg, assistance
critical given that respiratory causes of death are common in Lewy body in transfers and fall
dementia.24,32 Connecting patients and caregivers to social work resources helps reduction).
identify strategies to reduce caregiver burden. Dementia is a contributor to the

LEWY BODY DEMENTIAS
cause of death for most individuals diagnosed with Lewy body dementia,32 and
palliative care and hospice approaches are a critical component of quality care.33
TRENDS
It is likely that debates regarding the PD, PD dementia, and DLB diagnostic
categories will continue in the short term. Shifting to pathologic categorization
(eg, Lewy body disease-dementia, Lewy body disease-parkinsonism) has been
proposed and may become particularly relevant if α-synuclein biomarkers are
identified. Efforts are under way to identify both PD46 and DLB47 prodromal states,
efforts that will inevitably emphasize the overlap between the two conditions. The
focus on α-synuclein pathology has both therapeutic and diagnostic implications as
phase 2 studies testing anti–α-synuclein antibodies are now enrolling for the
treatment of PD.48,49
CONCLUSION
DLB and PD dementia have overlapping clinical and pathologic features, but the
timing of symptom onset and related disease challenges result in differences in
counseling and approach. Diagnosis is determined based on history, clinical
examination, and supportive diagnostic testing, if indicated, although
identification of comorbid pathology cannot exclude a Lewy body diagnosis. The
high prevalence of cognitive impairment with the progression of PD means
that individuals with PD should be regularly screened for cognitive changes and
educated regarding what to expect. Treatment is currently symptomatic and
consists of avoiding medications that may cause or exacerbate symptoms;
pharmacologic agents to address bothersome symptoms impacting quality of life;
exercise and physical, occupational, and speech-language therapy; education
and counseling; caregiver support; and palliative care referrals. Areas of active
research include defining prodromal states, refining diagnostic accuracy,
identifying biomarkers, developing disease-modifying therapies, and improving
end-of-life care.
USEFUL WEBSITES
LEWY BODY DEMENTIA ASSOCIATION
The Lewy Body Dementia Association provides
educational resources for medical professionals,
patients, and families regarding the diagnosis and
treatment of Lewy body dementia; links caregivers
to online and local support; and highlights Lewy
body dementia research opportunities.
lbda.org
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Parkinson’s disease dementia, and dementia 45 Mak MK, Wong-Yu IS, Shen X, Chung CL. Long-term
with Lewy bodies: systematic review with effects of exercise and physical therapy in people
meta-analysis and trial sequential analysis. with Parkinson disease. Nat Rev Neurol 2017;13(11):
J Neurol Neurosurg Psychiatry 2015;86(2):135–143. 689–703. doi:10.1038/nrneurol.2017.128.
doi:10.1136/jnnp-2014-307659.
46 Berg D, Postuma RB, Adler CH, et al. MDS research
36 Stinton C, McKeith I, Taylor JP, et al. Pharmacological criteria for prodromal Parkinson’s disease. Mov
management of Lewy body dementia: a systematic Disord 2015;30(12):1600–1611. doi:10.1002/mds.26431.
review and meta-analysis. Am J Psychiatry 2015; 47 McKeith I, Taylor JP, Thomas A, et al. Revisiting
172(8):731–742. doi:10.1176/appi.ajp.2015.14121582. DLB diagnosis: a consideration of prodromal DLB
37 Cummings J, Isaacson S, Mills R, et al. Pimavanserin and of the diagnostic overlap with Alzheimer
for patients with Parkinson’s disease psychosis: a disease. J Geriatr Psychiatry Neurol 2016;29(5):
randomised, placebo-controlled phase 3 trial. 249–253. doi:10.1177/0891988716656083.
[Erratum appears in Lancet 2014 Jul 5;384(9937): 48 ClinicalTrials.gov. Evaluating the safety,
28]. Lancet 2014;383(9916):533–540. doi:10.1016/ pharmacokinetics, and pharmacodynamics of
S0140-6736(13)62106-6. BIIB054 in participants with Parkinson’s disease
38 NUPLAZID (pimavanserin) prescribing (SPARK). clinicaltrials.gov/ct2/show/
information. accessdata.fda.gov/drugsatfda_ NCT03318523?cond=NCT03318523+%E2%80%93+
docs/label/2016/207318lbl.pdf. Revised April BIIB-054&rank=1. Accessed November 30, 2018.
2016. Accessed November 30, 2018. 49 ClinicalTrials.gov. A study to evaluate the efficacy of
prasinezumab (RO704615/PRX002) in participants
with early Parkinson’s disease (PASADENA).
clinicaltrials.gov/ct2/show/NCT03100149?cond=
NCT03100149+%E2%80%93+PRX002%2FRO7046015&
rank=1. Accessed November 30, 2018.
DISCLOSURE
Continued from page 128
Dr Armstrong receives research/grant support from
the Agency for Healthcare Research and Quality
(K08HS24159), 1Florida Alzheimer’s Disease Research
Center (AG047266), and the Lewy Body Dementia
Association Research Center of Excellence program
and receives publishing royalties from Oxford
University Press.
146 FEBRUARY 2019

Vascular Cognitive REVIEW ARTICLE
Impairment

C O N T I N U UM AUDIO
INTERVIEW AVAILABLE
ONLINE
By Jonathan Graff-Radford, MD
ABSTRACT
PURPOSE OF REVIEW: This article provides an overview of vascular cognitive
impairment; discusses its epidemiology, subtypes, and associations with
other neurodegenerative diseases; and reviews the diagnostic evaluation
and management of these disorders.
RECENT FINDINGS: Cerebrovascular disease is a common cause of dementia

and frequently coexists with neurodegenerative causes. The heterogeneity
of mechanisms leading to vascular cognitive impairment makes developing
unifying clinical and research criteria difficult. Recognizing the neuroimaging
hallmarks of different forms of vascular cognitive impairment can allow for
individualized treatment and management. In individuals with mild vascular
cognitive impairment, aerobic exercise appears to be a promising treatment
but requires further investigation.
SUMMARY: Vascular cognitive impairment can be caused by several

mechanisms. While treating vascular risk factors is rational to prevent
worsening of cognitive impairment, well-designed studies are needed to CITE AS:
demonstrate efficacy. CONTINUUM (MINNEAP MINN)
2019;25(1, DEMENTIA):147–164.
INTRODUCTION Dr Jonathan Graff-Radford,
Department of Neurology,
V
ascular cognitive impairment encompasses a range of disorders in Mayo Clinic, 200 First St SW,
which vascular factors cause or contribute to cognitive decline. Rochester, MN 55905,
Graff-Radford.Jonathan@
Our understanding of vascular cognitive impairment has evolved
mayo.edu.
over time. Traditionally, vascular dementia was clinically
distinguished from Alzheimer disease dementia by the course of RELATIONSHIP DISCLOSURE:
Dr. Graff-Radford receives
clinical symptoms, history of vascular disease, and focal findings on neurologic research/grant support from
examination. Recent evidence suggests vascular brain diseases are a critical part the National Institute on
of the expression of Alzheimer disease and other neurodegenerative diseases. Aging/National Institutes of
Health (K76AG057015).
Until pathologic data demonstrated that Alzheimer pathology was the most
common etiology of dementia, arteriolosclerosis was thought to be the most UNLABELED USE OF
common cause of dementia, and doctors attributed dementia to “hardening of PRODUCTS/INVESTIGATIONAL

USE DISCLOSURE:
the arteries.” Later, vascular dementia became synonymous with multi-infarct Dr Graff-Radford discusses the
dementia, which was coined by Hachinski and colleagues,1 who emphasized focal unlabeled/investigational use of
neurologic signs and symptoms and “stepwise” cognitive decline. acetylcholinesterase inhibitors
and memantine for vascular
As neuroimaging improved and large pathologic studies were published, a cognitive impairment.
broader range of vascular diseases resulting in cognitive impairment became
appreciated. The term vascular cognitive impairment was introduced to © 2019 American Academy
incorporate all types of cognitive impairment related to vascular disease, of Neurology.

VASCULAR COGNITIVE IMPAIRMENT
including multi-infarct and other vascular diseases causing dementia, those with
mild cognitive impairment not meeting criteria for dementia, and those with
mixed vascular and degenerative pathology.2
DIAGNOSTIC CRITERIA FOR VASCULAR COGNITIVE IMPAIRMENT

The heterogeneity of clinical phenotypes and vascular pathophysiology affecting
the brain complicates the development of unifying criteria for vascular cognitive
impairment. For many years, the National Institute of Neurological Disorders
and Stroke and the Association Internationale pour la Recherche et
l’Enseignement en Neurosciences (NINDS-AIREN) criteria for vascular
dementia were used.3 These criteria were shown to be specific but not sensitive,
with pathologic confirmation.4 Several newer criteria have been published but
require further clinical and pathologic validation.5–8 These newer criteria include
a mild cognitive impairment stage and propose subtypes based on mechanism.
Despite recent efforts to recognize that vascular cognitive impairment rarely
occurs in isolation, current diagnostic criteria have a bias toward considering the
diagnosis of vascular cognitive impairment as occurring as a sole etiologic agent
in a particular patient.
CLINICAL PRESENTATION
No typical clinical presentation exists for vascular cognitive impairment. Patients
with large-territory strokes may have a stepwise decline and focal signs (eg,
hemiparesis), while those with cerebral small vessel disease may present with an
insidious onset of cognitive slowing with gait disturbance and parkinsonism.9
Patients with a combination of Alzheimer disease and vascular disease may
present with an amnestic syndrome that is clinically indistinguishable from pure
Alzheimer disease.
NEUROPSYCHOLOGY
No single neuropsychological pattern distinguishes vascular cognitive
impairment from other etiologies of cognitive impairment on an individual
basis10; however, patterns emerge when studying groups of patients. Patients
with vascular cognitive impairment tend to perform worse on tests of executive
function compared to memory function. They also have more difficulty with
tasks requiring cognitive speed.11
EPIDEMIOLOGY
The epidemiology of vascular cognitive impairment is difficult to study because
of the heterogeneity of presentation and limitations of current diagnostic criteria.
In the population-based Rotterdam study, which used the conservative
NINDS-AIREN criteria, the incidence of vascular dementia was 0.1 per 1000
person-years in those aged 60 to 64 years.12 The incidence increased with age to
7.0 per 1000 person-years in those aged 90 to 94 years, with a higher risk of
vascular dementia in men. In an Olmsted County, Minnesota, population-based
study of autopsied dementia cases, 13% had pure vascular dementia and an
additional 12% had significant vascular contribution to the pathology, making
vascular disease an important component of at least 25% of dementia cases.13 In a
community-based clinical pathologic cohort of dementia participants, 38% had
Alzheimer disease and infarcts, 30% had pure Alzheimer disease pathology, 12%
had infarcts alone, and 4% had Alzheimer disease with infarcts and Lewy body
148 FEBRUARY 2019

disease pathology, suggesting a role for vascular disease in up to 54% of KEY POINTS
dementia cases.14
● Vascular cognitive
Much of the confusion about the frequency of vascular disease contributing to impairment represents a
cognitive impairment reflects the difference between the community and clinical spectrum of vascular
cohorts that have been studied. While community-based and population-based disorders that cause
studies have shown vascular cognitive impairment as a common cause of cognitive impairment.
cognitive impairment,14 clinical cohorts generally suggest that vascular cognitive
● No single
impairment is rare. Referral biases in cohorts from memory clinics appear to neuropsychological pattern
systematically underrepresent vascular cognitive impairment, in contrast to distinguishes vascular
population-based studies. For example, a significant difference is seen in the cognitive impairment from
pathology underlying a clinical diagnosis of Alzheimer disease between clinical other etiologies of cognitive
impairment; however,
and community cohorts. Mixed Alzheimer and vascular pathology is more patients with vascular
common in the community, and pure Alzheimer disease pathology is more cognitive impairment tend
common in clinical/referral cohorts.15 This was reflected in an autopsy series of to perform worse on tests
10 university medical centers specializing in Alzheimer disease that found six of executive function
compared to memory
cases of pure vascular dementia among 1929 autopsied dementia cases.16 With function.
the advent of amyloid positron emission tomography (PET) imaging, it became
possible to study the frequency of vascular cognitive impairment in the absence ● In the community setting,
of Alzheimer pathology in vivo. In a study of subcortical vascular dementia cerebrovascular disease
commonly occurs with
cases, two-thirds were negative for amyloid deposition, suggesting a vascular
neurodegenerative
dementia phenotype in the absence of Alzheimer disease that can be diseases.
appreciated antemortem.17
● Both clinical and
Poststroke Dementia so-called “silent” strokes
are significant risk factors
Many studies have highlighted the association between stroke and the for the development
development of dementia. About 10% of patients have dementia before their of dementia.
first stroke, 10% develop dementia shortly after their first stroke, and about
33% develop dementia after a recurrent stroke.18 In a population-based study,
the incidence of dementia after stroke was 9 times greater than expected.
Importantly, dementia risk remained double the control population even when
dementia was not present the first year after stroke.19 While cortical infarcts were
previously emphasized, emerging evidence suggests subcortical infarcts are
important risk factors for cognitive impairment. In a follow-up of the SPS3
(Secondary Prevention of Small Subcortical Strokes) trial, 47% of participants
had mild cognitive impairment.20
The criteria for poststroke dementia emphasize a temporal association
between the cognitive impairment and infarction, often suggesting a 6-month
window.8 While this is helpful in establishing a relationship between the
cognitive impairment and vascular disease, numerous studies have highlighted
the importance of “silent” infarcts (the presence of at least one infarct detected
on MRI without a clinical history of an associated stroke or transient ischemic
attack) in the development of dementia. Approximately 20% of the population
older than 65 years of age have silent infarctions that increase the risk of
developing dementia.21
VASCULAR COGNITIVE IMPAIRMENT SUBTYPES

O’Brien and colleagues2 have proposed the following subtypes of vascular
cognitive impairment: multi-infarct dementia, small vessel dementia, strategic
infarct dementia, hypoperfusion dementia, hemorrhagic dementia, hereditary
vascular dementia, and mixed dementia. Recent pathologic data support

microinfarcts as an important pathologic substrate of vascular cognitive

impairment often occurring with other vascular pathologies.
Neuroimaging has allowed improved understanding of the substrate
underlying vascular cognitive impairment. Dividing vascular pathologies
detected on brain MRI into broad mechanistic categories is another way to
categorize them: small vessel disease associated with hypertensive arteriopathy,
small vessel disease related to cerebral amyloid angiopathy, and large
vessel/embolic disease. Often individuals with vascular cognitive impairment
have more than one of these vascular mechanisms present. This division allows
individual patients to be classified and interventions to be tailored to mechanism.
Cerebral Small Vessel Disease Associated With Hypertensive Arteriopathy

Prior criteria published for subcortical vascular dementia referred to lacunar
strokes and white matter hyperintensity in a subcortical pattern.22 Lacunar
stroke and white matter hyperintensity are associated with a hypertensive
arteriopathy, although other vascular risk factors such as diabetes mellitus and
smoking contribute as well. FIGURE 7-1 demonstrates the spectrum of imaging
changes with hypertensive arteriopathy.
DEEP CEREBRAL MICROBLEEDS. Microbleeds are detected on hemosiderin-sensitive

MRI sequences (T2*gradient recalled echo [GRE] and susceptibility-weighted
imaging [SWI]). Deep cerebral microbleeds are thought to be a manifestation of
hypertensive vascular disease and are associated with the presence of lacunar
stroke23 and decline in motor functioning.24 They are associated with the
FIGURE 7-1
Spectrum of imaging changes with hypertensive arteriopathy.
MRI = magnetic resonance imaging.
150 FEBRUARY 2019

increased risk of developing a deep (hypertensive) hemorrhage. They are also
associated with risk of ischemic stroke.25 In patients with Alzheimer dementia,
the presence of deep cerebral microbleeds was associated with increased
cardiovascular mortality.26
BASAL GANGLIA (DEEP) MRI-VISIBLE PERIVASCULAR SPACES. The presence of

basal ganglia (deep) enlarged perivascular spaces is associated with deep cerebral
microbleeds, hypertension-related intracerebral hemorrhage, and increased
white matter T2 hyperintensity burden.27 In one study, increased burden of
basal ganglia perivascular spaces was associated with a diagnosis of subcortical
vascular cognitive impairment and negatively predicted the diagnosis of
Alzheimer dementia.28
WHITE MATTER HYPERINTENSITIES. White matter T2 hyperintensities are

commonly detected on brain MRI and increase with age. The presence of white
matter T2 hyperintensities is increasingly recognized as detrimental because of
their association with an increased risk of stroke, dementia,29 and, particularly,
worsening cognitive speed and executive function. Noncognitive correlates
include risk of depression30 and gait impairment.31 Progression of white matter
hyperintensity over time is associated with cognitive decline.32 While white
matter T2 hyperintensities are often considered vascular in origin because of
the association with vascular risk factors such as hypertension,33 the location
of the hyperintensities is important for understanding the underlying
pathophysiology. Hyperintensities in deep regions are more common in
individuals with a hypertensive intracerebral hemorrhage than in those with a
cerebral amyloid angiopathy–related hemorrhage.34 In patients with Alzheimer
dementia, parietal hyperintensity may reflect Alzheimer neuropathology rather
than a vascular origin.35 The cause of white matter T2 hyperintensity can be
heterogeneous, particularly in younger individuals with genetic, inflammatory,
or radiation-induced changes. Therefore, the presence of white matter
hyperintensity should not be considered as definitive evidence of
cerebrovascular disease.
LACUNAR STROKES. While lacunar infarcts commonly occur in the setting of

increased white matter T2 hyperintensities, both are independently associated
with worse cognition.36 The location of lacunar infarct is key. Thalamic and
putaminal locations are typically associated with a worse cognitive performance
than capsular, caudate, and white matter lacunar strokes.37 While the location of
lacunar stroke often predicts the cognitive domain involved, overall incident
lacunar infarcts predict decline in executive functions and psychomotor speed.38
In the Nun Study, participants with Alzheimer pathology were much more likely
to develop dementia if they also had lacunar strokes.39
Small Vessel Disease Related to Cerebral Amyloid Angiopathy

Cerebral amyloid angiopathy is caused by the pathologic deposition of amyloid-β
within the walls of cerebral blood vessels, leading to weakening of blood vessels
that increases the risk of hemorrhage. Cerebral amyloid angiopathy often occurs
with Alzheimer disease pathology but is also a common pathology of aging
and prevalent in community-based autopsy studies.40 While cerebral amyloid
angiopathy may be a risk factor for hemorrhagic stroke, it is also associated with
cognitive impairment even in the absence of clinical hemorrhage. Severe cerebral

amyloid angiopathy pathology is associated with impaired episodic memory and

decreased perceptual speed even after controlling for coexisting Alzheimer
disease pathology.40 In the Honolulu-Asia Aging Study, patients with Alzheimer
disease with coexisting cerebral amyloid angiopathy had worse cognitive
performance that those without coexisting cerebral amyloid angiopathy.41 Clinical
criteria (the Boston criteria) for the diagnosis of cerebral amyloid angiopathy
have been developed and modified to include superficial siderosis.42,43
Several neuroimaging biomarkers for the presence of cerebral amyloid
angiopathy exist and are summarized in FIGURE 7-2, including lobar microbleeds,
lobar intracerebral hemorrhage, cortical superficial siderosis, white matter
hyperintensity, convexity subarachnoid hemorrhage, and MRI-visible centrum
semiovale perivascular spaces.
LOBAR CEREBRAL MICROBLEEDS. Lobar cerebral microbleeds are an established

risk factor for intracerebral hemorrhage.44 The presence of multiple lobar
cerebral microbleeds is associated with increased risk of dementia and impaired
executive function and memory.24 In patients with Alzheimer dementia, lobar
cerebral microbleeds are associated with an increased risk of stroke-related
mortality.26
LOBAR INTRACEREBRAL HEMORRHAGE. Among individuals without dementia

who develop an intracerebral hemorrhage, the incidence of dementia is
approximately 28% at 4 years, highest among those with imaging features
suggestive of underlying cerebral amyloid angiopathy, including a lobar location.45
FIGURE 7-2
Spectrum of imaging changes associated with cerebral amyloid angiopathy (CAA).
MRI = magnetic resonance imaging.
152 FEBRUARY 2019

CORTICAL SUPERFICIAL SIDEROSIS. Cortical superficial siderosis refers to KEY POINTS
curvilinear hemosiderin deposition along superficial layers of the cerebral cortex;
● Neuroimaging biomarkers
it is a predictor of intracerebral hemorrhage risk.46 may allow for identification
of different mechanisms
CONVEXITY SUBARACHNOID HEMORRHAGE. Less commonly, cerebral amyloid leading to small vessel
angiopathy can present with convexity subarachnoid hemorrhage, often disease. For example, deep
presenting with recurrent transient spreading sensory and motor symptoms. cerebral microbleeds are
suggestive of hypertensive
MRI-VISIBLE CENTRUM SEMIOVALE PERIVASCULAR SPACES. Centrum semiovale arteriopathy, and lobar
cerebral microbleeds are
enlarged perivascular spaces occur more commonly in cerebral amyloid suggestive of cerebral
angiopathy–related intracerebral hemorrhage than in hypertensive intracerebral amyloid angiopathy.
hemorrhage and are also detected more frequently in Alzheimer dementia than
in vascular cognitive impairment.28 ● Several strategic brain
regions have been
associated with the
AMYLOID POSITRON EMISSION TOMOGRAPHY. Amyloid PET has been explored as
development of dementia
a biomarker of cerebral amyloid angiopathy and appears to be able to distinguish after an infarct, including
hemorrhages caused by hypertension from those caused by cerebral amyloid the angular gyrus, thalamus,
angiopathy.47 Although preliminary studies of amyloid PET are promising, caudate and putamen, basal
forebrain, posterior cerebral
further studies with pathologic confirmation are necessary before amyloid PET
artery (ie, hippocampus),
can be used to reliably identify cerebral amyloid angiopathy clinically. and anterior cerebral
artery territories.
Strategic Infarction
Strategic strokes can be either small vessel (lacunar) or large vessel in mechanism.
Targeted strokes can present with cognitive deficits, including memory loss. The
cause can often be distinguished from neurodegenerative disease by the time
course, which is sudden in onset with vascular causes. The NINDS-AIREN
criteria identify several brain regions in key cognitive networks associated with
the development of strategic cognitive impairment, including angular gyrus,
thalamus (CASE 7-1), basal forebrain, posterior cerebral artery (ie, hippocampus)
(CASE 7-2), and anterior cerebral artery (CASE 7-3) territories, which can be
injured after rupture of an anterior communicating artery aneurysm.3 Other
regions include the caudate (CASE 7-4) and putamen. While the area of injury
may be small, these lesions cause cognitive deficits by disrupting widespread
brain networks that can be defined with functional neuroimaging.
Large Vessel Disease

Two imaging manifestations of large vessel disease are shown in FIGURE 7-6. As
reviewed above, strategic infarct dementia can also be a manifestation of large
vessel disease. Intracranial atherosclerosis has been associated with dementia,
adjusting for the presence of vascular risk factors.51 This association is supported
by pathologic data.52,53 In contrast, extracranial carotid-intima thickness has
not consistently been associated with cognitive decline.54
MULTI-INFARCT DEMENTIA. Multi-infarct dementia was originally

conceptualized by Hachinski and colleagues1 as a condition in which multiple
cortical infarcts of different size and location led to cognitive impairment.
Multi-infarct dementia now represents a small subset of individuals with
vascular cognitive impairment. These patients may have an abrupt onset to their
symptoms, with a stepwise neurologic decline and focal neurologic findings on
examination (CASE 7-5). Imaging reveals multiple cortical strokes. Atrial
fibrillation, which can be the underlying cause of multiple cortical strokes, is

associated with cognitive decline even without a history of clinical stroke. The
association of atrial fibrillation with cognitive impairment varies by the presence
of subclinical “silent” infarctions.55
HYPOPERFUSION. Cardiac arrest, carotid occlusion, and hypotension may lead to

watershed infarcts (FIGURE 7-6), anoxic brain, or incomplete white matter
infarcts, which can result in cognitive impairment.
Genetic Causes
Several genetic disorders are associated with the development of vascular
cognitive impairment. Cerebral autosomal dominant arteriopathy with
CASE 7-1 A 75-year-old man with a history of

hypertension presented for a second
opinion regarding memory loss. He
repeatedly asked his wife “Can you tell
me where I am?” In the emergency
department, he was initially diagnosed
with transient global amnesia, but his
symptoms did not improve, so an MRI
was ordered, which revealed an
ischemic infarct in the anterior nucleus
of the thalamus (FIGURE 7-3). After
hospital discharge, he had persistent
anterograde amnesia and had
difficulty with navigation; his wife
FIGURE 7-3
reported that he got lost in his own Imaging of the patient in CASE 7-1. Axial
house and would go into the closet diffusion-weighted MRI shows an
looking for the bathroom. The stroke acute ischemic infarct in the anterior
was attributed to small vessel disease nucleus of the thalamus (arrow).
from his hypertension.
COMMENT The anterior nucleus of the thalamus is an important part of the network for
memory, which includes the cingulate gyrus, hippocampus, mammillary
body, and orbital and medial frontal lobes. The anterior nucleus of the
thalamus receives blood supply from the tuberothalamic artery, which
originates from the posterior communicating artery. The clinical phenotype
of anterior nucleus infarction is anterograde amnesia with preserved
recognition. The amnesia results from interruption of the mammillothalamic
tract and its cortical projections. Patients with left anterior nucleus
infarction typically have verbal memory difficulty and autobiographical
memory impairment, while patients with right anterior nucleus infarction,
such as this patient, develop topographic disorientation and visuospatial
dysfunction. Patients with anterior thalamic strokes have also been
described to develop palipsychism, which is superimposition of temporally
unrelated information.48 This presents as an interruption of current
dialogue with previously discussed unrelated topics.
154 FEBRUARY 2019

subcortical infarcts and leukoencephalopathy (CADASIL) is a genetic cerebral
small vessel disease caused by mutations in the NOTCH3 gene that codes for a
transmembrane receptor located on vascular smooth muscle cells (CASE 7-6).
This leads to deposition of granular osmophilic material in vascular smooth
muscle cells. Cognitive impairment is common, as are migraine headaches and
stroke. The pattern of cognitive deficits on neuropsychometric testing includes
impaired cognitive speed, executive function, and attention.56 MRI reveals
significant white matter T2 hyperintensities with ischemic lesions in subcortical
regions, including characteristic involvement of the anterior temporal lobe.
Cerebral autosomal recessive arteriopathy with subcortical infarcts and
A 73-year-old woman was brought to the emergency department by her CASE 7-2
family after she sent them a series of unusual emails. Her family members
indicated that she was acting “weird.” Her email read “Thank you for
getting my mail and for bringing me home. THANK YOU for hauling me
home and all my things. Many thanks for coming to get me and hauling my
stuff in. I cannot even remember if I thanked you. I do not mean to forget
my thanks when you do things that help so much for me. Thank you
for bringing me home and hauling my
things in. Makes me sad when I forget
to say thank you.”
In the emergency department, her
neurologic examination was notable
for a right homonymous hemianopia
that resolved by the next morning.
She was unable to recall four words
5 minutes after they were given to her.
She also had a visual object agnosia;
despite normal visual fields and intact
reading, she was unable to name
objects presented to her in the visual
sensory modality, but she correctly
named them when presented by
auditory or tactile sensory modalities.
FIGURE 7-4
MRI revealed an infarction
Imaging of the patient in CASE 7-2. Axial
of the left hippocampus as well as diffusion-weighted MRI shows an acute
the left ventral visual stream infarction in the left posterior cerebral
(occipitotemporal area) (FIGURE 7-4). artery distribution involving the left
hippocampus and the left ventral visual
When she was seen 6 months later,
stream (occipitotemporal area),
her memory and visual agnosia had resulting in dementia related to a
not improved. strategic infarct.
This case illustrates that strategic infarcts can result from large artery COMMENT
ischemia. This patient developed anterograde amnesia from her
hippocampal infarct and the visual agnosia from interruption of the ventral
visual stream.

leukoencephalopathy (CARASIL), another hereditary vascular dementia

syndrome, occurs due to mutations in the HTRA1 gene and is associated with
alopecia and spondylosis in addition to the cerebral small vessel disease.57
Familial cerebral amyloid angiopathy has been described with mutations in
the APP, ITM2B (or BRI2), and CST3 genes.58–60
Mixed Dementia
Mixed dementia is most often seen as combined cerebrovascular disease and
Alzheimer disease. As demonstrated by several community-based pathologic
cohorts, mixed vascular and degenerative pathology is perhaps the most
prevalent important cause of cognitive impairment. The presence of vascular
pathology lowers the threshold for the clinical expression of Alzheimer disease.
The presence of infarcts interacts with Alzheimer pathology to increase the
likelihood of dementia.61 In the Baltimore Longitudinal Study of Aging, the
presence of an infarction significantly increased the odds ratio for dementia
independently of whether the infarct was symptomatic.62 The overlap can also
be seen in epidemiologic studies in which Alzheimer disease dementia and
vascular cognitive impairment share treatable vascular risk factors, including
hypertension, dyslipidemia, and diabetes mellitus.62,63
Microinfarcts
Recent evidence suggests microinfarcts are an important contributor to
dementia. In one community-based sample, the population-
attributable risk of dementia for microinfarcts was 33%.64 The pathophysiology
of developing microinfarcts has recently been investigated. Cortical microinfarcts
are associated with the presence of cerebral amyloid angiopathy pathology,
while deep microinfarcts are associated with the presence of arteriosclerosis.65
Interestingly, brain atrophy in a watershed pattern is associated with the presence
CASE 7-3 A 60-year-old man was hospitalized following rupture of an anterior

communicating artery aneurysm complicated by vasospasm. After
several weeks, he had no focal neurologic deficits, but he had
confabulation and amnesia. He had previously worked as a car mechanic,
and on morning rounds in the hospital, when asked what he had done
the day before, he would describe the type of engine he was “repairing”
and where he was going to drop it off. He would incorporate objects
present in the room or what he was watching on the television into his
confabulations. Head CT demonstrated bilateral anterior cerebral artery
infarcts secondary to vasospasm with the associated artifact from his
aneurysm treatment.
COMMENT In 1985, Damasio and colleagues49 described the syndrome of basal

forebrain injury after anterior communicating artery aneurysm rupture or
tumor resection. Patients with this syndrome are able to learn separate
modal stimuli but cannot integrate the information. They also develop
confabulation. Performance in patients with this syndrome is significantly
improved by cuing.
156 FEBRUARY 2019

A 60-year-old man presented for evaluation of behavioral changes. CASE 7-4
Several months earlier, he developed sudden-onset facial droop, which
resolved within 24 hours. MRI revealed a right caudate infarct. Upon
returning to work, he received a poor work evaluation, which was
uncharacteristic of him. In addition, he shrugged off the criticism,
which, his wife noted, was very unusual. He also developed lack of
empathy and a sweet tooth, eating ice cream daily for breakfast.
Neuropsychological testing showed impairment on the Wisconsin Card
Sorting Test. Fludeoxyglucose positron emission tomography (FDG-PET)
revealed hypometabolism in areas functionally connected to the
caudate (FIGURE 7-550).
FIGURE 7-5
Imaging of the patient in CASE 7-4. A, Axial T2-weighted MRI shows an infarct involving the
right caudate. B, Fludeoxyglucose positron emission tomography (FDG-PET) statistical
map shows regions of significant hypometabolism relative to age-matched controls.
Hypometabolism is present in areas functionally connected to the caudate, including the
right medial prefrontal cortex, dorsolateral prefrontal cortex, and right anterior cingulate
cortex. Contralateral cerebellar hypometabolism is also seen.
Reprinted with permission from Graff-Radford J, et al, Neurology.50 © 2017 American Academy
of Neurology.
This case demonstrates how a strategic stroke can mimic the symptoms COMMENT
of behavioral variant frontotemporal dementia. In this patient, a single
lesion disrupted the connectivity of the caudate to the frontal lobe,
resulting in dorsolateral, medial prefrontal, and anterior cingulate cortical
dysfunction that manifested as corresponding disinhibition, apathy, loss of
empathy, and increased cravings for sweets.

FIGURE 7-6
Embolic disease and large vessel disease. Multiple cortical infarcts (left) due to cardiogenic
emboli and watershed infarct (right) related to hypoperfusion in the setting of a significant
carotid stenosis.
ACA = anterior cerebral artery; MCA = middle cerebral artery; PCA = posterior cerebral artery.
CASE 7-5 A 69-year-old right-handed man presented to the behavioral neurology

clinic with cognitive slowing, visuospatial difficulty, and trouble
multitasking. He indicated that his symptoms started abruptly 2 years
earlier, when he developed left-sided weakness and was diagnosed with
a stroke.
His neuropsychological examination revealed significantly slowed
cognitive speed, impaired cognitive flexibility (ie, perseverations), and
higher-order cognitive-set maintenance abilities (ie, executive skills). He
scored 11/15 on the delayed recall portion of the Rey Auditory Verbal
Learning Test. His neurologic examination was notable for pronator drift
on the left and left greater than right hyperreflexia. His MRI revealed
multiple areas of cortical infarction.
COMMENT This case illustrates the classic presentation of multi-infarct dementia.

This patient developed the sudden onset of cognitive problems and had
focal findings on examination, with an MRI revealing multiple cortically
based infarcts.
158 FEBRUARY 2019

A 49-year-old woman presented after developing sudden-onset CASE 7-6
left-sided weakness. MRI showed a right internal capsule stroke. She was
placed on aspirin and clopidogrel. Four months later, she developed
dizziness and confusion. MRI demonstrated a second stroke. She was
referred to the cerebrovascular clinic for a second opinion given her
two strokes and young age. Her mother had a stroke in her sixties,
developed dementia, and died in her seventies. Her maternal uncle also
had strokes in his sixties. Her sister had a stroke when she was 53. The
patient had no history of migraine. Her MRI was notable for subcortical
ischemic infarcts in addition to white matter T2 hyperintensities with
involvement of the anterior temporal lobes and external capsule
(FIGURE 7-7). Genetic testing confirmed the pathogenic mutation in the
NOTCH3 gene, confirming cerebral autosomal dominant arteriopathy
with subcortical infarcts and leukoencephalopathy (CADASIL).
FIGURE 7-7
Imaging of the patient in CASE 7-6. Axial fluid-attenuated inversion recovery (FLAIR) MRI
shows subcortical ischemic infarcts (A, B) in addition to white-matter T2 hyperintensities
with notable involvement of the anterior temporal lobes (C) and external capsule (A)
characteristic of cerebral autosomal dominant arteriopathy with subcortical infarcts and
leukoencephalopathy (CADASIL).
In this patient, CADASIL was suspected because of her young age, typical COMMENT
MRI findings, and family history. CADASIL can also be diagnosed via skin
biopsy to examine the walls of the vascular smooth muscle cells by
electron microscopy, which can demonstrate irregular deposits of granular
osmophilic material.

of microinfarcts after controlling for Alzheimer pathology.66 In addition,

subcortical microinfarcts are associated with declining blood pressure over time.67
Imaging studies have identified cerebral microinfarcts with 7T MRI. A subset
of these is also visible with 3T MRI.68 Since the majority of microinfarcts detected
pathologically are approximately 0.2 millimeters in size, these imaging
techniques detect a fraction of microinfarct burden.
TREATMENT
Overall management of vascular cognitive impairment, similar to most other
dementias, emphasizes education, counseling, and support of patients and caregivers;
home safety evaluation (including medication administration and assessment
of driving safety); and advance care planning. While aggressive treatment
of vascular risk factors to prevent cognitive decline due to vascular disease
seems logical, only a paucity of evidence exists at this time to support such
an approach.
Symptomatic Treatment
The American Heart Association/America Stroke Association have published
recommendations for the management of vascular cognitive impairment.5
Evidence for the symptomatic treatment of vascular cognitive impairment is
limited. Individuals with poststroke cognitive impairment may benefit from
cognitive rehabilitation. A 2016 trial demonstrated that aerobic exercise 3 times
a week benefited cognition in individuals with mild vascular cognitive
impairment, although the benefit diminished at long-term follow-up.69 Trials of
acetylcholinesterase inhibitors and memantine have shown mixed results, and
these medications are not US Food and Drug Administration (FDA) approved
for vascular cognitive impairment. As reviewed earlier, vascular cognitive
impairment often co-occurs with Alzheimer pathology, so the use of
acetylcholinesterase inhibitors to treat patients with dual pathologies seems
logical. Cerebrovascular disease is associated with neuropsychiatric symptoms,
including depression. In these cases, treatment with antidepressants such as
selective serotonin reuptake inhibitors (SSRIs) can be considered. Some patients
with vascular cognitive impairment develop pseudobulbar affect, and an SSRI
can potentially mitigate some of the symptoms. Other options include
combination dextromethorphan-quinidine, which is FDA approved for the
treatment of pseudobulbar affect, although the trials demonstrating its efficacy
were done in multiple sclerosis and amyotrophic lateral sclerosis.
Approach to the Patient With Possible Vascular Cognitive Impairment

As with the evaluation of patients with other causes of cognitive impairment,
patients should first be categorized as having normal cognition, mild cognitive
impairment, or dementia. In vascular cognitive impairment, the history is
important to determine whether a clinical history of stroke or transient ischemic
attack is present and assess for traditional cerebrovascular risk factors (eg,
smoking, diabetes mellitus, hypertension, hyperlipidemia, atrial fibrillation).
The neurologic examination can support a history of cerebrovascular disease
with the presence of focal neurologic signs consistent with stroke. Neuroimaging,
particularly with MRI, can confirm the presence and extent of cerebrovascular
disease, help determine the underlying mechanism, and allow for individualized
treatment, including the introduction of secondary prevention strategies. For
160 FEBRUARY 2019

example, in patients with embolic or cortically based infarcts, investigations such KEY POINTS
as vessel imaging (carotid ultrasound or magnetic resonance/CT angiography),
● While multi-infarct
prolonged cardiac monitoring, and echocardiography should be considered to dementia was once
identify and treat the infarct mechanism. In contrast, treatment for individuals considered synonymous
with neuroimaging evidence of hypertensive small vessel disease may concentrate with vascular dementia, it is
on vascular risk factors identified in the clinical evaluation. If cerebral amyloid now recognized that
multi-infarct dementia
angiopathy is present on neuroimaging, treatment may focus on minimizing or
represents a subset of
stopping antithrombotic medications and blood pressure control. individuals with vascular
cognitive impairment.
PREVENTIVE STUDIES
In the Syst-Eur (Systolic Hypertension in Europe) trial, aggressive blood pressure ● Cerebral autosomal
dominant arteriopathy with
management was associated with a reduced risk of developing dementia subcortical infarcts and
compared to placebo.68 Similarly, in the PROGRESS (Perindopril Protection leukoencephalopathy
Against Recurrent Stroke Study) trial, cognitive decline occurred in 9.1% of patients (CADASIL) is a genetic
on antihypertensive treatment and in 11.0% on placebo.70 The FINGER (Finnish cerebral small vessel disease
caused by mutations in the
Geriatric Intervention Study to Prevent Cognitive Impairment and Disability) NOTCH3 gene. Cognitive
trial investigated a multidomain intervention that included vascular risk factor impairment is common in
monitoring and demonstrated a decrease in cognitive decline over 2 years.71 In CADASIL, as are migraine
contrast, several studies have failed to demonstrate reduced risk of dementia headaches and stroke.
or cognitive decline with vascular risk factor treatment.72,73 However, the
● T2 hyperintensity
PREDIMED (Prevention With Mediterranean Diet) study, which was a involvement of the anterior
randomized controlled trial of the Mediterranean diet versus a low-fat diet, temporal lobes on MRI may
demonstrated that the Mediterranean diet supplemented with extra virgin olive suggest CADASIL as a
possible diagnosis.
oil reduced the incidence of cardiovascular events and was associated with
improved cognitive function.74 ● Cerebral autosomal
recessive arteriopathy with
subcortical infarcts and
CONCLUSION leukoencephalopathy
(CARASIL) occurs due to
Vascular cognitive impairment represents a spectrum of cerebrovascular diseases mutations in the HTRA1 gene
with different underlying mechanisms. The common co-occurrence of vascular and is associated with
changes in neurodegenerative dementias has reignited interest in treating alopecia and spondylosis in
vascular risk factors to prevent or slow cognitive decline. Prevention in middle addition to the cerebral
small vessel disease.
age with treatment of vascular risk factors is an important strategy. Recent data
support exercise and the Mediterranean diet as emerging treatment strategies, ● Microinfarcts are
but these lifestyle interventions require additional evidence. increasingly recognized as
an important contributor to
cognitive decline. Recent
advances in MRI techniques
ACKNOWLEDGMENT have allowed a subset to be
Research reported in this article was supported by the National Institute on imaged in vivo.
Aging/National Institutes of Health (K76AG057015).
● Treatment of vascular
risk factors in midlife,
aerobic exercise, and a
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164 FEBRUARY 2019

Normal Pressure REVIEW ARTICLE

Hydrocephalus C O N T I N U UM A U D I O
I NT E R V I E W A V A I L AB L E
ONLINE
By Neill R. Graff-Radford, MBBCH, FRCP, FAAN; David T. Jones, MD

VIDEO CONTENT
A V AI L A B L E O N L I N E
ABSTRACT
PURPOSE OF REVIEW: Since it was first described in 1965, normal pressure
hydrocephalus (NPH) has been a controversial subject. New studies have
shed light on its epidemiology and pathogenesis and provided objective
ways to measure outcome in patients with NPH. Neuroimaging has
improved and allows better recognition of both NPH and the presence
of overlapping diseases
RECENT FINDINGS: Several

recent epidemiologic studies confirm that NPH is a CITE AS:
rare disease, but the presence of large ventricles is a common finding with 2019;25(1, DEMENTIA):165–186.
aging. NPH may be multifactorial, including congenital causes, vascular
disease, and impaired CSF absorption. MRI features of NPH include Address correspondence to
enlarged ventricular size and CSF fluid collection outside the ventricles Dr Neill R. Graff-Radford,
Department of Neurology, Mayo
not due to atrophy. The term disproportionately enlarged subarachnoid Clinic Jacksonville, 4500 San
space hydrocephalus (DESH) has been used to describe prognostic MRI Pablo Rd, Jacksonville, FL 32224,
features in NPH, including a “tight high convexity” and enlargement of CSF Graff-radford.neill@mayo.edu.
spaces in the sylvian fissure. DESH has been included in the Japanese RELATIONSHIP DISCLOSURE:
guideline for the diagnosis and treatment of NPH. A new NPH scale has Dr Graff-Radford serves on the
editorial board of Alzheimer’s
been published that provides an objective framework for evaluating Research & Therapy and
patients with NPH before and after shunt placement. Programmable receives research/grant
shunts can noninvasively manage overdrainage complications. Surgical support from Abbvie Inc;
Axovant Sciences, Inc; Biogen;
outcome has been improving over time. Recent studies have led to Eli Lilly and Company; the
improved recognition of overlapping diseases such as Alzheimer pathology, National Institutes of Health
which co-occurs in about 30% of NPH cases. Fludeoxyglucose positron (P50AG16574, 1R01AG045390-01A1,
R56AG057195, UF1AG032438,
emission tomography (FDG-PET) is a promising imaging modality for U54NS092089, U01AG24904,
diagnosing NPH and detecting concomitant degenerative disease. U01NS100620); Novartis AG; and
the US Department of Defense
(WEI1872). Dr Jones receives
SUMMARY: A systematic approach to patients with possible NPH allows research/grant support from
recognition of the subset of patients who will respond to shunt surgery and the Minnesota Partnership for
Biotechnology and Medical
identification of those with alternative diagnoses. Genomics (P006598701) and the
National Institutes of Health
(U01EB 24450-1, R01DC14942-1,
U01AG52943, U01AG45390,
U19AG24904).
INTRODUCTION
A
dams and colleagues1 published the first article on normal pressure UNLABELED USE OF
hydrocephalus (NPH) in 1965 based on Hakim’s hypothesis that PRODUCTS/INVESTIGATIONAL
USE DISCLOSURE :
patients with hydrocephalus but normal CSF pressure on lumbar Drs Graff-Radford and Jones
puncture (LP) could improve with shunt surgery. Two key report no disclosures.
guidelines have been published on NPH, the international
guideline2 and the Japanese guideline.3 The American Academy of Neurology © 2019 American Academy
practice guideline on NPH concluded that clinicians may offer shunt placement of Neurology.

NORMAL PRESSURE HYDROCEPHALUS
as a treatment for patients with idiopathic NPH to treat their subjective

symptoms of idiopathic NPH and gait with Level C evidence but recommended
that additional well-designed randomized clinical trials are needed for NPH.4
Two recent randomized studies have been published on NPH. In the first trial,5
a group of patients with NPH was shunted immediately with a lumboperitoneal
shunt and compared to a control group of patients with NPH who underwent
lumboperitoneal shunt surgery after a 3-month delay. At 3 months, only 5% of the
delayed shunt group improved compared to 65% of the immediately shunted
group as measured by the modified Rankin Scale (mRS). Tisell and colleagues6
completed the only double-blind randomized study in NPH. Among 14 patients
with NPH, vascular risk factors, and no absorption problem, seven participants
had their shunts open immediately after surgery, while the other seven had their
shunts tied closed for 3 months. The group who had their shunts open improved
immediately, and the second group improved only when their shunts were
opened 3 months later.
Although limited by size, these two studies provide additional evidence of
the efficacy of shunt surgery for NPH, but a large double-blind study is still
necessary before practice guidelines can recommend shunt surgery with a higher
level of confidence. Because of the lack of a large randomized double-blind study,
the treatment of patients with NPH has been questioned by some, including in
a 2016 editorial.7
This article provides a practical approach to the management of NPH and
reviews NPH nomenclature, etiology, epidemiology, clinical findings, and the
approach to diagnosis, including for complicated cases with overlapping diseases.
Recent advances in MRI diagnosis are highlighted, and surgical considerations,
how to evaluate shunt outcome, and the prognosis of patients undergoing shunt
surgery are discussed.
NORMAL PRESSURE HYDROCEPHALUS NOMENCLATURE

CSF is produced in the choroid plexuses of the ventricular system at a rate of
20 mL per hour and flows from the lateral and third ventricles to the fourth
ventricle via the cerebral aqueduct. The fourth ventricle communicates with the
subarachnoid space via the midline foramen of Magendie and the two lateral
foramina of Luschka. The CSF then circulates through the subarachnoid space
over the cranial convexity and down the spinal canal before being reabsorbed
by arachnoid villi located along the intracranial venous sinuses and around the
spinal nerve roots. CSF is circulated through the ventricular and subarachnoid
spaces by a pulsatile wave induced by the expansion of the vascular compartment
within the rigid cranial vault associated with pulsatile flow in the cerebral
arteries. In healthy adults, the CSF volume is between 125 mL and 150 mL,
with 20% residing in the ventricular system and the remainder in the cerebral
(approximately 65%) and spinal (approximately 15%) subarachnoid spaces.
The term hydrocephalus is a compound word with origin from the Greek
words for water (hýdōr) and head (kephalos). In modern medical usage, the term
is meant to capture the clinical condition of increased CSF content within the
cranial vault caused by a variety of circumstances.
While the ventricular system is a common and salient location for increased
CSF content within the cranial vault, it should be emphasized that the term
hydrocephalus also encompasses increased CSF content in the extraventricular
cranial subarachnoid space. The term ventriculomegaly is used to describe
166 FEBRUARY 2019

increased CSF content in the ventricular system and the term subarachnoid KEY POINT
hydrocephalus to describe increased CSF content in the cranial portion of the
● Hydrocephalus can
subarachnoid space. occur as fluid accumulation
both inside and outside
ETIOLOGY the ventricles.
The following sections discuss factors that relate to NPH, including congenital
factors, poor CSF absorption, and vascular factors.
Congenital Factors
Traditionally, hydrocephalus has been divided into two broad categories:
obstructive and communicating. Obstructive hydrocephalus, also known as
noncommunicating, is secondary to a blockage of the normal CSF flow through
the ventricular and subarachnoid spaces associated with a congenital condition
or acquired with the development of a brain lesion that exerts obstructive mass
effect. Stenosis of the cerebral aqueduct is a common cause of hydrocephalus
in the young, but symptoms may not manifest until adulthood and may account
for the syndrome long-standing overt ventriculomegaly in adults (LOVA),
which has a clinical presentation similar to NPH (dementia, gait disturbance,
and urinary incontinence). The authors and others have shown that persons
diagnosed with NPH have a large head size in more than 10% of cases
(eg, 20% have a head size larger than the 90th percentile),8,9 supporting that
congenital factors may play a role in the development of hydrocephalus even
in adulthood. Secondary NPH may be suspected in the setting of a large head
size, triventriculomegaly without involvement of the fourth ventricle, little to no
T2 signal change around the ventricular system on fluid-attenuated inversion
recovery (FLAIR) imaging, and evidence of aqueductal stenosis and/or webbing
identified with special MRI sequences (refer to the MRI section) of the
cerebral aqueduct (FIGURE 8-1).
FIGURE 8-1
Long-standing overt ventriculomegaly in adults (LOVA). A, Axial fluid-attenuated inversion
recovery (FLAIR) MRI sequence shows ventriculomegaly without significant T2 signal around
the ventricles. A lack of subarachnoid hydrocephalus suggests a noncommunicating
etiology for the ventricular hydrocephalus. B, Sagittal fast imaging employing steady state
acquisition C (FIESTA-C) sequence in the same patient shows two membranes/webs (arrows)
within the cerebral aqueduct leading to stenosis and partial obstruction.

In contrast to obstructive hydrocephalus, communicating hydrocephalus is

characterized by an increase in intracranial CSF content without a gross anatomic
lesion obstructing flow. NPH, the topic of this article, is a form of communicating
hydrocephalus that occurs insidiously without substantially increasing CSF
pressure. The NPH syndrome can be primary, ie, without a known cause (referred
to as idiopathic NPH), or secondary to some condition that is known to impair
CSF absorption at the arachnoid granulations (eg, following infectious,
inflammatory, or hemorrhagic events involving the subarachnoid space).
Similar to obstructive hydrocephalus, the clinical symptoms associated with
primary and secondary forms of NPH are responsive to surgical treatment
(eg, ventriculoperitoneal shunt, ventriculopleural shunt, lumboperitoneal
shunt, or some other surgical CSF diversion procedure).
Cerebrospinal Fluid Absorption Impairment

The mechanisms that lead to the insidious increase in CSF volume in idiopathic
NPH are poorly understood, and the condition can likely occur from many
different etiologies that influence CSF dynamics (ie, production or flow, or
absorption) with a final common end point. The earliest theories regarding
idiopathic NPH involved decreased CSF absorption leading to increased CSF
volume over a protracted time frame, allowing for a compensatory increase in
ventricular volume to maintain normal intracranial pressure. In support of
these theories, a number of studies have shown a strong association between
poor CSF absorption and good outcome after shunt surgery for idiopathic NPH.
A study conducted by Boon and colleagues10 showed that a higher resistance to
outflow of CSF (known as Rout) was related to better surgical outcome.
Vascular Risk Factors

Animal models support that vascular mechanisms are related to the development
of hydrocephalus. The spontaneously hypertensive rat model is known to
produce hydrocephalus.11 Pettorossi and colleagues12 showed that increasing the
pulse pressure with a balloon in the ventricle of the brain of sheep led to
hydrocephalus in hours. Bering13 showed that unilateral choroid plexectomy
diminishes the amplitude of pressure pulsation in the one ventricle but not the
mean pressure in both ventricles, and hydrocephalus was prevented in that
ventricle. Human studies also support a role for vascular disease altering CSF
dynamics and contributing to the development of NPH. Epidemiologic studies
show that vascular risk factors are associated with NPH.14,15 In the ARIC
(Atherosclerosis Risk in Communities) study, pulse pressure and baseline systolic
blood pressure were associated with enlargement of ventricles over 10 years.16
As previously mentioned, Tisell and colleagues6 completed a double-blind
randomized study of 14 patients who had hydrocephalus, vascular risk factors,
and, on testing, no CSF absorption problem, and patients improved with shunting.
EPIDEMIOLOGY
In a population-based study of 220,000 persons in Norway, the prevalence and
incidence of NPH were 21.9 per 100,000 and 5.5 per 100,000, respectively.17 In a
large population-based sample using neuroimaging and clinical examinations,
Jaraj and colleagues18 found that the prevalence of probable NPH was 0.2% in
persons 70 to 79 years of age and 5.9% in those older than 80 years of age. An
estimate of ventricular enlargement (Evans index of >0.3) was present in 20.9%,
168 FEBRUARY 2019

but an important imaging feature that is typically found in NPH that allows the KEY POINTS
ventriculomegaly of NPH to be distinguished from neurodegenerative causes of
● Factors associated with
ventriculomegaly (occluded sulci at the high convexity) was only present in 5.4%. so-called idiopathic normal
Mori and colleagues3 summarized three epidemiologic NPH studies in Japan. pressure hydrocephalus
They reported the prevalence of idiopathic NPH with MRI support to be include impaired CSF
approximately 1.1% of persons older than 60 years of age. absorption, vascular
disease, and congenital
The population-based Mayo Clinic Study of Aging found that among
hydrocephalus. All these
1494 persons older than age 70 who had MRI scans, 20% had ventriculomegaly factors may alter CSF
(an Evans index of 0.3 or greater) and 5% had ventriculomegaly and either a dynamics in a way that can
tight high convexity (occluded sulci at the high convexity) or extraventricular lead to increased CSF
content in the cranial vault
hydrocephalus (CSF fluid collection outside the ventricles not due to atrophy).14
while maintaining a
relatively normal average
WHY NORMAL PRESSURE HYDROCEPHALUS IS HARD TO DIAGNOSE CSF pressure.
AND MANAGE
One reason NPH is difficult to diagnose is that all the key “hallmark” findings ● Normal pressure
hydrocephalus is an
are common in older persons and have many causes. Gait abnormality occurs in uncommon disease, but
20% of individuals older than age 75 and is associated with the development of large ventricles are
dementia.19 Incontinence occurs in 38% of women20 and 18% of men21 at this age. commonly seen in persons
Fourteen percent of persons older than 70 years of age have dementia.22 In 2017, older than 70 years of age.
the Alzheimer’s Association reported that 5.5 million persons in the United State
● No pathognomonic
had Alzheimer dementia.23 Ventricles enlarge with age24 and with individual or combination
neurodegenerative dementias.25 In the general population older than 70 years of clinical features exists
of age, 20% have ventriculomegaly (defined as an Evans index of >0.3). for normal pressure
hydrocephalus. Comorbid
Managing NPH is difficult because surgical complications with shunting are
diseases are common and
common. In a review of 30 studies conducted since 2006 that included should be evaluated.
1573 patients, Toma and colleagues26 summarized the complication rate of NPH
surgery: mortality was 0.2%, subdural hemorrhage 4.5%, intracranial ● The triad of gait
hemorrhage 0.2%, infection 3.5%, and revisions 13%. abnormality, incontinence,
and cognitive impairment
To date, all diagnostic tests for NPH have both false-positive and false- seen in normal pressure
negative results; these tests include absorption tests, monitoring CSF pressure, hydrocephalus may possibly
cisternography, flow in the cerebral aqueduct, high-volume lumbar puncture, be related to periventricular
and external CSF drainage.2 frontal cortical–basal
ganglia–thalamocortical
Patients with NPH commonly have overlapping comorbid diseases, including circuitry. Most often,
Alzheimer disease, Parkinson disease, parkinsonian syndromes, spinal stenosis, patients with normal
large joint disease, and neuropathy. For more information, refer to the authors’ pressure hydrocephalus do
review of the comorbidities in NPH.27 not have the full triad of
symptoms, and gait
abnormality usually
CLINICAL FEATURES presents first.
The classic clinical presentation of NPH is that of an insidiously progressive gait
syndrome, urinary urgency followed by incontinence, and cognitive impairment.
This clinical triad is thought to occur because of impairment of periventricular
frontal cortical–basal ganglia–thalamocortical circuitry in the setting of CSF
hypervolemia.28 In support of this, the authors have recently demonstrated that
patients with idiopathic NPH show hypometabolism in the caudate nucleus,29
and others have shown functional recovery of the supplementary motor area
after CSF drainage.30
Gait Dysfunction
The gait dysfunction in NPH has traditionally been described as that of a “magnetic”
or “glue-footed” gait, gait apraxia, or a frontal ataxia similar to what has been

described as Bruns ataxia. However, the gait abnormality can be highly variable and
likely depends on the nature of the specific cortical–basal ganglia–thalamocortical
circuitry disruption. The clinician considering a diagnosis of idiopathic NPH
should focus on differentiating the gait observed from other potential causes of
gait abnormalities in this clinical population (refer to the Approach to Diagnosis
section). The diagnosis should not be excluded if a magnetic gait is not seen.
Common features that are consistent with an idiopathic NPH-related gait
abnormality include small steps, wide base, difficulty with turns (usually taking
several steps to do so), and postural instability with a positive pull test.
Cognitive Impairment
The cognitive impairment in idiopathic NPH is usually described as frontosubcortical
dementia,31 but the exact quality and severity in any individual will depend on that
individual’s pattern of cortical–basal ganglia–thalamocortical circuitry disruption
related to the distribution of increased CSF content in the cranial vault and any
comorbid pathology. Some common cognitive features include psychomotor
slowing, decreased attention and concentration, impaired executive functions,
and apathy. Importantly, if an anomia is present,32,33 a comorbid cortical
neurodegenerative disease such as Alzheimer disease (AD) should be suspected.
Urinary Incontinence
The urinary symptoms of idiopathic NPH are consistent with the original clinical
description of frontal lobe incontinence and include urgency, frequency, and,
TABLE 8-1 Causes of Gait Abnormalities in the Differential Diagnosis of Normal

Pressure Hydrocephalus
Disease Entity Common Causes and Comments
Spinal disease Cervical and lumbar stenosis
Lower extremity large joint Hip and knee arthritis

disease
Peripheral neuropathy Diabetic neuropathy
Visual impairment Walking with bifocal lenses makes it hard to see the floor
Vestibular dysfunction Peripheral vestibular dysfunction
Parkinson disease The presence of a rest tremor, asymmetric signs/symptoms, or involvement of the face and
arms should raise the suspicion of Parkinson disease
Parkinsonian syndromes Lewy body disease, progressive supranuclear palsy, corticobasal degeneration, and multiple
system atrophy
Medications Phenothiazines and benzodiazepines
Alcohol abuse Cerebellar degeneration, peripheral neuropathy
Cerebrovascular disease Strokes and white matter changes
Cerebellar disease Alcohol abuse, spinocerebellar degeneration
Postural hypotension Blood pressure medications, alpha blockers for enlarged prostate, degenerative diseases (see
parkinsonian syndromes above) associated with autonomic dysfunction
170 FEBRUARY 2019

eventually, urgency incontinence.34 The original localization of this syndrome KEY POINTS
included the anteromedial frontal lobe, the genu of the corpus callosum, and the
● Cognitive features of
anterior cingulate cortex. These regions are frequently impacted by increased CSF normal pressure
content in the ventricles and the subarachnoid space of the longitudinal fissure in hydrocephalus include
idiopathic NPH. Urinary urgency is usually the first urinary sign of dysfunction, psychomotor slowing,
which then evolves into urge urinary incontinence. This symptom is typically decreased attention and
concentration, impaired
compounded by a slow gait, making timely travel to the bathroom difficult. After a
executive functions, and
successful CSF diversion procedure, patients are frequently surprised and quite apathy. Anomia suggests the
pleased with the degree of improvement in these urinary symptoms. presence of a cortical
dementia and is a poor
prognostic factor when
APPROACH TO DIAGNOSIS
deciding about shunt
Performing shunt surgery on patients with large ventricles and no gait abnormality placement.
has not been shown to be helpful. This was first noted by Miller Fisher35 in 1978, and
several other studies have confirmed it.33,36 The approach should be to concentrate ● The differential diagnosis
on patients with large ventricles and gait abnormality; to that end, clinicians should of gait abnormalities in the
elderly is broad and should
keep the differential diagnosis of gait abnormality in this age group in mind be reviewed in detail when
(TABLE 8-1). When taking the history and performing an examination, evaluating patients for
identifying prognostic features and common causes of gait dysfunction and normal pressure
incontinence can help in evaluating a patient for a shunt (TABLE 8-237–40). hydrocephalus.
● A focused history and

Diagnostic Tests examination should be
Many tests have been evaluated to predict which patients with ventriculomegaly performed looking for
will improve with shunt surgery. As discussed earlier in this article, the diseases that can co-occur
or mimic the symptoms
mechanisms that lead to NPH are many; therefore, identifying a single diagnostic
of normal pressure
test to predict shunt outcome has been challenging. Cisternography has not hydrocephalus and looking
proven to be consistently helpful.41 Absorption studies or resistance to outflow for factors that may
(Rout) may have false negatives,42 although when abnormal, they are correlated influence management.
with good outcome. CSF flow study through the aqueduct may have false
positives,43 and monitoring CSF pressure and quantifying B waves may have false
negatives.33,44 Some of these tests evaluate the pathogenesis of a subset of NPH,
such as impaired absorption,10 and result in false negatives.10 Further, it has been
shown that patients without absorption problems can improve with a shunt.10
In the authors’ opinion, the most important tests are the MRI and tests that
evaluate whether a shunt may improve symptoms, including an LP with high-
volume CSF removal or external CSF drainage. The latter tests are not specific to
the pathogenesis but evaluate whether a shunt will improve symptoms.
MAGNETIC RESONANCE IMAGING. The routine evaluation of the NPH clinical

syndrome always begins with neuroimaging. High-resolution structural MRI
with orthogonal reconstructions can allow for a more thorough examination
of the relevant anatomic effects of hydrocephalus. The first step is usually
establishing the presence of ventriculomegaly. This can quickly be quantified
by measuring the Evans index (FIGURE 8-2), which is the ratio of the largest
width of the frontal horns and the widest measure of the inner table of the
skull at that level. When this ratio is greater than 0.3, the ventricles are
considered to be enlarged.2 One weakness in measuring the Evans index is that
it correlates poorly with ventricular volume because the measurement is
one-dimensional and dependent on the level at which the index is measured45
(this issue is especially problematic for measures of the callosal angle). The
Mayo Clinic Study of Aging found that quantitative volume ratios between the

frontal horns of the lateral ventricles divided by the total intracranial volume
correlate better than the Evans index with measures of gait speed and cognition
both cross-sectionally and longitudinally.14 Nonetheless, the Evans index is
easy to measure in the office and readily available to all.
In a true communicating hydrocephalus syndrome, CSF has the potential to
increase volume not only in the ventricular system but also in the communicating
subarachnoid space. In such cases, the CSF tends to collect in the major
fissures in the brain and displace the surrounding brain tissue, leading to a
compressed appearance of adjacent sulci. A characteristic pattern known as
TABLE 8-2 Pertinent Features in History and Examination for Normal Pressure
Hydrocephalus
Feature Why Feature Should Be Addressed
History
Was gait difficulty onset before, at same time as, or after Gait onset before or at same time as cognitive difficulty is
cognitive decline? associated with a good prognosis with shunting; dementia
preceding the gait difficulty is associated with a poor
prognosis with shunting35,37
How long has the patient had cognitive difficulty? Two or more years of cognitive decline before presentation
indicates poor prognosis with shunting33,38
Does the patient have urinary difficulty? If so, what type and Urinary urgency is the most common problem; incontinence
for how long? is not necessary for the diagnosis
Has the patient fallen? Stronger indication to intervene
Was the patient assessed for vascular risk factors? Risk factors are associated with normal pressure
hydrocephalus15
Does the patient have a history of alcohol abuse? Poor prognosis from shunt point of view32
Does patient have a history of secondary causes, such as head Good prognosis from shunt point of view
injury, meningitis, brain surgery, previous brain hemorrhage?
Is the patient on an anticoagulant? Important if considering lumbar puncture or surgery
Does the patient have sleep apnea? Valsalva at night theoretically may aggravate hydrocephalus39
Is the patient in heart failure? May raise CSF pressure
Does the patient have any spinal diseases? Important contributor to gait dysfunction
Does the patient have any major arthritis? Important contributor to gait dysfunction
Does the patient have diabetes mellitus? Associated with peripheral neuropathy
Does the patient have any visual problems? May affect gait
Does the patient have any auditory or vestibular difficulty? May affect gait
Does the patient have any family history of neurologic disease? Could be related to ataxia
Is the patient taking medications that affect gait or lower Examples are phenothiazines, benzodiazepines,
blood pressure? antihypertensives, and alpha blockers for prostate
hypertrophy
172 FEBRUARY 2019

disproportionately enlarged subarachnoid space hydrocephalus (DESH) was first
defined in 2010.46 DESH includes a tight high convexity and enlarged sylvian
fissures with ventriculomegaly (FIGURE 8-3). DESH is associated with a good
response to shunting and is now included in in the Japanese guideline for
management of NPH.3 The ventriculomegaly combined with sylvian fissure
expansion leads to displacement of the CSF from sulci at the convexity and
medial portion of the brain, leading to the so-called tight appearance.
Tightness at the high convexity has been shown to be predictive of a
shunt-responsive NPH clinical syndrome.47 When fluid in the sylvian fissure
Feature Why Feature Should Be Addressed

Examination
Measure head size 10% or more of patients with normal pressure hydrocephalus
have a head size larger than the 98th percentile8,9 (57.5 cm
for women and 59 cm for men)
Measure postural blood pressure Look for orthostatic hypotension
Evaluate reflexes for radiculopathy, signs of stroke, and Brain, spinal cord, nerve root, and peripheral nerve diseases
myelopathy affect gait
Check vision May affect gait
Test hearing and vestibular function May affect gait
Evaluate for peripheral neuropathy May affect gait
Examine for parkinsonism May affect gait
Check for ataxia May affect gait
Check for arthritis May affect gait
Measure body mass index This correlates with elevated opening pressure40
CSF = cerebrospinal fluid.

accumulates in connected sulci,

the brain takes on an unusual
anatomic appearance, especially
when viewed on axial slices
(FIGURE 8-4). This subarachnoid
space expansion is frequently
mistaken for atrophy or an
arachnoid cyst, complicating the
evaluation of patients with NPH.
It is thus important for clinicians
to become familiar with the
anatomic patterns of fluid
collection within the major brain
fissures. Fluid tends to accumulate
not only in the sylvian fissure
but also in other major fissures
(eg, calcarine, parietooccipital,
and longitudinal fissures) and
FIGURE 8-2 connected sulci (FIGURE 8-5). The
Evans index. The Evans index is the maximal
authors have found that this
ventricular width in the frontal horns divided by
the largest distance between the inner tables of imaging appearance can
the skull measured at the same level. When the complicate NPH evaluation when
Evans index is greater than 0.3, the ventricles are it is mistaken for atrophy and the
in the top 20% in size of persons older than
concomitant ventriculomegaly
70 years of age.
is interpreted as being ex vacuo
(CASE 8-1).
In addition to high-resolution
structural MRI for evaluation of
anatomic patterns, axial FLAIR
MRI is useful for evaluating for
evidence of transependymal flow
(FIGURE 8-6A) in addition to
coexisting vascular pathology.
The authors have also found it
useful to include sagittal MRI
sequences that have high signal
from CSF to evaluate for partial
obstruction (eg, fast imaging
employing steady state
acquisition C [FIESTA-C] or
constructive interference in
steady state [CISS] sequences,
FIGURE 8-3 FIGURE 8-1).
Disproportionately enlarged subarachnoid space
hydrocephalus (DESH). Coronal T1-weighted MRI
sequence with the three features characteristic of HIGH-VOLUME LUMBAR PUNCTURE
DESH highlighted. Ventriculomegaly (asterisk), TEST. The exact way to perform
increased CSF volume in the sylvian fissure a high-volume LP test for the
(arrow), and the tight high convexity (oval). This
finding has been incorporated into the Japanese
evaluation of NPH is a matter of
guidelines for management of normal pressure controversy. Differences among
hydrocephalus. studies include using different
174 FEBRUARY 2019

measures for outcome, measuring the KEY POINTS
outcomes at different times after the LP,
● In the assessment
and taking off different amounts of CSF. A of patients for NPH,
meta-analysis looked at the eight “best” establish that there is
studies.49 Patients were evaluated at ventriculomegaly; look for
different times after the LP, from 2 hours congenital factors such as
aqueductal stenosis or
to 1 to 2 days later. The timing of when the webbing; and recognize
patient is reevaluated for improvement the features of
after the high-volume LP is important disproportionately enlarged
because CSF is made at a rate of 0.3 mL/min; subarachnoid space
hydrocephalus (DESH), not
therefore, after 3 hours, the CSF withdrawn mistaking DESH for atrophy.
has been replaced. Yet, anecdotally, some
patients report improvement 24 hours ● The two best diagnostic
after the high-volume LP test. Several tests for normal pressure
hydrocephalus are
studies have used the LP as an indication
evaluating the MRI for the
for surgery, so the sensitivity could not be characteristic features, and
FIGURE 8-4
calculated. The meta-analysis concluded Characteristic finding of fluid performance of a
that if the high-volume LP test shows collection in the anterior and posterior high-volume lumbar
puncture, measuring gait
improvement in gait, the patient has an aspects of the sylvian fissure in normal
pressure hydrocephalus. Axial head CT features objectively before
excellent chance of improving with and within 30 minutes after
shows fluid pockets surrounded by
shunt surgery. tight sulci. This characteristic finding in the lumbar puncture.
The authors perform the high-volume normal pressure hydrocephalus is
LP test by videotaping the patient’s gait sometimes mistaken for atrophy or
before the LP. After removing 30 mL CSF arachnoid cysts when viewed on only
one of the three anatomic planes.
with the LP, the patient’s gait is again
videotaped within 30 minutes. Three
measures of the gait are documented:
(1) the time taken to walk 10 meters, turn 180 degrees, and return to the starting
point; (2) the number of steps needed to turn 180 degrees twice, averaged;
(3) the number of steps needed to turn 360 degrees 3 times, averaged.
Improvement on any one of these measures is regarded as gait improvement
(VIDEO 8-1, links.lww.com/CONT/A268). It has been shown that some patients
who did not improve with a high-volume LP test may still improve with shunt
surgery, suggesting that high-volume LP tests may result in false negatives.50
This study50 should be interpreted cautiously because patients were evaluated
6 to 8 hours after the LP. Nonetheless, the authors advise patients that if the LP test
is negative, a subset of patients who have the clinical and imaging features of
NPH may still have a chance of improving with a shunt, but this is much less likely
than if the LP test was positive.
EXTERNAL LUMBAR DRAINAGE. For an external lumbar drain, patients are

admitted to the hospital for placement of the drain. One method is to remove
10 mL CSF per hour. This study can be done for 1 to 3 days. The patient is
evaluated for improvement in gait, cognition, or both. Despite the more invasive
nature of an external lumbar drain, false negatives still occur,50 similar to the
LP test. Meningitis is an important complication with an external lumbar drain,
and in a large series, 3.6% of patients developed an infection.51 Placement of an
external lumbar drain is most often undertaken in experienced centers and is
considered in patients who have a negative LP test and when the patient, family,
and doctors are struggling with the decision to decide on surgery.

OVERLAPPING DISEASES
The average age of patients
who receive shunts for NPH is
approximately 75, when many
of the comorbid diseases
discussed become common.36
Thus, it is not surprising that
persons being considered for
shunt surgery may have
several diseases that can
complicate diagnosis.27
Considering whether
coexisting AD is present is
important. In an autopsy series
of persons without dementia,
Braak and Braak52 noted that at
71 to 75 years of age, 26% of
patients had stage B and stage
C amyloid pathology and 21%
had stage III to stage VI tau
pathology. At 76 to 80 years of
age, 40% had stage B and stage
C amyloid pathology and 37%
had stage III to stage VI tau
pathology. In four studies in
which the brain was biopsied
at the time of the shunt
placement for NPH, about
30% of patients had AD
FIGURE 8-5
Anatomic patterns of subarachnoid hydrocephalus
pathology by biopsy,53–56
within major brain fissures and connected sulci. The consistent with the expected
anatomic patterns of subarachnoid hydrocephalus percentage based on age from
are best appreciated on yoked orthogonal MRI the Braak and Braak study.
sections (sagittal, coronal, and axial views centered
on the same point in the image). A, MRI of a patient
Therefore, it should be
with prominent subarachnoid hydrocephalus in the suspected that about 30% of
bilateral sylvian fissures and connected sulci is persons shunted have
displayed using three orthogonal sections coexisting AD pathology.
highlighting the posterior aspect of the fissure (S1),
While AD pathology is an
the middle portion of the fissure (S2), and the
anterior portion of the fissure (S3). B, The same important comorbid disease
patient also had prominent subarachnoid confounding the cognitive
hydrocephalus in the parietooccipital (POC) and features of NPH, Parkinson
calcarine fissures. The CSF volume in these fissures
disease and other
dramatically reduced after a ventriculoperitoneal
shunting procedure (not shown). C, MRI of a neurodegenerative
different patient demonstrates anatomic patterns parkinsonian syndromes
that can be observed with subarachnoid causing gait abnormality are
hydrocephalus involving the longitudinal fissure and important conditions to
connected sulci, such as the cingulate sulcus. Note
the tight sulci seen on the midsagittal slice above the consider when evaluating the
calcarine fissure (L-Sag) and the tight sulci on the motor aspects of NPH.57
upper cuts on the posterior portion of the axial Dopamine transporter single-
slices (L-Ax). photon emission computed
176 FEBRUARY 2019

tomography (SPECT) scanning58 and iodine-123 metaiodobenzylguanidine KEY POINTS
[MIBG] SPECT scanning of the heart59 have been proposed as biomarkers of
● Overlapping chronic
neurodegenerative parkinsonian syndromes that may predict a poor response to diseases are common in
shunt. However, these modalities are limited in that they are only able to persons being considered
detect a subset of comorbid neurodegenerative conditions and do not have for shunt surgery because
positive findings suggestive of the presence of NPH. FDG-PET may also serve their average age is about
74 years. At this age, 30% of
as a useful diagnostic biomarker in evaluating a patient for NPH because,
cognitively normal persons
in addition to detecting an AD pattern of hypometabolism,60 FDG-PET is have Alzheimer disease
abnormal in a wide range of neurodegenerative diseases. The presence of pathology. Fludeoxyglucose
caudate hypometabolism has been identified as a potential biomarker in NPH.29 positron emission
tomography may help
In addition to evaluating for the presence of comorbid neurodegenerative
reveal a concomitant
diseases with FDG-PET, normal cortical metabolism will rule out most degenerative disease.
neurodegenerative sources of ex vacuo ventriculomegaly and limit
misinterpretation of subarachnoid hydrocephalus (FIGURE 8-6). ● In idiopathic normal
Spinal diseases, arthritis, peripheral neuropathy, cerebellar diseases, and pressure hydrocephalus,
most metabolic proteins are
orthostatic hypotension are crucial to recognize when evaluating a patient low in the CSF, so Alzheimer
for NPH.27 biomarkers (eg, amyloid-β1-42
and phosphorylated tau)
CEREBROSPINAL FLUID BIOMARKERS are also low and are not
helpful in distinguishing
CSF measures of AD proteins were considered potential biomarkers to readily Alzheimer disease from
distinguish patients with AD from patients with NPH. In AD, amyloid-β1-42 is low idiopathic normal pressure
in the CSF, while total tau (t-tau) and phosphorylated tau (p-tau) are elevated. hydrocephalus.
In patients with NPH, however, many proteins, including metabolites of amyloid
precursor protein (APP) (eg, amyloid-β1-40, amyloid-β1-42, soluble amyloid
precursor protein α [sAPPα], and soluble amyloid precursor protein β [sAPPβ]),
t-tau, and p-tau are low, and these normalize after a shunt is placed.61 The
finding of low amyloid-β1-42 and low tau in NPH has been confirmed in several
studies.62,63 The exact reason these proteins are low in NPH is unknown, but
studies have shown that during sleep the nerve cells shrink and the interstitial
space increases, facilitating metabolic product drainage.64 The authors65 have
hypothesized that in NPH, the typical drainage of metabolic products is impaired
because the cells and interstitial space are tight, resulting in many proteins
being low when measured in the CSF of patients with NPH, but these proteins
return to normal after a shunt is placed.61 Because amyloid-β1-42 is low in both
NPH and AD, the utility of CSF biomarkers in distinguishing AD from NPH is
limited. The presence of elevated t-tau or p-tau would be inconsistent with NPH
and suggestive of a primary or at least coexisting neurodegenerative disease.
SURGICAL CONSIDERATIONS
Important surgical considerations in NPH include the use of adjustable shunts,
the complications of surgery, and setting the valve opening pressure.
Adjustable Shunts Versus Fixed-Opening-Pressure Shunts

Over the past decades, adjustable shunts have slowly replaced fixed-pressure
shunts. In the Swedish registry of patients with NPH who underwent shunt
surgery between 2004 and 2015,66 10% developed subdural hematomas. Of
these, 103 subdural hematomas were treated by adjusting the shunts, while
66 had surgical drainage and 15 had no treatment. Of those with fixed-pressure
shunt valves, 90% were treated with surgery, but only 30% with adjustable
valves were treated surgically. The study concluded that subdural hematomas are

CASE 8-1 A 68-year-old woman presented with a 2-year history of progressive gait
disturbance. She had used a walker for the past 4 months and had
noticed difficulty with turning and imbalance but no freezing. She had no
tremors, delusions, hallucinations, dream enactment, head trauma, or
history of central nervous system infection but had memory difficulty.
She had experienced urinary incontinence for 6 years, which worsened
when treated with oxybutynin.
Lumbar spine MRI demonstrated mild to moderate canal stenosis at L3
through L5. MRI of the cervical spine demonstrated moderately severe
bilateral neural foraminal stenosis at C4 to C5. Brain MRI demonstrated
hydrocephalus with high periventricular fluid-attenuated inversion
recovery (FLAIR) signal suggestive of normal pressure hydrocephalus.
CSF collections outside of the ventricle were seen as well (FIGURE 8-6A).
The patient had undergone a high-volume lumbar puncture by a previous
neurologist and reported improvement in her symptoms; however, the
diagnosis was questioned, and she sought a second opinion.
FIGURE 8-6
Ventricular, sylvian fissure, and longitudinal fissure hydrocephalus in the absence of
neurodegenerative hypometabolism in the patient in CASE 8-1. A, Baseline axial fluid-
attenuated inversion recovery (FLAIR) MRI sequence demonstrates ventriculomegaly with
subarachnoid hydrocephalus in the sylvian and longitudinal fissures. Periventricular
high T2 signal is also present. B, Baseline fludeoxyglucose positron emission tomography
(FDG-PET) demonstrating normal cortical metabolism in the brain tissue around the sylvian
and longitudinal fissures with subtle artifactual hypometabolism seen in these same areas
(green-colored regions) related to partial volume averaging. There is a notable absence of
a neurodegenerative pattern of hypometabolism. True hypometabolism is seen in the
striatum, which commonly occurs in normal pressure hydrocephalus. C, Axial CT scan
demonstrating resolution of the ventricular, sylvian fissure, and longitudinal fissure
hydrocephalus 17 months after a ventriculoperitoneal shunt was placed.
178 FEBRUARY 2019

On examination, she scored 29/38 on the Kokmen Short Test of Mental
Status (orientation 6/8, digit span 5/7, learning 4/4 with two trials,
calculation 3/4, abstraction 3/3, construction 4/4, information 4/4,
recall 2/4). (The normal score on the Kokmen Short Test of Mental Status
is 34.2 +/– 2.4.48) Speech and language were normal. Her neurologic
examination was normal with the exception of having a wide base while
standing, difficulty moving while sitting on the examination table, and
walking slowly with a wide base. She took nine steps to turn 180 degrees.
She did not freeze while walking.
Her neuropsychological testing demonstrated prominent cognitive
slowing along with mild to moderate deficits in aspects of executive
function, learning, and memory. The patient needed assistance with
activities of daily living, so the findings were in keeping with a mild
dementia.
A high-volume lumbar puncture (30 mL) was performed and
demonstrated significant improvement in her walking speed and turns.
The opening pressure was 232 mm H2O, and the CSF cell count, protein,
and glucose were normal. Fludeoxyglucose positron emission
tomography (FDG-PET) demonstrated normal cortical metabolism,
providing evidence against a neurodegenerative etiology (FIGURE 8-6B).
She underwent ventriculoperitoneal shunt placement. On her
return visit 17 months after surgery, her CT scan showed improvement in
ventricular size and fluid in the sylvian and longitudinal fissures
(FIGURE 8-6C). Clinically, her cognition also improved (she scored 35/38 on
the Kokmen Short Test of Mental Status). Her gait was normal, and her
urinary incontinence had resolved.
This case illustrates the major clinical features of normal pressure COMMENT
hydrocephalus. The patient’s main problem was gait difficulty, but she also
had clear cognitive and urinary problems, which all resolved with shunting.
The fluid collections outside of the ventricles made the diagnosis difficult,
with some suspicion that the fluid collections were due to atrophy.
FDG-PET was helpful because it showed no cortical hypometabolism,
supporting that a concomitant degenerative disease was unlikely. Her
follow-up scan showed improvement in the fluid collections outside of the
ventricles, indicating that this was part of the hydrocephalus and
confirming the fluid collections were not secondary to atrophy.

common after shunt surgery, but adjustable shunts decrease the need for surgical
intervention. TABLE 8-3 reports the declining complication rate of shunt
placement by decade.
Setting the Opening Valve Pressure

When the opening valve pressure is set to a level much lower than the opening LP
CSF pressure, a greater chance of overdrainage complications exists, such as
subdural hematoma, subdural hygroma, or headache.40 The patient’s body mass
index has been associated with the LP opening pressure, with patients who are
overweight having higher LP opening pressures. The authors’ practice has
changed to now set the valve opening pressure at the LP opening pressure to try
to decrease overdrainage. The authors recommend that each center review its
own complication rate so that specific advice can be given when advising a
patient and family regarding complications of shunt surgery.
How to Evaluate Improvement

The authors recommend both the mRS and the Normal Pressure Hydrocephalus
Scale for detailed evaluation of improvement in NPH.
MODIFIED RANKIN SCALE. The mRS has been used in NPH and stroke studies.5
It is a subjective assessment of change but has a track record in important clinical trials;
it measures patient functionality, which is crucial in judging shunt benefit. Use of
this scale allows comparison of patients and their outcomes to those in other NPH
studies that used the scale. Reliability is improved with a structured interview.67
NORMAL PRESSURE HYDROCEPHALUS SCALE. A standardized Normal Pressure

Hydrocephalus Scale68 was used in the European Multicenter NPH study to
quantitatively measure the cardinal clinical features of NPH. It is a 0- to 100-point
scale that measures the key features of NPH: gait, cognition, balance, and urine
control. All items are weighted equally except gait, which contributes double weight
compared to the other components. Hellström and colleagues68 give the details of
how to combine the individual measures to obtain an overall 0 to 100 score.
TABLE 8-3 Complication Rate in Normal Pressure Hydrocephalus by Decadea
Number Number Subdural Intracranial Infection Seizures Revision

Decade of Studies of Patients Mortality (%) Hematoma (%) Hemorrhage (%) (%) (%) Rate (%)
1970s 2 92 9.5 4.1 0 8.2 1.3 17.8
1980s 8 262 5 15 1.3 1.7 4.8 14
1990s 12 459 3.2 14 0 2 0.7 27
2000s 42 2250 0.3 4.8 0.4 3.6 0 19
2006 to 30 1573 0.2 4.5 0.2 3.5 0 13

October
2010
a
Reprinted with permission from Toma AK, et al, Acta Neurochir (Wien).26 © 2013 Springer-Verlag Wien.
180 FEBRUARY 2019

GAIT SCALE. The gait scale consists of three measures:
u A timed walk for 10 meters (free pace)

u The number of steps the patient took to make this walk
u An ordinal scale from 1 to 8 for walking (TABLE 8-4)
COGNITIVE SCALE. The cognitive scale consists of three tests that contribute four
cognitive variables. The grooved pegboard test evaluates speed of manual
dexterity. The patient must place 25 pegs into holes with randomly positioned
slots as quickly as possible. The task is performed once with each hand, beginning
with the dominant hand. Time to completion for the faster hand is used to
determine the test score. The Rey Auditory Verbal Learning Test is a 15-word
list-learning test. The words are read aloud by the examiner at a rate of
approximately one word per second; immediately afterward, the patient is asked
to recall as many words as possible from the list. The same list is read five
consecutive times, and the sum of words recalled correctly across all trials
contributes to the overall cognitive score. The Swedish Stroop test is a task that
measures processing speed and complex attention/executive function. Two tasks
are administered: a color-naming task and an interference task. In the
color-naming task, the patient is asked to name the colors of 100 rectangles
presented in a 10 by 10 matrix as quickly as possible. In the interference task, the
patient is asked to name, again as quickly as possible, the color of the ink of
100 incongruently colored color words (eg, the word green printed in yellow).
BALANCE SCALE. The balance scale consists of an ordinal scale converted to

100 points based on observations of the patient’s efforts to stand up straight on
one or both legs. An ordinal rating is given (TABLE 8-5).
CONTINENCE SCALE. The continence scale is also an ordinal scale (TABLE 8-6). The
rating is based on information of the most trustworthy source available, as
patients with reduced insight may deny incontinence despite its presence.
OTHER ASSESSMENTS FOR IMPROVEMENT. From a clinical point of view, physicians

could also use a combination of videotaping the patient’s gait (eg, walking 10
Gait Scale of Normal Pressure Hydrocephalus Scalea TABLE 8-4
1 Normal
2 Slight disturbance of tandem walk and turning
3 Wide-based gait with sway, without foot corrections
4 Tendency to fall, with foot corrections
5 Walking with cane
6 Bimanual support needed
7 Aided
8 Wheelchair dependent
a
Reprinted with permission from Hellström P, et al, Acta Neurol Scand.68 © 2012 John Wiley & Sons.

TABLE 8-5 Balance Scale of Normal Pressure Hydrocephalus Scalea
1 Able to stand independently for 30 seconds or more on either lower extremity alone
2 Able to stand independently for less than 30 seconds on either lower extremity alone
3 Able to stand independently with the feet together (at the heels) for more than 30 seconds
or more
4 Able to stand independently with the feet together for less than 30 seconds
5 Able to stand independently with the feet 1 foot apart for 30 seconds or more
6 Able to stand independently with the feet 1 foot apart for less than 30 seconds
7 Unable to stand without assistance
a
TABLE 8-6 Incontinence Scale of Normal Pressure Hydrocephalus Scalea
1 Normal urinary function

2 Urgency without incontinence
3 Infrequent incontinence without a diaper
4 Frequent incontinence with a diaper
5 Bladder incontinence
6 Bladder and bowel incontinence
a
TABLE 8-7 Long-term Outcome of Shunt Surgery by Decadea
Improved at Improved at Improved at More

Decade Studies (N) Patients (N) Age (Mean) 3 Months (%) 1 Year (%) Than 3 Years (%)
1970s 2 92 67 67.5 45 No data available
1980s 8 262 67 68 53 No data available
1990s 12 459 68 64 81 40
2000s 42 2250 70 74 79 72
2006 to October 2010 30 1573 71 81 82 73
a
Reprinted with permission from Toma, AK, et al, Acta Neurochir.26 © 2013 Springer-Verlag.
182 FEBRUARY 2019

meters, turning 180 degrees, and returning) and a standardized short test such as KEY POINTS
the Kokmen Short Test of Mental Status,69 Mini-Mental State Examination
● Surgical complications
(MMSE),70 or the Montreal Cognitive Assessment (MoCA).71 following shunt surgery are
common but have
Prognosis After Shunting decreased over the
Determining the long-term outcomes after shunt surgery is a controversial decades. Adjustable shunts
area. One meta-analysis shows that surgical prognosis has improved over time allow treatment of
overdrainage without
(TABLE 8-7). Others have pointed out that in an intention-to-treat analysis, the
surgical intervention.
number of individuals improving would be lower.72
When the authors discuss the high complication risk and the long-term ● Objective measurements
outcome for shunt surgery with patients and their families, patients most to assess patient change
frequently still choose to undergo the procedure and take the risk because the with shunt placement are
very helpful in management.
alternatives are so bleak. A patient with difficulty walking and incontinence has a
large chance of being cared for in a nursing home. Further, the patients’ risk of ● Surgical outcome is
falling increases their risk of hospitalization. improving, and patients who
are seen in follow-up 3 years
after shunt surgery have a
good chance of remaining
CONCLUSION improved.
NPH is a rare, but treatable, disease. The diagnosis can be difficult because many
diseases can cause cognitive impairment, incontinence, and gait dysfunction.
Treating well-selected patients can result in clinical improvement, but the risks
and benefits of the shunt procedure must be weighed. Recent improvements in
understanding the neuroimaging features of NPH have allowed improved
identification and selection of patients with NPH. In the future, a randomized
double-blind clinical trial is needed to evaluate the short- and long-term clinical
outcome and complication rate for NPH. Since shunts now have a virtual “off”
setting, this could potentially be completed with half the shunted patients having
the shunt set at “off” for a period and half having the shunt set at “on”
immediately.7
VIDEO LEGEND
VIDEO 8-1
Gait in normal pressure hydrocephalus before and
after high-volume lumbar puncture test and after
ventriculoperitoneal shunt surgery. A 64-year-old
woman with normal pressure hydrocephalus.
Video on the left demonstrates the baseline gait
of the patient. Video on the right shows her gait
30 minutes after removing 30 mL CSF and her
gait 6 months after shunting.
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186 FEBRUARY 2019

Chronic Traumatic REVIEW ARTICLE
Encephalopathy

C O N T I N U UM AUDIO
INTERVIEW AVAILABLE
ONLINE
By Katherine W. Turk, MD; Andrew E. Budson, MD
ABSTRACT
PURPOSE OF REVIEW: This article provides a discussion on the current state of
knowledge of chronic traumatic encephalopathy (CTE), with an emphasis
on clinical features and emerging biomarkers of the condition.
CITE AS:
RECENT FINDINGS: The results of several large brain bank case series among 2019;25(1, DEMENTIA):187–207.
subjects with a history of contact sports or repetitive head trauma have

indicated that a high frequency of CTE may exist in this population. Dr Katherine W. Turk, VA Boston
However, the true prevalence of CTE among individuals with a history of Healthcare System, 150 S
head trauma remains unknown, given that individuals who experienced Huntington Ave, 151-C, Jamaica
Plain, MA 02130, kturk@bu.edu.
cognitive, behavioral, and mood symptoms during life are more likely to
have their brains donated for autopsy at death and epidemiologic studies RELATIONSHIP DISCLOSURE:
of the condition are lacking. Neuropathologic consensus criteria have been Dr Turk receives research/grant
support from the Alzheimer’s
published. Research-based clinical criteria have been proposed and are Association. Dr Budson has
beginning to be applied, but the definitive diagnosis of CTE in a living served as a consultant for
Axovant Sciences, Inc, and
patient remains impossible without effective biomarkers for the condition,
Eli Lilly and Company and has
which is an active area of study. received personal
engagements from Eli Lilly and
SUMMARY: The field
of CTE research is rapidly growing and parallels many of Company. Dr Budson receives
the advances seen for other neurodegenerative conditions, such as research/grant support from
Alzheimer disease decades ago. the US Department of Veterans
Affairs (I01CX000736) and
publishing royalties from
Elsevier and Oxford
University Press.
INTRODUCTION
C
UNLABELED USE OF
hronic traumatic encephalopathy (CTE) is a neurodegenerative PRODUCTS/INVESTIGATIONAL
disorder with unique neuropathologic findings distinct from other USE DISCLOSURE:
degenerative disorders, namely characteristic perivascular Drs Turk and Budson discuss
the unlabeled/investigational
accumulations of phosphorylated tau (p-tau) in neurons and use of several classes of
astrocytes.1 As early as 1928, Martland2 noted a progressive clinical medications for chronic
syndrome of behavioral, cognitive, and mood symptoms associated with retired traumatic encephalopathy,
including cholinesterase
boxers, which he termed punch-drunk syndrome. However, the disorder was inhibitors for memory-related
not clearly differentiated from other neurodegenerative conditions until 1973, issues, selective serotonin
when Corsellis and colleagues3 described 15 cases with clinical and pathologic reuptake inhibitors for mood
and behavioral issues,
features, which he termed dementia pugilistica. CTE is the current term used for memantine for attentional
this progressive neurodegenerative disorder thought to result from repeated issues in those with advanced
dementia, and atypical
concussive or subconcussive head injury.4–6 A 2005 case report described the antipsychotics for those who
first neuropathologically confirmed CTE case in a former professional football are disinhibited and violent.
player (note that in this article, the term football is used to refer to American
football),6 which renewed interest in the disease and has ushered in an exciting © 2019 American Academy
period of inquiry into this previously underrecognized condition. Our knowledge of Neurology.

CHRONIC TRAUMATIC ENCEPHALOPATHY
of CTE is quickly advancing, yet it is currently in a state of infancy compared to

that of other neurodegenerative conditions.
Although a strong association exists between repeated blows to the head and
chronic cognitive and behavioral impairment, epidemiologic, cross-sectional,
and prospective studies that firmly establish the causal link between repetitive
head trauma and the characteristic neuropathology of the disorder are lacking,
making the diagnosis of CTE in life challenging.7 The frequency, severity, and
total exposure to head trauma and the exact pathophysiologic mechanism by
which blows to the head result in CTE are active areas of research. Exposure to
TABLE 9-1 National Institute of Neurological Disorders and Stroke Pathologic Criteria
for Chronic Traumatic Encephalopathy Diagnosisa
Required for Diagnosis of Chronic Traumatic Encephalopathy

◆ The pathognomonic lesion consists of phosphorylated tau (p-tau) aggregates in neurons,
astrocytes, and cell processes around small vessels in an irregular pattern at the depths
of the cortical sulci
Supportive Neuropathologic Features of Chronic Traumatic Encephalopathy
◆ P-tau–related pathologies
◇ Abnormal p-tau immunoreactive pretangles and neurofibrillary tangles preferentially
affecting superficial layers (layers II–III), in contrast to layers III and V as in Alzheimer disease
◇ In the hippocampus, pretangles, neurofibrillary tangles, or extracellular tangles
preferentially affecting CA2 and pretangles and prominent proximal dendritic swellings
in CA4. These regional p-tau pathologies differ from the preferential involvement of CA1
and subiculum found in Alzheimer disease
◇ Abnormal p-tau immunoreactive neuronal and astrocytic aggregates in subcortical
nuclei, including the mammillary bodies and other hypothalamic nuclei, amygdala,
nucleus accumbens, thalamus, midbrain tegmentum, and isodendritic core (nucleus
basalis of Meynert, raphe nuclei, substantia nigra, and locus coeruleus)
◇ P-tau immunoreactive thorny astrocytes at the glial limitans most commonly found in the
subpial and periventricular regions
◇ P-tau immunoreactive large grainlike and dotlike structures (in addition to some
threadlike neurites)
◆ Non–p-tau–related pathologies
◇ Macroscopic features: disproportionate dilatation of the third ventricle, septal
abnormalities, mammillary body atrophy, and contusions or other signs of previous traumatic
injury
◇ Transactive response DNA-binding protein 43 (TDP-43) immunoreactive neuronal
cytoplasmic inclusions and dotlike structures in the hippocampus, anteromedial
temporal cortex, and amygdala
Age-related P-tau Astrogliopathy That May Be Present; Nondiagnostic and Nonsupportive
◆ Patches of thorn-shaped astrocytes in subcortical white matter
◆ Subependymal, periventricular, and perivascular thorn-shaped astrocytes in the
mediobasal regions
◆ Thorn-shaped astrocytes in amygdala or hippocampus
a
Modified with permission from McKee AC, et al, Acta Neuropathol.1 © 2016 The Authors.
188 FEBRUARY 2019

head injuries is thought to be a necessary factor in developing CTE, yet head KEY POINTS
injuries in isolation are not sufficient to cause the condition, thus a search is
● Chronic traumatic
under way to define the additional susceptibility factors that increase risk of the encephalopathy is a
disease. Factors under investigation include modifiable lifestyle risk factors; pathologically defined
genetics; and quantity, severity, time course, and duration of exposure to head neurodegenerative disorder
injuries. As a result, CTE is currently defined by its hallmark neuropathology. associated with repetitive
concussive or
CTE neuropathology has been recognized in the brains of many contact sport
subconcussive head injury.
athletes, most notably football players and boxers, but has also been found in
other individuals exposed to head trauma, including wrestlers, soccer players, ● The frequency, severity,
hockey players, and military service members.8–13 Most symptoms of CTE are and total exposure to head
thought to occur years to decades following the initial head trauma.4,13 Although trauma and the exact
pathophysiologic
CTE is thought to result in characteristic clinical deficits involving cognition, mechanism by which blows
behavior, and mood as well as possible motor deficits, no validated consensus to the head result in chronic
clinical criteria have yet been developed. Research diagnostic criteria have been traumatic encephalopathy
proposed and are discussed in detail below. are active areas of research.
The terminology in the field of head injury has led to confusion. Traumatic ● Head injury is an
brain injury (TBI) and concussion are often defined based on the time course of important but nonsufficient
postconcussive symptoms.14 The terms mild traumatic brain injury and concussion risk factor in the
are used somewhat interchangeably, without clear distinction, with concussion development of chronic
traumatic encephalopathy;
often being preferred by the sports community and mild TBI by the medical
other exposure and genetic
community. Concussion is defined as a clinical syndrome of impaired brain risk factors are under
function, typically impacting memory and orientation, with or without loss of investigation.
consciousness, that results from some type of impact to the head.15 Postconcussive
syndrome is a constellation of clinical signs and symptoms that may remain ● Currently, no validated
clinical diagnostic criteria
weeks, months, or years following a concussion in a small number of patients. for chronic traumatic
Typical signs and symptoms of postconcussive syndrome include headache, encephalopathy exist,
insomnia, vertigo, tinnitus, anxiety, and fatigue, among other symptoms.16 CTE although research
should not be confused with the postconcussive syndrome that may result diagnostic criteria have
been developed.
from a symptomatic head injury. CTE is a separate long-term consequence of
concussive and subconcussive repetitive head impact.4,13 Studies have ● Concussion is a clinical
demonstrated that asymptomatic subconcussive impacts are associated with syndrome of impaired brain
CTE pathology.17 function, typically impacting
memory and orientation,
with or without loss of
PATHOLOGIC CRITERIA consciousness that results
In 2015, the first consensus neuropathologic criteria for the diagnosis of CTE from head injury.
were developed by a panel of seven expert neuropathologists organized by the
National Institute of Neurological Disorders and Stroke (NINDS) and the ● Chronic traumatic
encephalopathy is defined
National Institute of Biomedical Imaging and Bioengineering (NIBIB) by neuropathology:
(TABLE 9-1).1 The neuropathologists evaluated 25 cases of various tauopathies, perivascular aggregation of
blinded to clinical data, and arrived at an agreed-upon set of criteria to diagnose phosphorylated tau protein
CTE. The hallmark lesion of CTE, capable of distinguishing the disorder from within neurons and
astrocytes that begins in the
other tauopathies, was an accumulation of abnormal p-tau in neurons and depths of sulci and
astroglia distributed around small blood vessels at the depths of cortical sulci in a progresses to involve the
patchy, irregular pattern (TABLE 9-1). Pathognomonic accumulation of medial temporal lobes and
perivascular tau at the sulcal depths is thus a required element for the diagnosis of other parts of the brain.
CTE. In addition, several supportive neuropathologic criteria may be present in
CTE cases but are not necessary for a diagnosis (TABLE 9-1). The supportive
features include specific types of p-tau pathologies as well as non–p-tau–related
pathologies, such as transactive response DNA-binding protein 43 (TDP-43)
neuronal inclusions in the hippocampus, anteromedial temporal cortex, and

amygdala. Macroscopic features of CTE include dilation of the third ventricle,

septal abnormalities, atrophy of the mammillary bodies, and contusions.
Following the development of the NINDS-NIBIB criteria, most cases of CTE in
the literature have been diagnosed postmortem using these newly developed
pathologic criteria along with standardized clinical case interviews of informants
for retrospective evaluation of potential clinical characteristics that may be
associated with the pathology to allow clinicopathologic correlation.9 This
association between pathologic findings and reported clinical symptoms led to
the development of proposed staging criteria for both neuropathology and
clinical features (TABLE 9-218).
CLINICAL PRESENTATION
Although CTE is thought to result from the long-term consequences of head
injury, the amount and type of head injury required to produce the resulting
clinical syndrome and neuropathology are still under investigation. The CTE
phenotype varies and can involve a clinical constellation of often-progressive
cognitive, behavior, and mood changes as well as possible motor deficits.
Informants have reported in retrospective postmortem interviews that up
to 43% of patients with CTE had behavior or mood symptoms at initial
presentation.9
TABLE 9-2 Pathologic and Clinical Stages of Chronic Traumatic Encephalopathya
Stage Pathology Clinical Signs and Symptoms
I Perivascular phosphorylated tau Headache and loss of attention and

neurofibrillary tangles in focal epicenters concentration
at the depths of sulci in frontal cortex
II Stage I plus neurofibrillary tangles in Depression and mood swings,

superficial cortical layers adjacent to the explosivity, loss of attention and
focal epicenters, the nucleus basalis of concentration, headache, and short-
Meynert, and locus coeruleus term memory loss
III Stage II plus mild cerebral atrophy; septal Cognitive impairment with memory loss,
abnormalities; ventricular dilation, executive dysfunction, loss of attention
concave third ventricle, depigmentation and concentration, depression,
of locus coeruleus and substantia nigra; explosivity, and visuospatial
dense p-tau pathology in the cortex, abnormalities
medial temporal lobe, diencephalon,
brainstem, and spinal cord
IV Stage III plus further cerebral, medial Dementia with profound short-term
temporal lobe, hypothalamic, thalamic, memory loss, executive dysfunction,
and mammillary body atrophy; septal attention and concentration loss,
abnormalities; ventricular dilation; pallor explosivity, and aggression; most also
of substantia nigra and locus coeruleus; show paranoia, depression and
p-tau in widespread regions, including impulsivity, and visuospatial
white matter, with prominent neuronal abnormalities; many also have
loss, gliosis of cortex, and hippocampal parkinsonism, speech, and gait
sclerosis abnormalities
a
Reprinted with permission from Budson AE, Solomon PR,18 using data from McKee AC, et al, Brain.13
© 2016 Elsevier, Inc.
190 FEBRUARY 2019

NEUROPSYCHOLOGICAL SYMPTOMS
The cognitive profile of CTE involves impaired memory and executive
function.19 Patients with CTE may also have problems with concentration,
judgment, and problem-solving.1,13,19,20 The clinical features most commonly
seen in CTE by order of frequency at time of clinical presentation are listed in
TABLE 9-3. The cognitive and behavioral deficits may lead to substance abuse,
20
bankruptcy, and failed relationships.5,6,13,19,21
TIME COURSE AND PROGNOSIS

In a review of 202 published cases of CTE, 68% had a progressive clinical course
similar to other degenerative brain diseases.22 McKee and colleagues13 estimated
the rate of progression between any two successive pathologic stages of CTE to
be approximately 11 to 14 years. Although most cases have been described as
progressive, cases exist in younger individuals with predominant behavior/mood
symptoms that are thought to be more stable than when the disease manifests
in older individuals.22,23 Since a progressive course is a hallmark of neurodegenerative
diseases, this group of younger individuals with a predominantly behavioral/mood
presentation presents a diagnostic challenge for clinicians.
DIAGNOSTIC CRITERIA
Currently, no validated clinical diagnostic consensus criteria for CTE exist;
however, research diagnostic criteria have been developed by Montenigro and
colleagues22 to better classify the clinical spectrum of symptoms that can be
Clinical Features at Initial Presentation of Patients With Autopsy-Confirmed TABLE 9-3

Chronic Traumatic Encephalopathya,b
◆ Memory impairment (85%)

◆ Executive dysfunction (79%)
◆ Attention and concentration difficulties (73%)
◆ Sadness/depression (64%)
◆ Hopelessness (64%)
◆ Explosivity (58%)
◆ Language impairment (58%)
◆ Visuospatial difficulties (55%)
◆ “Out of control” (52%)
◆ Physically violent (52%)
◆ Verbally violent (49%)
◆ Impulse and control problems (46%)
◆ Suicidal ideation/attempts (30%)
◆ Motor symptoms (30%)
Reprinted with permission from Budson AE, Solomon PR,18 using data from Stern RA, et al, Neurology.19
© 2016 Elsevier, Inc.
b
Percentage of individuals with autopsy-proven chronic traumatic encephalopathy who had each feature at
presentation.

seen with the disorder (TABLE 9-4). Similar to other neurodegenerative

conditions, including Alzheimer disease (AD), neuropathologic findings are the
gold standard for diagnosis; definitive diagnosis of CTE in a living person is not
yet possible. Thus, the research diagnostic criteria use the terms probable,
possible, and unlikely CTE. The research diagnostic criteria are meant to build
upon prior published diagnostic criteria by Jordan24 and are based upon
literature review of CTE case series as well as the clinical presentation of
neuropathologically confirmed cases of CTE.4 Importantly, these research
criteria do not conflate the clinical syndromes being reported with definite,
pathologically proven CTE.
The term traumatic encephalopathy syndrome (TES) is used in the research
diagnostic criteria to refer to the clinical syndrome associated with repetitive
blows to the head. Some individuals with TES may have CTE neuropathologic
changes, although others may not; they may, instead, have other pathologies or
even predominantly psychiatric conditions without a clear neuropathologic
correlate. Importantly, TES criteria do not broadly apply to the acute or postacute
signs and symptoms following concussion, postconcussive syndrome, or
moderate to severe TBI. The proposed TES diagnostic criteria include five
general criteria, three core clinical features, and nine supportive features. The
general criteria were selected based on prior literature with the intention of
maximizing sensitivity over specificity. Core clinical features were
retrospectively reported by family members at a minimal rate of 70% among
pathologically confirmed CTE cases.19 The nine supportive features were selected
to increase specificity and were based on clinical features described in the
CTE literature.22
The research diagnostic criteria describe four TES subtypes: (1) a
behavioral/mood variant, occurring in younger patients; (2) a cognitive variant,
which occurs later in life; (3) a mixed variant (CASE 9-1); and (4) a TES dementia
form.22 The two main subtypes of TES are the behavioral/mood variant, which
had an average age of clinical symptom onset of 34.5 years, and the cognitive
variant (CASE 9-2), which had average age of clinical onset of 58.5 years.19 The
relative frequency of the subtypes is not known. In neuropathologically
confirmed cases, the initial clinical presentation has been described as mood
predominant without cognitive impairment in 28% of cases, cognitive without
mood or behavioral difficulties in 32%, and initially mixed between cognitive
and mood symptoms in 40%.22 The current research diagnostic criteria also
include a minimum amount of head injury exposure to consider a diagnosis of
TES (TABLE 9-5).
The classification of patients into the diagnostic categories probable, possible,
and unlikely CTE (TABLE 9-4) relies, in part, on the results of proposed
research-based biomarker findings (amyloid and tau positron emission
tomography [PET] imaging results or tau CSF levels) and the presence of a
cavum septum pellucidum, and/or cortical atrophy as seen on structural
imaging studies. TABLE 9-6 provides a full description of proposed CTE
biomarkers. Of note, these proposed biomarkers are still under active
investigation and are not yet recommended for routine clinical care (refer to
the Trends section for information on biomarkers under active investigation).
A cavum septum pellucidum, a fluid-filled space between the leaflets of the
septum pellucidum (FIGURE 9-3), is present in up to 15% of healthy individuals.
A cavum septum pellucidum is thought to be present in increased frequency
192 FEBRUARY 2019

within the CTE population, although the exact rate is unknown.25 During head KEY POINTS
trauma, fluid waves may produce fenestrations within the septum and allow
● Chronic traumatic
the entry of fluid between the leaflets, creating the cavum (separation) within encephalopathy deficits
the structure.26 involve progressive
cognitive, behavior, and
EVALUATION mood changes as well as
possible motor deficits.
The evaluation of patients for possible CTE should include questions about a
history of repetitive head trauma, with or without concussion, including ● The most common
exposures during contact sports, military service, domestic abuse, assault, and cognitive difficulties in
motor vehicle accidents. The clinician should also obtain a history of the patients with chronic
behavioral, mood, cognitive, and possible motor symptoms that have been traumatic encephalopathy
involve memory and
reported in individuals with CTE pathology. As in other neurodegenerative executive function.
diseases, determining the time course of decline in cognition, behavior, mood,
and activities of daily living is important. The neurologic examination should be ● Four traumatic
completed with a focus on the mental status examination as well as motor and encephalopathy syndrome
subtypes have been
gait evaluations. Specifically, clinicians should evaluate for fasciculations or described: (1) a
upper motor neuron signs that would suggest motor neuron disease and evaluate behavioral/mood variant,
for signs of parkinsonism, as both have been associated with head injury. occurring in younger
patients; (2) a cognitive
variant, which occurs later in
DIFFERENTIAL DIAGNOSIS
life; (3) a mixed variant; and
While the pathologic hallmark of CTE is distinct, the clinical presentation of CTE (4) a dementia form.
can mimic other disorders and can co-occur with other neurodegenerative
pathologies. Individuals with pathologically proven CTE have often been ● The classification of
clinically characterized by poor impulse control, executive dysfunction, and a patients into the diagnostic
categories probable,
young age of onset, similar to behavioral variant frontotemporal dementia. In possible, and unlikely
addition, motor neuron disease can occur with frontotemporal dementia (often chronic traumatic
related to C9orf72 mutation) and has been associated with CTE.27 Despite the encephalopathy relies, in
overlap in clinical features, patients with CTE have a history of repetitive or part, on results of potential
research-based biomarker
subconcussive head injury during contact sports and more memory loss than findings, thus diagnoses are
patients with behavioral variant frontotemporal dementia. AD dementia is often for use in research, not
considered as a cause of memory loss and should be included in the differential in clinical settings.
cases of possible CTE. Although behavioral changes, often apathy or irritability,
● The evaluation for
may be seen in AD dementia, these problems are distinct from the explosivity
possible chronic traumatic
and disinhibition typically seen in individuals with CTE pathology. Dementia encephalopathy should
and parkinsonism can be seen in combination in CTE and dementia with Lewy include asking about a
bodies (DLB). However, parkinsonism tends to be a late feature of CTE, if present. history of repetitive head
trauma, with or without
Additionally, prominent disinhibition and explosivity are rare in DLB,28 while in
concussion, including
CTE, these features are early and prominent. The presence of rapid eye movement exposures during contact
(REM) sleep behavior disorder strongly suggests DLB rather than CTE. sports, military service,
domestic abuse, assault,
SYMPTOMATIC TREATMENT and motor vehicle
accidents.
Treatment of CTE is currently supportive, as no medication is US Food and Drug
Administration (FDA) approved for the treatment of CTE. Several classes of ● The differential diagnosis
medications that are commonly used in other patients with cognitive impairment for chronic traumatic
can be trialed on an empiric basis to help with symptom management. Trials encephalopathy often
includes frontotemporal
of empiric medications may also be reasonable clinically, given the possibility dementia and Alzheimer
that other neurodegenerative pathologies may coexist, especially among older disease.
patients (refer to the section Overlap With Other Neurodegenerative
Pathologies). Medications to consider include a trial of acetylcholinesterase
inhibitors for memory-related issues, selective serotonin reuptake inhibitors

TABLE 9-4 Research Diagnostic Criteria for Traumatic Encephalopathy Syndromea
General Criteria for Traumatic Encephalopathy Syndrome (TES) (all five criteria must be met)
1 History of multiple impacts to the head based upon the type of injury and source of
exposure
Types of injuries
Mild traumatic brain injuries or concussions, minimum of four
Moderate or severe traumatic brain injury
Subconcussive trauma
Source of exposures
Involvement of high-exposure contact sports for minimum of 6 years, including at least
2 at college level or higher
Military service
History of any other significant exposure to repetitive hits to the head
For moderate/severe traumatic brain injury, any activity resulting in the injury
2 No other neurologic disorder present that likely accounts for all clinical features
3 Clinical features must be present for a minimum of 12 months
4 At least one core clinical feature must be present and considered a change from baseline
5 At least two supportive features must be present
Core Clinical Features of TES (at least one must be met)
1 Cognitive: difficulties in cognition as reported by either self or informant, by history, or
clinician’s report of decline and substantiated by impairment on standardized tests
2 Behavioral: emotionally explosive, physically and/or verbally violent
3 Mood: feeling overly sad, depressed, and/or hopeless
Supportive Features of TES (at least two must be present)
1 Impulsivity: impaired impulse control as demonstrated by new behaviors
2 Anxiety: history of anxious mood, agitation, excessive fears, or obsessive and/or
compulsive behavior
3 Apathy: loss of interest in usual activities, loss of motivation and emotions, and/or reduction
in voluntary goal-directed behaviors
4 Paranoia: delusional beliefs of suspicion, persecution, and/or unwarranted jealousy
5 Suicidality: history of suicidal thoughts or attempts
6 Headache: significant and chronic headache, with at least one episode per month for 6 months
7 Motor signs: dysarthria, dysgraphia, bradykinesia, tremor, rigidity, gait disturbance, falls
and/or signs for a minimum of 1 year
8 Documented decline: progressive decline in function and/or a progression in symptoms
and/or signs for a minimum of 1 year
9 Delayed onset: delayed onset of clinical features after significant head impact exposure, usually
at least 2 years and, in many cases, several years after the period of maximal exposure
194 FEBRUARY 2019

Chronic Traumatic Encephalopathy (CTE) Diagnostic Classification

1 Probable CTE: meets classification for any TES subtype; progressive course; does not meet
diagnostic criteria for another disorder more consistently than TES; has a minimum of one
positive potential biomarker for CTE
2 Possible CTE: meets classification for any TES subtype; progressive course; and (1) has not
undergone any potential biomarker testing, (2) has had negative results on one or more
biomarkers with the exception of tau PET imaging (if tau PET imaging was performed and is
negative, necessary classification is “unlikely CTE”), or (3) meets the diagnostic criteria for
another disorder that, on its own, could account for the clinical presentation
3 Unlikely CTE: does not meet TES diagnostic criteria or has had a negative tau PET imaging
scan or both
Traumatic Encephalopathy Syndrome Diagnostic Subtypes
Behavioral/mood variant
Cognitive variant
Mixed variant
Dementia
Criteria for Traumatic Encephalopathy Syndrome Dementia
1 Progressive course of cognitive core features, with or without behavioral and/or mood
core features
2 Cognitive impairment (or cognitive impairment exacerbated by behavioral and/or mood
symptoms) severe enough to interfere with the ability to function independently at work
or in the usual activities, including hobbies and instrumental activities of daily living
PET = positron emission tomography

a
Data from Montenigro PH, et al, Alzheimers Res Ther.22

CASE 9-1 A former rugby player who began playing at age 16 and continued for more
than 20 years committed suicide by firearm at age 46. He had played the
equivalent of quarterback in rugby, a sport in which no head protection is
used in games. Although he was never diagnosed with a concussion and
never missed a game because of head injury, his teammates reported that
he was confused on the field many times because of a head injury but
kept playing. He had no family history of neurologic or psychiatric
disorders.
He developed behavioral symptoms in his early thirties. His personality
changed, and he overreacted and became stressed out and anxious about
minor things that previously did not bother him. He developed emotional
volatility and lost his temper quickly. Subsequently, his memory
deteriorated, and he would forget to pick up his daughter from school,
which was previously uncharacteristic for him. He developed word-finding
difficulties and became much less communicative with family. At one
point, he stopped paying the family’s bills and, when confronted by his
wife, could not verbalize why he was no longer paying them. He initially
was depressed for a week at a time, but his depression gradually increased
in frequency and length over the 15 years until his death.
He developed a “short fuse,” began yelling without a trigger, and was
very paranoid about his wife’s fidelity, not wanting her to go out without
him. He became interested in unusual sexual practices that he had
previously never expressed any desire for. He impulsively pushed his wife
once, which was completely out of character. He verbalized that he
had a baseball bat in the trunk and threatened her.
He had no gait instability, falls, or tremor. He was working part time
as a teacher until the months before his death but had stopped cooking
several months before he died, a role he had previously maintained within
his family. He reported frequent severe headaches starting 6 months
before he died. He began using alcohol excessively 2 years before his
death, often drinking during the day, which was very unusual for him.
In the months before he died, he told his best friend he wanted to learn
how to shoot a gun, which was very surprising because, as a younger
person, he had refused to touch a gun. He had previously expressed he
was against suicide throughout his life and had never expressed suicidal
ideation. After his death, pathologists at Boston University diagnosed
stage II chronic traumatic encephalopathy.
COMMENT This patient meets all five of the general traumatic encephalopathy
syndrome (TES) criteria (TABLE 9-4), given a 20-year history of exposure to
head injury through rugby. Clinical features were present over 15 years, and
he displayed all three core clinical features of TES: cognitive, behavioral,
and mood changes. He also had seven of the nine supportive features of
TES present: impulsivity, anxiety, paranoia, suicidality, headache,
documented decline, and delayed onset. In the absence of an autopsy, a
clinician or researcher might consider this a case of possible chronic
traumatic encephalopathy, mixed variant, given the presence of both
cognitive core features and behavioral and mood core features.
196 FEBRUARY 2019

(SSRIs) for depression and anxiety, and memantine for attentional issues in those KEY POINTS
with advanced dementia; rarely, atypical antipsychotics may be used for those
● No disease-modifying or
who are disinhibited and violent. However, it is important to note that, as a class, symptomatic treatments
antipsychotics carry an FDA boxed warning of increased mortality in patients with for chronic traumatic
dementia, and thus the decision to use this class should be made on a case-by encephalopathy are
case-basis after weighing the risks and benefits with the patient and family. US Food and Drug
Administration approved.
All medication management
EPIDEMIOLOGY is off-label and
The true incidence and prevalence of CTE is unknown because of a lack of symptom-based, and
epidemiologic data, including a dearth of cross-sectional and prospective studies can include
acetylcholinesterase
in the general population. However, the incidence of CTE is potentially high
inhibitors, selective
within the professional contact sports community and in others exposed to head serotonin reuptake
trauma. CTE has been found in the brains of individuals who engaged in a wide inhibitors, and memantine.
variety of contact sports during life, including boxing, football, wrestling, ice
hockey, rugby, soccer, and others.5,6,11–13,29,30 An early study of prevalence of ● The incidence and
prevalence of chronic
neurologic deficits among professional boxers reported a 17% rate of neurologic traumatic encephalopathy is
diagnoses attributable to the sport, with risk factors including later retirement unknown because of a lack
from boxing, boxing for more than 10 years, and engagement in 150 matches or of epidemiologic data.
more.31 Using the 2015 NINDS-NIBIB consensus pathologic criteria for CTE, However, the frequency of
chronic traumatic
1721 cases in the Mayo Clinic Brain Bank were reviewed for CTE pathology; encephalopathy is
contact sport athletes had CTE present at a rate of 32%, with no cases of CTE potentially increased within
found in 162 control brains without a TBI or contact sport history and no cases the professional contact
of CTE found among 33 individuals with a history of a single TBI.8 In the largest sports community and
others exposed to
CTE case series to date, of 202 deceased individuals who had a significant
head trauma.
history of repetitive head trauma related to either contact sports or military
service, Mez and colleagues9 reported that CTE was diagnosed in 177 former ● The age of clinical
professional football players (or 87% of the cases) and, more specifically, in 110 onset of traumatic
out of 111 (99%) of the former National Football League (NFL) players. The encephalopathy
syndrome/chronic
authors noted that the study was limited by ascertainment bias since individuals traumatic encephalopathy
with symptoms consistent with possible CTE were much more likely to symptoms is delayed by
participate in the brain donation program, and, therefore, the true frequency several years or decades
of CTE pathology is unknown. following exposure to head
injuries and is currently
Annually in the United States, approximately 2 million to 4 million individuals estimated to be between
experience sports-related concussions,32 with the number of youth sports–related 30 and 65 years of age.
concussions growing.33 Additionally, it is thought that the incidence of
subconcussive blows to the head is much higher than clinical concussions.34 Others
have reported that in a single season of high school football, a player receives an
average of 652 head blows, most of which involve more than 15 g of force.35 Age
of clinical onset of TES/CTE symptoms is thought to be delayed by several years
or decades following exposure to head injuries. The current age of onset is
estimated to be between 30 and 65 on average, with case reports of tau aggregates
already present in the brains of teenage football players.23 In a retrospective
study of causes of mortality in former professional football players,
neurodegenerative mortality in former players was 3 times higher than in the
general population, and Alzheimer disease–related and amyotrophic lateral
sclerosis–related mortality was 4 times higher.36 Importantly, the retrospective
nature of the study, in which cases were evaluated from a period before the
establishment of CTE as a pathologic diagnosis, means it is likely that some of the
neurodegenerative disease burden in this population may, in fact, be better
accounted for by CTE.

CASE 9-2 A former football player developed cognitive and behavioral changes
beginning in his midforties. He had played football in high school, then in
college for 4 years, and subsequently for several seasons in the National
Football League. Although he never reported a head injury while playing,
he did report to his wife that his “bell was rung a bunch” as a professional
player. He had no family history of psychiatric or neurologic disorders.
In his midforties, his wife noticed that he began going to the wrong
school to pick up his kids and became much more angry and defensive.
He became confused about which city they lived in. A previously
successful businessman, he began making bad financial decisions. He
made impulsive purchases he previously would not have made. He once
wrote a check to the bank for 10 times more than he intended, writing the
entire check upside down. His wife found the taxes from years prior in his
desk drawer, completed but never sent; previously, he never would have
forgotten to pay the taxes or a bill.
He became socially withdrawn and angered more easily, yelling at
family and friends without a reason. He would also yell in socially
inappropriate settings, such as yelling at a teacher in his daughter’s
school on parent night when he was in his fifties.
He developed frequent severe headaches in his fifties that worsened
over time. He became very anxious and developed nervous, anxious
behaviors, including rubbing his hands together frequently until the skin
peeled off. At times, he was quite depressed and apathetic, sitting for
days at a time at home looking at the wall. Previously social, he withdrew
from family and friends. When he did speak, he paused to find words and
spoke tangentially and circuitously.
In his fifties and sixties, he would forget conversations. He became
paranoid about his wife and her whereabouts. His mood worsened, and
he made statements to his wife such as, “You would be better off if I
weren’t here.”
Previously an avid golfer, he suddenly stopped playing in his sixties
and watched the golf channel for hours, holding his clubs and crying,
saying that if he watched some more, he might be able to remember
how to play. His gait gradually became unsteady, and he was noted to
have a tremor when writing and performing other activities. He
developed difficulty swallowing and unintentionally lost weight in the
last years of his life. He died at home at age 70, requiring 24-hour care
before his death. Autopsy of his brain revealed irregularly distributed
phosphorylated tau aggregates at the depth of cerebral sulci in
multiple locations throughout the cortex, consistent with stage IV
chronic traumatic encephalopathy (FIGURE 9-1, FIGURE 9-2).
198 FEBRUARY 2019

FIGURE 9-1
Low magnification of phosphorylated (p-tau)–stained slides showing irregular distribution of
chronic traumatic encephalopathy pathology from the brain of the patient in CASE 9-2. A,
AT8-stained frontal cortex sulcus (asterisk) at 25x, showing patchy distribution of p-tau,
densest at the depths of cerebral sulci, and characteristic AT8 staining (arrows). B,
AT8-stained dorsolateral frontal sulcus (asterisk) at 40x showing characteristic AT8 staining
(arrows).
FIGURE 9-2
High-power characteristic phosphorylated (p-tau) accumulation seen in the patient in CASE 9-2
with neuropathologically confirmed chronic traumatic encephalopathy. A, B, Dorsolateral
frontal cortex sections stained with AT8 showing characteristic neurofibrillary tangle staining
at 400x (arrows). C, Dorsolateral frontal cortex stained with AT8 showing characteristic
neurofibrillary tangle staining at 100x (arrow). D, AT8 staining of perivascular region in
dorsolateral frontal cortex at 200x showing an accumulation of neurofibrillary tangles
(arrow).
CONTINUED ON
PAGE 200

CHRONIC TRAUMATIC ENCEPHALOPATHY AMONG VETERANS AND

MILITARY SERVICE MEMBERS
Soldiers experience head injuries at a higher rate than the general population,
approaching one-fourth of all returning veterans.37,38 Posttraumatic stress
disorder (PTSD), a common result of combat, has a prevalence similar to TBI,
as high as 17% among veterans.39 Furthermore, recognition of a potential
association between PTSD and the long-term effects of TBI is growing; the two
have many overlapping symptoms and often co-occur in veterans. In a 2008
survey of more than 2500 American soldiers 3 to 4 months following their return
home from yearlong deployments to Iraq, nearly 5% reported head trauma with
a loss of consciousness and 10% reported head injuries with resulting altered
mental status. Of those who reported loss of consciousness, 43.9% met criteria for
PTSD, and 27.3% of those who had altered mental status following a TBI met
criteria for PTSD. In contrast, 9.1% of the soldiers without TBI met criteria for
PTSD.40 The exact nature of the complex relationship between head trauma and
PTSD requires further study in the veteran population, as it is unclear whether
the two disorders share a common pathogenesis.
Similarly, the frequency of CTE in the veteran population is currently unknown.
CTE has been reported in association with military combat exposures and in
association with veterans who engage in contact sports.41,42 In the majority of
military CTE case reports, concomitant PTSD is described. It has been recognized,
however, that the clinical constellation of symptoms seen in PTSD, postconcussive
disorder, and CTE share many common elements, including difficulty with
concentration, changes in mood, memory problems, irritability, and sleep
disturbances. Thus, it has been hypothesized that some proportion of veterans with
PTSD may instead have a diagnosis of CTE.43 Some case reports exist of behavioral
changes before death and tau aggregates at autopsy, allowing postmortem
diagnosis of CTE in military service members.10 However, large-scale investigations
into the incidence of CTE in the military veteran population are lacking.
OVERLAP WITH OTHER NEURODEGENERATIVE PATHOLOGIES

Although not an essential component of CTE pathologic diagnostic criteria, CTE
frequently occurs with TDP-43 pathology.44 A variety of diseases that involve
CONTINUED FROM
PAGE 199
COMMENT The patient in this case meets all five of the general traumatic encephalopathy
syndrome (TES) criteria (TABLE 9-4), given a 14-year history of exposure to
head injury through football. Clinical features were present over 25 years,
and he displayed all three core clinical features of TES: cognitive,
behavioral, and mood changes. He also had all nine supportive features of
TES: impulsivity, anxiety, apathy, paranoia, suicidality, headache, motor
symptoms, documented decline, and delayed onset. In the absence of an
autopsy, a clinician or researcher might consider this a case of possible
chronic traumatic encephalopathy, cognitive subtype, given the older age at
presentation and prominence of cognitive deficits.
200 FEBRUARY 2019

Required Minimum Types of Injuries and Exposures as Part of General TABLE 9-5
Criteria for Traumatic Encephalopathy Syndromea
Must have at least one injury type and one exposure type from the list below
◆ Mild traumatic brain injury or concussion, minimum documented four episodes
◆ Moderate or severe traumatic brain injury, two episodes, defined as loss of consciousness
of at least 30 minutes with alteration of consciousness or mental state of more than
24 hours, posttraumatic amnesia of more than 24 hours and Glasgow Coma Scale score of
less than 1314
◆ Subconcussive trauma
◆ High-exposure contact sport involvement (including, but not limited to, boxing, football, ice
hockey, lacrosse, rugby, wrestling, or soccer) for a minimum of 6 years (at least 2 of which are
at college level or higher)
◆ Military service including blasts or other explosions as well as noncombat exposure to
explosives or to combatant or breach training
◆ Repetitive hits to the head including, but not limited to, domestic abuse and head banging or
door breaching by police
a
Data from Montenigro PH, et al, Alzheimers Res Ther.22
Potential Biomarkers for the Diagnosis of Probable Chronic Traumatic TABLE 9-6
Encephalopathya
Biomarker Findings
Cavum septum pellucidum Cavum septum pellucidum, cavum vergae, or fenestrations based on neuroimaging
study
Normal CSF amyloid-β levels CSF amyloid-β levels in the normal range for age rather than in the decreased range,
which can be suggestive of Alzheimer disease
Elevated CSF phosphorylated tau to CSF phosphorylated tau to total tau ratio above the normal range for age
total tau ratio
Negative amyloid imaging PET amyloid imaging in the normal range, not suggestive of Alzheimer disease
Positive tau imaging PET paired helical filament tau imaging suggestive of abnormal tau deposition; it
should be noted that this remains an experimental procedure and requires additional
validation before use as a clinical diagnostic tool
Cortical thinning Based on MRI measurement, evidence of increased cortical thinning consistent with
neurodegeneration
Cortical atrophy Based on MRI or CT, generalized cortical atrophy beyond that expected for age,
particularly in the frontal, thalamic, hippocampal, and/or amygdalar regions
CSF = cerebrospinal fluid; CT = computed tomography; MRI = magnetic resonance imaging; PET = positron emission tomography.
a
Modified from Montenigro PH, et al, Alzheimers Res Ther.22 © 2014 The Authors.

abnormal tau accumulation, including

frontotemporal dementia, are also
associated with TDP-43 accumulation.45
The range of TDP-43 pathologies seen in
CTE is varied and can include accumulation
of TDP-43 in neurons colocalizing with
p-tau inclusions or in glia.46 The extent of
TDP-43 accumulation in brain structures is
also thought to progress with CTE pathologic
stages, beginning in the subcortical white
matter and fornix in stage I disease; then
involving the brainstem, medial temporal
lobe, periventricular, and perivascular regions
in stage II; accumulating in the cerebral
cortex in stage III; and accumulating in
FIGURE 9-3
Axial fluid-attenuated inversion
structures as widespread as the spinal cord,
recovery (FLAIR) MRI of the cavum diencephalon, and basal ganglia in stage IV
septum pellucidum of a patient with a disease.13 Also, the frequency with which
history of head injury and memory loss. TDP-43 is observed tends to increase with
each stage, such that in stage IV disease
nearly all individuals display TDP-43
inclusions.47 TDP-43 accumulation patterns observed in CTE may also overlap with
that of individuals found to have frontotemporal lobar degeneration (FTLD).48
CTE is known to co-occur with other neurodegenerative diseases as
individuals age.13,46 Of 177 neuropathologically confirmed CTE cases in the
Veterans Affairs-Boston University-Concussion Legacy Foundation
(VA-BU-CLF) CTE Brain Bank, 11 were found to also have pathology consistent
with motor neuron disease, 23 had pathology consistent with AD, 34 had
pathology consistent with Lewy body disease, 14 had pathology consistent with
frontotemporal dementia, and 98 were reported as having CTE alone
(FIGURE 9-4).9 Three cases overlapped between the neurodegenerative
diseases, resulting in a total higher than 177 cases.
When CTE occurs with other neurodegenerative diseases, it is unclear if these
individuals have developed a mixed-pathology neurodegenerative disorder or
whether a synergistic relationship exists between CTE and other pathologies.
Older individuals with CTE pathology are more likely to have concurrent amyloid-β
plaques consistent with AD13 and may develop amyloid-β accumulation at a
younger age than individuals without head injuries.49 In one study of a cohort of
114 deceased military veterans and athletes with neuropathologically
confirmed CTE, 52% of the cases displayed some degree of amyloid-β
deposition.49 Individuals with CTE and motor neuron disease often display
greater accumulations of TDP-43 at earlier CTE disease stages than in cases of
CTE without motor neuron disease.47 About one-third of CTE cases with
concomitant motor neuron disease pathology display behavioral and cognitive
changes as the presenting symptoms years before the onset of motor changes.47
PROSPECTIVE SUSCEPTIBILITY FACTORS

The investigation of genetic and nongenetic risk factors is an important
additional area of research that will allow clinicians to understand why some
patients with a history of head trauma develop CTE, while others do not.
202 FEBRUARY 2019

Genetic Modifiers KEY POINTS
The main genetic risk factor
● Posttraumatic stress
investigated in association with disorder and traumatic brain
head injury and CTE, the APOE injury often co-occur in
ε4 allele, is most well-known for military veterans and may
its association with AD. Some share a common
pathophysiology.
association may also exist
between APOE ε4 and risk of ● Posttraumatic stress
worse outcomes following disorder, postconcussive
recurrent mild TBI.23 APOE may disorder, and chronic
be expressed by neurons traumatic encephalopathy
share many common
following injury.50 Boxers who symptoms, including
were carriers of the allele were difficulty with
more impaired on scales of FIGURE 9-4
concentration, changes in
motor, cognitive, and mood, memory problems,
Neuropathologic diagnoses among a cohort of
irritability, and sleep
psychiatric deficits.51 Similar 177 football players from the Veterans Affairs-
disturbances.
results have been found among Boston University-Concussion Legacy Foundation
(VA-BU-CLF) brain bank who were diagnosed
53 professional football players ● Chronic traumatic
with chronic traumatic encephalopathy (CTE) by
who were ε4 allele carriers and autopsy. Ninety-eight cases (55%) exhibited pure
encephalopathy frequently
involves TDP-43 pathology,
showed greater deficits in CTE pathology, and the remaining cases exhibited
but TDP-43 is not necessary
cognition, processing speed, and overlap with another neurodegenerative condition:
for pathologic confirmation.
52 23 (13%) had a pathologic diagnosis of Alzheimer
attention than did noncarriers.
disease (AD) in addition to CTE, 34 (19%) had a
Recent work has suggested that ● Chronic traumatic
diagnosis of Lewy body disease (LBD) with CTE,
APOE ε4 may be a risk factor for encephalopathy can
8 (5%) had a diagnosis of frontotemporal lobar
co-occur pathologically
CTE severity, especially earlier degeneration with transactive response DNA-
with other
binding protein 43 (FTLD TDP-43) pathology and
in the disease course and at neurodegenerative
CTE, 6 (3%) had a diagnosis of frontotemporal
lower levels of head impact lobar degeneration with tau pathology (FTLD-Tau)
conditions, including motor
exposure.53 In CTE cohorts and CTE, and 11 (6%) had motor neuron disease
neuron disease, Alzheimer
disease, Lewy body disease,
without comorbid pathologies, it (MND) and CTE. Three cases overlapped between
and frontotemporal
has been reported that APOE ε4 the neurodegenerative diseases, resulting in a
dementia.
total higher than 177 cases.
was overrepresented compared Data from Mez J, et al, JAMA.9
to the general population.19 The ● The main genetic risk
factor investigated in
APOE ε4 allele may lower the
association with head injury
threshold for an individual to develop cognitive deficits following repeated and chronic traumatic
head injury, although one study found no difference in the frequency of APOE encephalopathy is the APOE
ε4 carriers among a CTE cohort of 68 cases compared to the allele carrier rate ε4 allele.
in the population at large.13 The search continues for other heritable risk
● The APOE ε4 allele may
factors that may explain a genetic predisposition to CTE other than APOE ε4 lower the threshold for an
carrier status. individual to develop
cognitive deficits following
Nongenetic Risk Factors repeated head injury.
Nongenetic potential risk factors are just starting to be investigated and ● Nongenetic potential risk
include cognitive reserve, age of first exposure, and cumulative exposure to factors for chronic traumatic
head injuries. Cognitive reserve in the form of occupational attainment was encephalopathy include
associated with later symptom onset in a sample of neuropathologically cognitive reserve, age of
first exposure, and
confirmed cases of stage II and stage IV CTE in deceased former football
cumulative exposure to
players.54 However, number of years of education was not associated with head injuries.
CTE symptom onset. The significance of this discrepancy between occupation
and years of education as markers of cognitive reserve is still under
investigation. Age of first exposure to football or other sources of head injuries

may represent a modifier of later neurologic outcomes. It is hypothesized that

head impacts may have increased effects on later neurologic outcomes when
exposures occur during key periods in brain development. White matter
changes have been reported in a group of 8- to-13-year-olds following
exposure to repetitive head injuries during a single season of youth football.55
Similarly, former NFL players who began playing before age 12 showed
increased rates of neuropsychological and brain structural changes, including
verbal memory losses, executive dysfunction, and alterations of the
microstructure of the corpus callosum.56 More recent work has found that among
214 former football players, those who were playing before age 12 had double
the risk of clinical impairments in behavior, including apathy and executive
function, and a threefold increased risk of having depression compared to those
who began playing at age 12 or older.57
TRENDS
Tau imaging and nonimaging CSF biomarkers are important areas of inquiry
within the CTE field as they are potential avenues for the definitive diagnosis of
patients with CTE. The use of these techniques is currently strictly for
research settings.
Tau Imaging
PET imaging using tau-specific tracers is being developed with the intent to
diagnose CTE during life. Tau-specific radioligands were first developed in
association with the imaging of AD patients.58 Several tracers have been developed
specifically for aggregated tau.59–62 These tracers have been investigated and
validated mainly in animal models of AD and in postmortem AD cases that showed
increased tau ligand binding in the cortex of patients with AD compared to healthy
age-matched controls.59,63 Tau PET investigations of retired athletes who have
sustained head injuries are on the horizon. An important area of investigation
will be a potential tracer’s ability to sensitively and specifically bind the p-tau
aggregates seen in CTE versus those in other neurodegenerative diseases that
involve tau.
Other Biomarkers
Other potential non-PET biomarkers of CTE are under active investigation
given some of the limitations of PET imaging, including radiation, expense, and
limited availability. Some researchers have considered using CSF as a possible
biomarker. Neurofilament light polypeptide and tau protein in the CSF have
been found to be elevated immediately after boxing matches, and these
elevations normalize in the following days and weeks after rest from head
injury.64,65 However, CSF techniques require a lumbar puncture, and therefore
serum biomarkers are also under active investigation. A study evaluating total tau
(t-tau) plasma levels reported that all former NFL players had a concentration
greater than or equal to 3.56 pg/mL, indicating that t-tau elevations may be a
promising biomarker for the presence of remote head injuries.66 While t-tau serum
elevations were seen exclusively in former players, levels did not correlate with
cognitive testing, and t-tau elevations are seen in other neurodegenerative and
cerebrovascular conditions, limiting its role in diagnosis. T-tau is, therefore, likely
a general marker of brain injury that occurs with a variety of disorders, including
AD, frontotemporal degeneration, and stroke.67,68
204 FEBRUARY 2019

KEY POINT
CONCLUSION
The science of CTE is advancing rapidly as we learn more each year about the ● Serum tau concentration
ongoing, often lifelong, impacts of head injuries in our patients. It has been elevations may indicate the
established in the past decade that some amount of repetitive head injuries existence of prior head
injury but have not been
combined with unknown genetic, exposure, and other susceptibility factors
found to correlate with
ultimately leads to CTE, a neurodegenerative condition marked by perivascular cognitive function.
accumulations of tau at the depths of the sulci. The exact clinical features and
premorbid hallmarks of CTE are under investigation, yet at the same time
we are seeing patients and caregivers of patients with extensive contact sport
or military service histories who wonder if changes in behavior are related to
prior head injuries. Research in AD and other neurodegenerative conditions
will continue to guide the way in CTE research as we seek to diagnose patients
during life, perhaps in the future using validated clinical consensus criteria
and biomarkers being developed, such as tau PET imaging. In the future,
studies of the long-term effects of head injuries in military veterans and
other specific populations will be important to advancing the scientific
understanding of this important condition.
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REVIEW ARTICLE

Hippocampal Sclerosis,
ONLINE
Argyrophilic Grain
Disease, and Primary
Age-Related Tauopathy
By Gregory A. Jicha, MD, PhD; Peter T. Nelson, MD, PhD
CITE AS:
ABSTRACT
CONTINUUM (MINNEAP MINN) PURPOSE OF REVIEW: Hippocampal sclerosis, argyrophilic grain disease, and
2019;25(1, DEMENTIA):208–233. primary age-related tauopathy are common Alzheimer disease mimics that
currently lack clinical diagnostic criteria. Increased understanding of these
Dr Gregory A, Jicha, pathologic entities is important for the neurologist who may encounter
Sanders-Brown Center on Aging, patients with an unusually slowly progressive degenerative dementia that
1030 S Broadway, Ste #5,
may appear to meet criteria for Alzheimer disease but who progress to
Lexington, KY 40504,
gregory.jicha@uky.edu. develop symptoms that are unusual for classic Alzheimer disease
Dr Jicha serves as a consultant
RECENT FINDINGS: Hippocampal sclerosis has traditionally been associated
for the Cure Alzheimer’s Fund with hypoxic/ischemic injury and poorly controlled epilepsy, but it is now
and provides contract research recognized that hippocampal sclerosis may also be associated with a
for AbbVie Inc; Alltech; Axovant
Sciences, Inc; Eli Lilly and unique degenerative disease of aging or may be an associated pathologic
Company; Eisai Inc; Janssen finding in many cases of frontotemporal lobar degeneration. Argyrophilic
Global Services, LLC; Novartis grain disease has been recognized as an enigma in the field of pathology
AG; Suven Life Sciences
Limited; and VTV Therapeutics. for over 30 years, but recent discoveries suggest that it may overlap with
Dr Jicha receives research/grant other tau-related disorders within the spectrum of frontotemporal lobar
support from the National
Institutes of Health
degeneration. Primary age-related tauopathy has long been recognized as
(UH2 NS100606, R01 AG054130, a distinct clinical entity that lies on the Alzheimer pathologic spectrum,
U19 AG010483, U24 AG057437, with the presence of neurofibrillary tangles that lack the coexistent
P30 AG028383, R01 HD064993,
R01 AG057187, R01 AG042419,
Alzheimer plaque development; thus, it is thought to represent a distinct
R01 NR014189). Dr Nelson serves pathologic entity.
on the National Institutes of
Health/National Institute on
Aging external advisory boards SUMMARY: Despite advances in dementia diagnosis that suggest that we
of Mayo Clinic and Rush have identified and unlocked the mysteries of the major degenerative
University and as an associate
disease states responsible for cognitive decline and dementia in the
editor for Acta
Neuropathologica and the elderly, diseases such as hippocampal sclerosis, argyrophilic grain
Journal of Neuropathology & disease, and primary age-related tauopathy demonstrate that we
Experimental Neurology.
remain on the frontier of discovery and that our diagnostic repertoire of
UNLABELED USE OF diseases responsible for such clinical symptoms remains in its infancy.
PRODUCTS/INVESTIGATIONAL Understanding such diagnostic confounds is important for the neurologist
USE DISCLOSURE:
Drs Jicha and Nelson report no in assigning appropriate diagnoses and selecting appropriate therapeutic
disclosures. management strategies for patients with mild cognitive impairment and
dementia.
of Neurology.
208 FEBRUARY 2019

KEY POINTS
INTRODUCTION
I
t is widely recognized that the diagnostic accuracy of the clinical diagnosis of ● Several clinically
Alzheimer disease (AD) is less than 80% in most centers.1 The important uncharacterized
question that emerges from this finding is what is the neuropathologic neuropathologic disease
states are found at high
substrate for the 20% of cases that are misdiagnosed? Is it simply overlap in frequency in the elderly
clinical features with other common neuropathologic conditions? Amnestic population and may
variants of dementia with Lewy bodies (DLB), frontotemporal dementia (FTD), contribute to the observed
or vascular dementia might be considered.2 Or is the underlying disorder instead inaccuracy of clinical
diagnostic criteria in
related to the many other prevalent neuropathologic conditions that remain clinicopathologic
poorly characterized clinically, such as hippocampal sclerosis of aging, correlation studies
argyrophilic grain disease, or primary age-related tauopathy (PART)? These in dementia.
clinically uncharacterized neuropathologic disease states are found at high
● Recent and ongoing work
frequency in the elderly population and are likely contributors to the observed
over the past several
inaccuracy of clinical diagnostic criteria in clinicopathologic correlation studies. decades has brought to light
Recent and ongoing work over the past several decades has brought to light the importance and high
the importance and high prevalence of diseases such as hippocampal sclerosis,3 prevalence of diseases such
argyrophilic grain disease,4 and PART5 as common mimics of AD and other as hippocampal sclerosis,
argyrophilic grain disease,
dementing disorders, largely because their own clinical phenotype has been and primary age-related
poorly elucidated to date. Each of these diseases can be found in isolation at tauopathy as common
autopsy, but they are more commonly found in association with other comorbid mimics of Alzheimer disease
pathologies, further complicating our understanding of the clinical phenotype and other dementing
disorders, largely because
for the diseases.1,2,6 Yet their prevalence can be as high as 20% of normal controls their own clinical phenotype
and higher than 50% in individuals with clinical dementia.1,2,6 This article focuses has been poorly elucidated
on our understanding of the pathology and clinical features of these conditions, to date.
including signs and symptoms, imaging findings, biomarker discoveries, and
● The prevalence of
familial and genetic predisposition, which have not yet been fully embraced
diseases such as
within clinics and medical institutions as part of the standard antemortem hippocampal sclerosis,
diagnostic considerations responsible for cognitive decline and dementia in the argyrophilic grain disease,
aging population today (CASE 10-1). It should be noted that this article focuses and primary age-related
tauopathy can be as
on distinct pathologic disease states that do not yet have established clinical
high as 20% of normal
diagnostic criteria. Atypical clinical characteristics of other pathologically controls and higher than
defined degenerative diseases that may mimic alternative clinical diagnoses 50% in individuals with
(such as DLB or vascular dementia mimicking AD or vice versa) are discussed clinical dementia.
in other articles in this issue.
HIPPOCAMPAL SCLEROSIS
Hippocampal sclerosis is a term that describes two key pathologic features that
frequently involve the hippocampus and associated structures: neuronal loss and
widespread gliosis.3,7 These pathologies can be seen in association with a variety
of potentially causative conditions, including advanced aging, anoxic/hypoxic
injury, frontotemporal lobar degeneration (FTLD), temporal lobe epilepsy,
and chronic traumatic encephalopathy.7–9 Indeed, the hippocampus and its
associated structures appear highly vulnerable to a variety of pathologic insults
that can lead to both the neuronal loss and the widespread gliosis that define
hippocampal sclerosis generically. Yet, despite the superficially similar pathologic
end points, the distinct causes of hippocampal sclerosis may actually be quite
different from one another in terms of pathogenic mechanisms.
It is widely appreciated that some of the neuronal populations in the
hippocampus are particularly vulnerable to anoxic/hypoxic injury.10 The

HIPPOCAMPAL SCLEROSIS, ARGYROPHILIC GRAIN DISEASE, AND PART
neuronal degeneration and gliosis associated with hippocampal sclerosis is

largely seen within the CA1 hippocampal subfield and subiculum, with relative
sparing of the CA2–CA4 hippocampal subfields and other neighboring or
anatomically connected regions (FIGURE 10-2).11 The precise causes for the
selective vulnerability may include the high degree of plasticity seen in this
cortical area, its location in a watershed distribution between the anterior and
posterior choroidal arteries, and the high prevalence of glutamatergic synapses in
this “feed-forward” hippocampal circuit, leading to excess calcium influx in
CASE 10-1 An 82-year-old woman presented for evaluation of short-term memory

loss. The patient was able to converse normally, and she personally
described only mild memory problems described as difficulty
remembering the names of casual acquaintances. She denied any
difficulties with her daily function. Her husband, however, stated that he
had noticed progressive short-term memory decline with frequent
repeating behavior over the past 4 years. He stated that this had barely
changed over time, although, looking back over the past 4 years, he noted
that she was clearly more impaired now than when he first noticed her
problems. She frequently misplaced items and forgot dates and
appointments unless reminded, but he stated she was otherwise fully
engaged in all her daily activities at home, including more complex
activities such as cooking and managing the household. She had been
driving without incident, and her husband had no concerns about her
driving ability. She remained engaged socially with both church activities
and a local gardening club. She had no family history of dementia but
noted that she had a grandfather who died of amyotrophic lateral
sclerosis. Her past medical history was notable only for hypertension that
was well-controlled on lisinopril 10 mg/d.
Assessment (MoCA), missing three points on orientation and all five
points on delayed recall. Her performance was fully intact on the
remainder of the examination. Her neurologic examination was otherwise
normal, without evidence of focal neurologic deficits, motor neuron
disease, or parkinsonism.
Laboratory workup for reversible causes of dementia was unrevealing.
MRI of her brain (similar to that presented in FIGURE 10-1) demonstrated
focal hippocampal and medial temporal lobe atrophy with a question of
increased T2 signal in the hippocampus bilaterally. Amyloid positron
emission tomography (PET) was negative for cerebral amyloid. CSF
showed normal levels of amyloid β1-42 and phosphorylated tau protein.
Other than the negative molecular biomarkers, she met clinical
diagnostic criteria for mild cognitive impairment of the Alzheimer type,
which was felt to be consistent with the MRI results. She was treated
with donepezil for her cognitive decline and had follow-up appointments
for another 6 years before she died.
210 FEBRUARY 2019

times of stress and the triggering of the excitotoxic and apoptotic cascade.11–14
These same features may help to explain the high vulnerability of hippocampal
neurons to excitotoxic stresses caused by recurrent seizure activity, which may
be primarily mediated through N-methyl-D-aspartate (NMDA) receptors in
this region.12 Epilepsy and anoxia/hypoxia were considered primary in the
development of hippocampal sclerosis until the recent discovery of the
association of hippocampal sclerosis with some forms of FTLD seen at autopsy.15,16
The discovery of abnormal accumulations of transactive response DNA-binding
At autopsy, the gross weight of her brain was 1180 g (2.6 lb), and mild
global cerebral atrophy and bilateral gross focal medial temporal and
hippocampal atrophy were noted on visual inspection. No appreciable
vascular lesions were noted on macroscopic or microscopic examination.
She was found to have Braak stage I neurofibrillary tangles in the entorhinal
cortex and an almost complete absence of even diffuse amyloid plaque
deposition. Hematoxylin and eosin (H&E) stains of the hippocampus
revealed severe neuronal loss and gliosis throughout the CA1 sector and
subiculum. Transactive response DNA-binding protein 43 (TDP-43)
antibody staining showed characteristic Type A neuronal inclusions.
FIGURE 10-1
Hippocampal sclerosis of aging. A, Coronal T1-weighted MRI of the medial temporal lobes
shows atrophy of the hippocampus and neighboring medial temporal lobe structures
(arrows) similar to that seen in the patient in CASE 10-1. B, Coronal T2-weighted MRI shows
ex vacuo enlargement of the adjacent temporal horn of the lateral ventricle (arrow). Note
the relative absence of atrophy outside the medial temporal lobe structures.
The primary pathologic diagnosis given was hippocampal sclerosis of aging COMMENT
despite a clinical presentation consistent with an antemortem diagnosis of
Alzheimer disease. This case illustrates the confound inherent in clinical
diagnosis of an early amnestic syndrome and highlights the importance of
consideration of alternative pathologic diagnoses in such cases.

FIGURE 10-2
Histopathology of a normal hippocampus compared to hippocampal sclerosis. Hematoxylin
and eosin (H&E) staining of a healthy control hippocampus (A) and hippocampus with
hippocampal sclerosis (B) highlights selective involvement of the CA1 sector of the
hippocampus and subiculum (Su) in hippocampal sclerosis. Note that panels A and B were
taken at the same magnification. A normal subiculum stained with H&E, with a pyramidal
neuron (C, green arrowhead) and the subiculum of a patient with hippocampal sclerosis of
aging, in which the cellular population of neurons has been replaced by reactive astrocytes
(D, green arrowhead). Transactive response DNA-binding protein 43 (TDP-43) is normally
present in cell nuclei, as shown here by using an antibody against nonphosphorylated
TDP-43 in the dentate granule cells (E). By contrast, in hippocampal sclerosis of aging,
phosphorylated TDP-43 pathology is seen in cells of the dentate granule neurons (F, green
arrowheads) and inside cells (G; green arrowhead indicates intranuclear deposit). Neuritic
pathology is seen in the CA1 sector of the hippocampus (G, blue arrowhead). Scale bars: 5 mm
in A, B; 300 microns in C, D; 50 microns in E, F; 60 microns in G.
212 FEBRUARY 2019

protein 43 (TDP-43) in forms of FTLD and the subsequent development of KEY POINT
antibodies detecting these pathologic inclusions has greatly enhanced our
● It is now recognized that
understanding of hippocampal sclerosis.9,17,18 hippocampal sclerosis
Before our ability to sensitively and specifically detect TDP-43 inclusions, occurs not only in “pure” or
the diagnosis of hippocampal sclerosis was largely made using hematoxylin isolated forms but is
and eosin (H&E)–stained slides looking for the neuronal dropout and gliosis frequently found to be a
comorbid process,
characteristic of hippocampal sclerosis (FIGURE 10-2).7 This method was
coexisting with other
relatively nonspecific and failed to detect a large number of autopsy cases in neurodegenerative
which the pathology was subtle or found in a comorbid state with diseases such pathologies such as
as AD that also lead to neuronal dropout and gliosis within the hippocampus.3,9 Alzheimer disease,
dementia with Lewy bodies,
It is now recognized that hippocampal sclerosis occurs not only in “pure” or
progressive supranuclear
isolated forms but is frequently found to be a comorbid process, coexisting with palsy, and amyotrophic
other neurodegenerative pathologies such as AD, DLB, progressive supranuclear lateral sclerosis.
palsy (PSP), and amyotrophic lateral sclerosis (ALS).2,18–20 Hippocampal
sclerosis also often develops in the course of FTLD. In aged individuals, the
pathogenesis of hippocampal sclerosis is now more likely to be associated
with a comorbid neurodegenerative process than the prior associations with
anoxic/hypoxic insults and temporal lobe epilepsy that were historically assumed
to be the primary causes for hippocampal sclerosis in the elderly.9,11,12,21,22
These findings also began to open the door for exploration into genetic
contributions to FTLD associations with hippocampal sclerosis.
Frontotemporal Lobar Degeneration–Related Hippocampal Sclerosis

Hippocampal sclerosis has been identified as an associated pathologic finding in
both young and old patients with FTLD who are devoid of a history of epilepsy or
anoxic/hypoxic injury.15,16,23,24 This finding was of uncertain significance until
the discovery of TDP-43 pathologic inclusions in FTLD cases and the subsequent
elucidation of familial genetics in FTLD linked to hippocampal sclerosis.
FTLD-related mutations in the GRN gene (a hexanucleotide repeat expansion in
a region in chromosome 9 locus strongly associated with both ALS and FTLD
[C9orf72]) and the TMEM106B gene have been shown to be strongly associated
with the development of hippocampal sclerosis.25–27 The known products
of these genes may all contribute to hippocampal sclerosis through shared
or independent pathways. GRN has been implicated in neuronal survival,
inflammatory pathways in the central nervous system, and the modulation of
central nervous system angiogenesis.28 The protein product of the C9orf72
gene, influenced by TMEM106B, has been suggested to contribute to
actin-mediated cytoskeletal homeostasis, membrane lipid trafficking, and
neuronal autophagy, each of which may play a role in the development of
hippocampal sclerosis associated with FTLD and ALS.26,27 These proposed
mechanisms may all contribute to the development of hippocampal
sclerosis in FTLD and highlight the now-accepted premise that hippocampal
sclerosis is not just a downstream effect of pathology but is a distinct
degenerative process.
PATHOLOGY. On H&E stain, hippocampal sclerosis–FTLD is indistinguishable

from the other potential causes of hippocampal sclerosis seen in advanced aging,
epilepsy, anoxic/hypoxic injury, and chronic traumatic encephalopathy.11
Selective neuronal loss in the CA1 sector of the hippocampus and subiculum and
widespread gliosis in these regions is observed across all these disease states.11

Hippocampal sclerosis–FTLD, however, is strongly associated with TDP-43

inclusions within the affected regions. While TDP-43 immunoreactivity can
present in several different forms, the TDP-43 inclusions seen in hippocampal
sclerosis–FTLD are exclusively Type A, characterized by widespread TDP-43
reactive neurites with associated intraneuronal cytoplasmic TDP-43 inclusions,
irrespective of genetic association with GRN or C9orf72 mutations.3,9,17,29
These pathologic findings are seen in the hippocampal CA1 subfield, subiculum,
and amygdala. It is important to note that hippocampal sclerosis–FTLD, as
with the more widespread cortical and subcortical pathology seen in FTLD,
can frequently be unilateral on gross inspection of the brain.30 The overt
signs of hippocampal and amygdala atrophy can frequently be unilateral as
well. However, if the apparently unaffected side is evaluated with TDP-43
immunohistochemistry, the Type A TDP-43 neuritic and cytoplasmic inclusions
are present bilaterally irrespective of the apparent unilaterality of the gross
atrophy and apparent sclerosis visualized on H&E staining.
CLINICAL PRESENTATION. While the clinical presentation of FTLD in general

is quite heterogeneous, encompassing both behavioral and a variety of
language-predominant clinical syndromes, the specific presence of hippocampal
sclerosis pathology in FTD dictates common findings attributed to the loss of
hippocampal function. In other words, hippocampal injury leads to a decline in
anterograde memory function, detected as a decline in delayed recall on formal
cognitive testing. To date, clinical diagnostic criteria to evaluate the presence
or absence of hippocampal sclerosis in clinical cases meeting criteria for FTD are
lacking. The potential for hippocampal sclerosis should be actively pursued in
cases with associated motor neuron disease and in the semantic dementia variant
of FTD. However, the presence of hippocampal sclerosis should always be
suspected in patients diagnosed with FTD who demonstrate appreciable
anterograde amnestic signs and symptoms, irrespective of other associated
clinical features or diagnoses.
Hippocampal Sclerosis of Aging

Hippocampal sclerosis has long been recognized as seen at autopsy in a relatively
large proportion of the “oldest-old” (older than 85 years of age).3,7 Hippocampal
sclerosis can be seen in the absence of TDP-43 inclusions, presumably in these
cases due to either anoxic/hypoxic brain injury or the presence of clinically
evident, clinically silent, or undiagnosed seizure activity.7 Hippocampal sclerosis
without concomitant TDP-43 pathology is relatively uncommon in the aging
population.3 Extensive review of the clinical histories of most patients with
TDP-43–negative hippocampal sclerosis of aging pathology typically fails to
reveal evidence of a prior anoxic/hypoxic event. Nonetheless, it is possible that
reduced oxygen, nutrient delivery, or glucose fluxes secondary to systemic or
vascular disease may produce a chronic state of insufficient vascular flow to
support neuronal health, leading to the pathologic findings of TDP-43–negative
hippocampal sclerosis of aging pathology. Other conditions, such as chronic
hypoxia from chronic obstructive pulmonary disease, emphysema, or severe
obstructive sleep apnea, could also be potential contributors to the development
of hippocampal sclerosis in affected individuals. Epilepsy, while commonly
associated with hippocampal sclerosis in the young, has not been convincingly
demonstrated to be a potential cause of hippocampal sclerosis among elderly
214 FEBRUARY 2019

individuals. Survival effects in patients with uncontrolled epilepsy who may KEY POINTS
die prematurely, never achieving the advanced age characteristic of hippocampal
● The presence of
sclerosis of aging, may bias the aged population evaluated for hippocampal hippocampal sclerosis
sclerosis of aging against consideration of this possibility. A counterargument should always be suspected
could be made, however, that over 10% of patients with dementia develop in patients diagnosed with
seizures that are often atypical clinically as their disease progresses.31,32 frontotemporal dementia
who demonstrate
Frequently, such seizures remain undiagnosed, and the potential prevalence
appreciable anterograde
of unrecognized recurrent seizure activity or a predisposition to seizures amnestic signs and
determined by routine EEG in the aging population with dementia may approach symptoms, irrespective of
38%.32 Thus, the possibility that unrecognized or undiagnosed late-life epilepsy other associated clinical
features or diagnoses.
could be a contributor to hippocampal sclerosis in advanced age remains
a possibility. ● The extent of TDP-43
pathology seen in
PATHOLOGY. In hippocampal sclerosis of aging, as in hippocampal hippocampal sclerosis of
sclerosis–FTLD, TDP-43 inclusions, when found as they are in the vast aging can frequently extend
well beyond the medial
majority of cases, are best classified as Type A, with predominant TDP-43 temporal lobe to include
immunoreactive neurites and neuronal cytoplasmic inclusions in the setting neighboring regions of the
of widespread neuronal loss and gliosis in the hippocampal CA1 subfield, frontal and temporal
subiculum, and amygdala.3,9 Recent confounds identified in the pathologic cortices as well as
subcortical regions,
diagnosis of hippocampal sclerosis of aging include the potential for unilateral demonstrating that
rather than bilateral sclerosis to be present and the recently appreciated issue of hippocampal sclerosis of
“segmental” hippocampal sclerosis of aging.9,30,33 In segmental hippocampal aging is not confined to the
sclerosis of aging, the sclerosis is patchy, so the pathologic diagnosis of medial temporal lobe
structures but instead can
hippocampal sclerosis of aging may be missed if multiple sections through the
be associated with more
hippocampus are not analyzed.33 This phenomenon has implications not only widespread pathology.
as a confound in the recognition of hippocampal sclerosis of aging but also for
research into why specific hippocampal regions may or may not be affected with
the disease process. This finding further raises questions about the early stages
of hippocampal sclerosis of aging and whether all hippocampal sclerosis of aging
will spread to the entire hippocampus and beyond or whether it can remain
isolated to segmental regions of the hippocampus.
It is important to note that the extent of TDP-43 pathology seen commonly,
if not almost universally, in hippocampal sclerosis of aging can frequently extend
well beyond the medial temporal lobe to include neighboring regions of the
frontal and temporal cortices as well as subcortical regions,3,29 demonstrating
that hippocampal sclerosis of aging is not confined to the medial temporal lobe
structures but instead can be associated with more widespread pathology. The
pathologic overlap between hippocampal sclerosis of aging and hippocampal
sclerosis–FTLD has led some to conclude that hippocampal sclerosis of aging
may be more representative of a forme fruste of FTLD than a unique
neurodegenerative disease of aging.
Pathologic studies have also demonstrated an association between
TDP-43–positive hippocampal sclerosis of aging and brain arteriolosclerosis,
suggesting that a chronic reduction in blood flow to the microvasculature in
vulnerable watershed areas such as the hippocampus may play a role in the
development of hippocampal sclerosis of aging.13 This is in contrast to a clear
association between cerebrovascular risk factors that lead to traditional
arteriolosclerosis and other pathologic features of cerebrovascular disease, such
as large vessel atherosclerosis, cerebral amyloid angiopathy, lacunar infarcts, and
large vessel cardioembolic or atheroembolic stroke.7,13 These data suggest that

unique contributions to small arteriolar insufficiency, specifically involving the

vasculature of the hippocampus, subiculum, and amygdala, may be part of the
pathologic cascade of events leading to hippocampal sclerosis of aging that are
not directly related to the conventional mechanisms of cerebrovascular disease.13
This hypothesis has found some support regarding the identified genetic
associations with hippocampal sclerosis of aging that are discussed below.
Appreciation of the widespread prevalence of hippocampal sclerosis
pathology in late-age sporadic AD (approximately 50%) has added greatly to
the complexity of both pathologic and clinical diagnostic criteria regarding
mixed-pathology disease states. This further highlights the potential for shared
mechanisms of disease progression, wherein the development of TDP-43 and
hippocampal sclerosis pathology may represent a later downstream stage
confluence of pathologic disease mechanisms that contribute to such
shared pathology.
GENETICS. A growing appreciation of the importance of hippocampal sclerosis of

aging as a unique or comorbid pathologic condition contributing to cognitive
decline and dementia and the recognition of the genetic linkage of hippocampal
sclerosis with the GRN, TMEM106B, and C9orf72 familial forms of FTLD have
recently led researchers to search for genes that may be related to hippocampal
sclerosis of aging.3,9,17,29 Despite extensive genetic investigations, linkages between
hippocampal sclerosis of aging and AD-related genetic risk loci have not been
found.34,35 These findings suggested to researchers that there may be a unique
pathogenetic pathway leading to hippocampal sclerosis, propelling further genetic
research in the field of hippocampal sclerosis of aging.
Recent genome-wide association studies identified a linkage between two
additional genes, ABCC9 and KCNMB2.26,36 The gene product of ABCC9
encodes potassium channel regulators that can influence vascular responses to
anoxia/hypoxia and inflammation, providing a plausible mechanism for its
relationship with hippocampal sclerosis of aging.26,34,36 Of note, ABCC9 has also
been linked to the development of arteriolosclerosis in advanced age, irrespective
of the presence of known cerebrovascular risk factors or the presence of other
overt cerebrovascular lesions.13,26 This ties in well with the pathologic findings
demonstrating an association of hippocampal sclerosis of aging with
arteriolosclerosis as described above.13 KCNMB2, like ABCC9, also encodes for
potassium channel regulators that have been specifically linked to normal
hippocampal physiologic responses important for memory formation.26,36 In
addition, the ABCC9 locus resides on human chromosome 12 near another gene,
SLCO1C1, which encodes for a protein that regulates brain levels of thyroid
hormone, specifically T4 uptake from blood.37 The association of thyroid
hormone dysregulation with hippocampal sclerosis of aging was further
supported by the finding of increased thyroid hormone levels in the CSF of
subjects with hippocampal sclerosis of aging despite normal serum thyroid
hormone and other thyroid function testing, suggesting that hippocampal
sclerosis of aging may be related to a brain-specific dysregulation of thyroid
function.37 Interestingly, a 2018 study found evidence that mutations in ABCC9
and the paralogous gene ABCC8 may be linked to the progression rate of ALS
(another TDP-43 disease).38 Otherwise, ABCC9, SLCO1C1, and KCNMB2 have
not been linked to FTLD, suggesting that hippocampal sclerosis of aging is a
unique neurodegenerative disease, despite sharing overlapping features with
216 FEBRUARY 2019

other disease processes such as FTLD, vascular dementia associated with
arteriolosclerosis, and AD.
CLINICAL FEATURES. Despite the lack of clinical diagnostic criteria for

hippocampal sclerosis of aging, the involvement of medial temporal lobe
structures with relative (albeit not absolute) sparing of other cortical and
subcortical areas is suggestive of a phenotype that may allow the development
of such criteria. Such a phenotype would be expected to specifically impair
short-term memory mechanisms, leading to a profound anterograde amnesia in
the absence of other associated dementia symptoms. Such a diagnostic feature
may distinguish hippocampal sclerosis of aging from other amnestic disorders
such as AD in its fulminant state as well as other degenerative or vascular
processes contributing to cognitive decline and dementia in the aging population
today. A caveat is the confounding clinical phenotype of early mild cognitive
impairment (MCI) of the AD type, single domain, in which short-term memory
loss and an anterograde amnesia are the only findings.39–41 In such cases,
longitudinal observation may eventually distinguish MCI of the AD type and
hippocampal sclerosis of aging.
While initial reports of a diagnostic algorithm involving a ratio of delayed
recall to verbal fluency performance suggest a statistically significant difference
in the ratio of word list delayed recall to verbal fluency in subjects with AD
compared to those with hippocampal sclerosis of aging, it remains unclear if this
algorithm is useful in determining the presence or absence of the disease in a
specific patient during life.9 Despite this caveat, the data are intriguing and
suggest that additional work focused on the discriminatory ability of either
specific cognitive tests or combinations thereof may move the field of
neuropsychology closer to developing clinical criteria useful for individualized
diagnosis of hippocampal sclerosis of aging rather than simply descriptive of
group differences.
The epidemiology of hippocampal sclerosis of aging may also provide
diagnostic clues that could eventually be incorporated into clinical diagnostic
criteria. Prior studies have suggested that by 85 years of age, hippocampal
sclerosis of aging is seen in approximately 10% of the population, increasing to
30% by the age of 100.3,9 A 2018 study further corroborated this and additionally
found that hippocampal sclerosis of aging, when present, could account for
25% of prevalent dementia cases as the third leading cause of degenerative
dementia in the aging population after AD and DLB.42 As such, considerations
of this diagnosis should be reserved for those older than the age of 85 in whom the
pretest probability for hippocampal sclerosis of aging is high enough to make
clinical diagnostic criteria useful for diagnosis in specific individuals. Prior
studies have not found evidence of a role of race, sex, or educational differences
to aid in the development of specific clinical diagnostic criteria.
Several studies have described the clinical features of persons with eventual
autopsy-confirmed hippocampal sclerosis of aging. While the number of such
cases is low at present, it does appear as though cognitive functions that are
reliant on neuroanatomic regions outside the hippocampus are relatively
spared. In addition, there is a relative paucity or attenuation of neuropsychiatric
and behavioral symptoms that would otherwise be seen in confounding
neurodegenerative disease states.3,9,22,29 Social functions and daily activities that
do not require short-term memory function may remain preserved for many

years, with a very slow progression from subjective and objective short-term
memory loss to the state of dementia in which functional impairment is evident
in daily activities.9,29
Other clinical findings that are often commonly associated with degenerative
disease states, such as focal sensory or motor neurologic deficits, aphasia,
parkinsonism, motor neuron disease, and apraxia, have not been described in the
setting of “pure” hippocampal sclerosis of aging.9,29 The presence of such
findings, however, could be associated with hippocampal sclerosis of aging in the
setting of mixed pathologic disease states, including other degenerative disorders
such as AD, DLB, FTD, motor neuron disease, and vascular dementia. Thus, as
diagnostic criteria for even pure hippocampal sclerosis of aging remain elusive,
the likelihood that clinical diagnostic criteria for the presence or absence of
hippocampal sclerosis of aging in mixed comorbid disease states could be
developed remains uncertain for the foreseeable future.
IMAGING. Given the lack of antemortem clinical diagnostic criteria for

hippocampal sclerosis of aging, limited data are available on specific imaging
findings to guide clinical antemortem diagnosis. Few autopsy-confirmed studies
of antemortem imaging have been performed. The most noteworthy of these,
a report by Zarow and colleagues,30 describes the extent of hippocampal atrophy
in hippocampal sclerosis of aging as statistically more severe than that seen in
AD. Postmortem MRI studies confirm the finding of increased hippocampal
atrophy in hippocampal sclerosis of aging over that seen in AD.43 These findings
are expected given the neuroanatomic focus of disease-defined and pathologic
studies (FIGURE 10-2). It remains unclear whether the relative absence or
reduced extent of global or more focal brain atrophy in regions outside the
hippocampal formations that differ between persons with hippocampal sclerosis
of aging and other pathologic disease states can be used to indicate a lower
likelihood of pure hippocampal sclerosis of aging. If so, it should be noted that
this approach would not be helpful in defining hippocampal sclerosis of aging
in the setting of comorbid AD or other disease states that can contribute to focal
or more global cerebral atrophy. Thus, while hippocampal atrophy on MRI
may be highly sensitive for the diagnosis of hippocampal sclerosis of aging, it
clearly lacks the specificity required for accurate diagnostic determination and
usefulness as a biomarker of the underlying pathologic disease state.
Techniques looking at the discrete three-dimensional structure of the
hippocampus have been developed that demonstrate specific atrophy within
subfields of the hippocampus in AD.44 These techniques have not been tested
on or validated in hippocampal sclerosis of aging, yet they show significant
promise in detecting patterns of focal atrophy that may differ between AD
and hippocampal sclerosis of aging. Such techniques may also be helpful in
evaluating for unilateral or segmental hippocampal sclerosis of aging.33 It is clear
that further work in the area of MRI neuroimaging is needed before a biomarker
for hippocampal sclerosis of aging is proven to meet the thresholds for both
sensitivity and specificity required for diagnostic use.
Fludeoxyglucose positron emission tomography (FDG-PET) techniques
have been developed to look at hypometabolism in the hippocampus. Such
techniques can clearly demonstrate differences in metabolic activities in these
areas between controls and patients with AD.45 Unfortunately, such techniques
are not regularly used or validated in the area of hippocampal sclerosis of aging,
218 FEBRUARY 2019

so their diagnostic utility remains unknown. The development of amyloid PET
and tau PET imaging enables detection of the (presumed) pathology of AD in
the antemortem state. Such methods could be adopted to rule out comorbid
diagnoses such as AD that could confound the diagnostic accuracy of measures
such as MRI for hippocampal atrophy. Thus, a case with advanced hippocampal
atrophy that is amyloid and tau negative by PET scanning would have a high
probability of representing a case of pure hippocampal sclerosis of aging.
Recently, cases of tau-negative amnestic dementia with significant hippocampal
atrophy have been reported, which likely represent hippocampal sclerosis of
aging.45,46 Indeed, such cases are widely recognized and have been referred
to as suspected non-Alzheimer pathology (SNAP), a disease description
based on antemortem biomarker findings that may include degenerative
processes other than hippocampal sclerosis of aging, including cerebrovascular
disease, argyrophilic grain disease, and primary age-related tauopathy
(PART).47,48 The development of molecular imaging techniques to visualize
TDP-43 pathology may greatly accelerate work in hippocampal sclerosis of
aging. However, the development of such imaging agents remains in its infancy.
Further work characterizing the imaging findings of hippocampal sclerosis
of aging is needed to define whether such imaging abnormalities may
demonstrate specificity.
FLUID BIOMARKERS. Because of the lack of clinical antemortem diagnostic criteria

for hippocampal sclerosis of aging, fluid biomarkers have yet to be discovered.
However, fluid biomarkers such as amyloid and phosphorylated tau levels in CSF
can be used as a proxy for the presence or, more important, the absence of AD
pathology to appropriately guide diagnostic thinking regarding a consideration
of hippocampal sclerosis of aging as the cause for any clinical symptoms seen.48
A combination of biomarkers could enable the identification of pure hippocampal
sclerosis of aging in the presence of short-term memory loss with relative
preservation of other cognitive domain function and advanced isolated
hippocampal atrophy on MRI. The identification of elevated T3 CSF levels in
hippocampal sclerosis of aging that are not seen in controls or patients with AD
could also eventually prove useful as an antemortem biomarker for hippocampal
sclerosis of aging.37 Confirmatory analysis in a validation cohort, however, is
required before this consideration can move forward. Other biomarkers,
including inflammatory and angiogenic profiles, are not likely to yield specific
results given that alterations in these nonspecific processes are seen frequently in
a variety of disease states. The development of CSF and serum assays for TDP-43
is under way, yet none have shown convincing results to date. The use of
proteomic and metabolic approaches to identify yet-undiscovered biomarkers
of hippocampal sclerosis of aging should be explored.
IMPLICATIONS FOR THERAPEUTIC INTERVENTION. No therapeutic interventions

have been approved for this common, yet understudied, disease. Indeed, to
the authors’ knowledge, a clinical trial investigating the utility of any available
or experimental agents for hippocampal sclerosis of aging has never been
conducted. In terms of symptomatic improvement, the potential for
acetylcholinesterase inhibitors to help with symptoms of hippocampal sclerosis
of aging is uncertain. Likewise, the potential benefits of NMDA partial
antagonists, such as memantine, remain unknown, although the possibility exists

for both acetylcholinesterase inhibitors and NMDA partial antagonists to be

used, as their effects across disparate disease states such as AD, DLB, and
vascular dementia suggest generalized improvement in cognitive function
irrespective of underlying pathologic cause.
The development of potential experimental therapeutics for hippocampal
sclerosis of aging could rely on strategies that attempt to ameliorate risk factor
contributions, implicated genetic mechanisms, or the pathologic features of
hippocampal sclerosis of aging. Potential strategies could include a focus on
arteriolosclerosis, with a myriad of agents developed to treat the risk factors of
small vessel ischemic disease and overt cerebrovascular injury as a result of such
disease.13 The potential use of antihypertensive, antiplatelet, and anticoagulant
therapies could be helpful in reducing the impact of arteriolosclerosis on
hippocampal sclerosis of aging disease progression. Prospective clinical trials are
currently limited by the inability to objectively operationalize antemortem
criteria for inclusion in such studies. Proangiogenic strategies may also prove
fruitful given the association of hippocampal sclerosis of aging with haplotype
insufficiency (reduced levels of the gene product as a result of the genetic
mutation inactivating one copy of the gene) in progranulin levels that may
exert their effect through this mechanism. Anti-inflammatory and immune-
modulatory strategies could also prove beneficial given the extreme gliosis
seen in hippocampal sclerosis of aging. Anti–TDP-43 strategies that may be
developed in the future for use in FTLD could likewise be repurposed for use in
hippocampal sclerosis of aging.
While this major disease of aging continues to exert a significant impact on the
most rapidly growing segment of our population (the oldest-old), research
advances moving us forward to potential treatments are moving at an accelerated
rate, leveraged by our discoveries over the past several decades in other
neurodegenerative diseases of aging. Potential treatments and the development
of clinical diagnostic criteria could be seen in as soon as the next few years.
ARGYROPHILIC GRAIN DISEASE

Argyrophilic grain disease was first described as a disease-defining
neuropathologic finding in the brains of aged individuals at autopsy.49,50 The
neuropathologic features include small (4 μm to 8 μm), spindle-shaped
argyrophilic inclusions (“grains”) within the dendritic harbor of neurons that
are preferentially evident in medial temporal and limbic regions, including the
ambient gyrus, entorhinal cortex, hippocampus, and amygdala, but can also
commonly be seen in the lateral hypothalamus and neighboring temporal and
extratemporal cortical regions (FIGURE 10-3).49,51 Originally identified using
silver staining techniques and then later with tau protein immunohistochemistry,
these grains were often difficult to distinguish from the dystrophic neurites
that can be widespread in AD.49,50,52,53 They can, however, be distinguished,
even with silver staining techniques, by their unique morphology, which is
distinct from that typically seen as neuritic pathology in AD.49 Associated
neuropathologic changes with argyrophilic grain disease include the presence
of “coiled bodies,” which are oligodendroglial tau inclusions; “ballooned”
neurons; and “tufted” and/or “thorny” astrocytes.49,50,52,53 All of these pathologic
features involve accumulation of phosphorylated tau protein, suggesting its
central role in the pathogenesis of argyrophilic grain disease. At the time of their
original description, it was understood that they were associated with an
220 FEBRUARY 2019

increased frequency of clinical KEY POINT
dementia, but their presence is
● The “coiled bodies,”
not an absolute determinant “ballooned” neurons, and
of clinical dementia. “tufted” or “thorny”
Further elucidation of the astrocytes seen in
pathologic features of argyrophilic argyrophilic grain disease all
involve accumulation of
grain disease revealed that the
phosphorylated tau protein,
inclusions were largely composed suggesting its central role in
of 4-repeat tau isoforms that can the pathogenesis of the
be visualized using specific disease. At the time of their
original description, it was
immunostains for exon 10 of the
understood that they were
tau gene.54–56 Exon 10 of tau associated with an
encodes the second of four increased frequency of
microtubule-binding domains clinical dementia, but
seen in the full-length tau their presence is not an
absolute determinant of
molecule, frequently referred to as clinical dementia.
“adult” tau, in contrast to 3-repeat
isoforms referred to as “fetal” tau.
This differs from the dendritic
neurites seen in AD, which are
composed of both 3-repeat and
4-repeat isoforms of the tau
protein. The development of
specific monoclonal antibodies
recognizing exon 10 greatly
enhanced our ability to visualize
these specific pathologic features
that frequently coexist within a
milieu of AD-type pathology.54 FIGURE 10-3
Subtypes of tauopathy. A, Immunostaining shows
Additional biochemical analysis phosphorylated tau (brown) and counterstaining
of the tau protein in argyrophilic hematoxylin shows cell nuclei (blue) in argyrophilic
grain disease has suggested a grain disease. Note the roundish, approximately
reduction in or absence of tau 5-micron immunostained structures (green
arrowheads), which constitute “grains.” B, In
acetylation as well as differential contrast, silver staining highlights Alzheimer
phosphorylation patterns that, disease–type neurofibrillary pathology that
again, can be used to distinguish includes threadlike structures (yellow arrowheads)
these frequently comorbid and neurofibrillary tangles in neuronal cytoplasm
57 (blue arrowheads). Scale bars: 50 microns in A;
pathologies. In addition,
40 microns in B.
pathologic studies have revealed
that argyrophilic grain disease has
a predilection for affecting the CA2 sector of the hippocampus, in contrast to AD,
hippocampal sclerosis, and other hippocampal insults, which frequently manifest
their pathologic features in the CA1 sector of the hippocampus.53 These
discoveries suggest that argyrophilic grain disease represents a unique and
distinct neuropathologic entity that can be comorbid with AD but is not a
manifestation of the primary neuronal degenerative pathologic features of AD.
Argyrophilic Grain Disease of Aging

The initial reports of argyrophilic grain disease pathology from autopsy series
demonstrated an increased frequency with advanced age as well as dementia.49

The prevalence of argyrophilic grain disease pathology in cases of dementia with

advanced age can be as high as 42%.4 Argyrophilic grain disease has also been
reported to affect 30% of centenarians lacking the signs and symptoms of overt
dementia.49,58 The clinical features of argyrophilic grain disease have been described
as indistinguishable from those of late-onset AD; however, important differences
have been noted. Increasing recognition of this entity as a distinct disease state
and enhanced immunohistochemical methods to identify this pathologic disease
state as a unique contributor to mixed dementia have led to some understanding
of the clinical phenotype associated with argyrophilic grain disease.
The relative prevalence of argyrophilic grain disease appears higher in subjects
with MCI that in those with overt dementia, suggestive of relatively isolated
involvement of medial temporal lobe structures in argyrophilic grain disease as
opposed to more widespread cortical progression in cases of late-onset AD.59 In
addition, the progression of MCI due to argyrophilic grain disease appeared to be
much slower than that seen in MCI related to AD.59 Other than the slower
longitudinal course of disease, neuropsychological test findings distinguishing
argyrophilic grain disease from MCI related to AD have not been reliably
described and validated in the literature. The lack of a diagnostic clinical
phenotype and clinical diagnostic criteria for argyrophilic grain disease has
limited our ability to advance the field both in antemortem diagnosis and the
development of specific treatment modalities that may provide symptomatic
relief or slow or halt the progression of argyrophilic grain disease.
Comorbid Argyrophilic Grain Disease in Frontotemporal Lobar

Degeneration–Tau
The heterogeneous group of diseases classified as FTLD contains a subgroup of
disorders linked to abnormal tau accumulations (now termed FTLD-tau),
including the familial forms of disease that are linked to specific mutations
within the gene encoding the tau protein on chromosome 17 as well as PSP and
corticobasal degeneration (CBD). Many of the mutations within the tau gene
lie in intronic regions of the gene and appear to influence the relative ratio of
4-repeat to 3-repeat isoforms as a result of transcriptional mRNA processing. In
addition, both PSP and CBD are widely recognized as 4-repeat tauopathies. This
has led to some speculation of a linkage between all 4-repeat tauopathies. The
presence of many of the associated pathologic features of argyrophilic grain
disease, including coiled bodies, ballooned neurons, and tufted and/or thorny
astrocytes, that are also recognized as core neuropathologic features seen in PSP
and CBD lends further credence to this hypothesis. In contrast, pathologic studies
to date have not identified argyrophilic grain disease as an invariant feature of
FTLD linked to intronic mutations in the tau gene that specifically overexpress
4-repeat tau isoforms, suggesting that a predilection for 4-repeat isoform
overexpression of the tau gene is not, in itself, sufficient to produce the
neuropathologic features and degeneration characteristic of argyrophilic grain
disease. In addition, it should be noted that not all cases of PSP or CBD show the
characteristic pathology of argyrophilic grain disease, although many do (CASE 10-2).60
Over recent years, a number of cases with pathologically confirmed
argyrophilic grain disease have been described with significant behavioral and
psychiatric symptoms in patients with an earlier onset of symptoms than
previously described as attributable to argyrophilic grain disease of aging.4,61–65
The coexistence of argyrophilic grain disease pathology with subtypes of
222 FEBRUARY 2019

FTLD-tau have also been described. All these cases appear to be associated
with 4-repeat tauopathies such as PSP and CBD, with the exception of several
cases linked to point mutations in the tau gene that are associated with a
phosphorylation state rather than isoform expression.61,66,67 These findings
have raised speculation that argyrophilic grain disease may exist on the FTLD
spectrum rather than as a unique degenerative disease of aging.
Genetics
Some genetic studies in argyrophilic grain disease have suggested an association
with the H1 haplotype of the tau gene, which has also been implicated in the
development of PSP, but other studies have demonstrated no such association.68,69
It is conceivable that the heterogeneity in the expression of argyrophilic grain
disease may be responsible for the varied results in genetic associations between
studies that have examined distinct populations, with those enriched for diseases
A 72-year-old man presented with a 2-year history of recurrent falls and CASE 10-2
gait difficulties. Over the past year, he had noticed his voice becoming
more monotone and had several instances of swallowing difficulties but
had never aspirated. His wife described him as “stiff” and noted that at
times he appeared “robotic.” He had previously been diagnosed with
Parkinson disease and was started on carbidopa/levodopa, but it failed
to improve his motor difficulties and so was discontinued. He had
experienced uncontrollable and, at times, inappropriate laughing and
crying spells. Over the previous 6 months, his wife had noticed
progressive decline in his short-term memory in addition to his
progressive motor issues and labile affect.
On examination, he had a mild pseudobulbar affect and impaired
downgaze, with prominent axial rigidity. He was also noted to have
frequent repeating behavior during history taking. On mental status
examination, his delayed recall was completely absent, and he had some
difficulties with orientation to time, but otherwise his bedside cognitive
testing appeared intact. His brain MRI showed a classic hummingbird sign
representing midbrain atrophy. He was diagnosed with progressive
supranuclear palsy (PSP) and conservative symptomatic management
was initiated.
At autopsy 3 years later, the patient was found to have globose tangles
and tufted astrocytes, particularly involving the subthalamic nucleus,
substantia nigra, and globus pallidus, which met criteria for a pathologic
diagnosis of PSP. Additional findings included widespread argyrophilic
grains in the hippocampus particularly affecting the CA2 subfield.
Argyrophilic grain disease in the setting of PSP was considered responsible COMMENT
for the prominent memory deficits seen in this patient. The memory deficit,
originally considered a result of PSP pathology or comorbid Alzheimer
disease, highlights the need to develop clinical diagnostic criteria for this
pathologic entity.

such as PSP demonstrating associations and those excluding such cases failing to
find an association. Other studies have demonstrated the linkage between
argyrophilic grain disease and the S305I and S305S mutations on chromosome
17 that are linked to PSP and FTLD, respectively.61,66 These genetic findings
again support an overlap or shared pathogenesis between FTLD and argyrophilic
grain disease. Argyrophilic grain disease in individuals with advanced age has
been found to be associated with the APOE *2 allele.70,71 This allele is typically
recognized as protective against AD, again suggesting that late-onset
argyrophilic grain disease and AD are distinct entities rather than shared
expressions of a single pathogenetic mechanism.
Clinical Features
When argyrophilic grain disease is found in a relatively restricted pathologic
distribution involving limbic regions, the clinical phenotype is, again, often a
slowly progressive pure amnestic syndrome that can also be seen in association
with emotional and personality changes reflecting the limbic predominance of
such pathology.4,59,63–65,72,73 Such distributions of argyrophilic grain disease
pathology have also been seen in cases of Parkinson disease and are associated
with an earlier onset of symptomatic psychotic features such as hallucinations,
delusions, and paranoia. Yet other cases with profound behavioral, personality,
and psychotic features that appear to exhibit the clinical phenotype of FTD have
been shown to have more widespread cortical argyrophilic grain disease
pathology in addition to the limbic predominance of this disease.64,65 These
findings suggest that the clinical features of argyrophilic grain disease exist on a
spectrum, with the clinical presentation mirroring the underlying anatomic
involvement of argyrophilic grain disease–specific pathology.
Imaging and Biomarker Studies

Given the lack of antemortem diagnostic criteria for argyrophilic grain disease,
the development of fluid and imaging biomarkers of the disease remains in its
infancy. It has been suggested that medial temporal lobe atrophy, such as that
seen in AD and hippocampal sclerosis of aging, may also be the most prevalent
finding in isolated, “pure” argyrophilic grain disease.4 Other imaging findings in
argyrophilic grain disease have not been reported, but the development of tau
PET ligands may hold promise for detecting argyrophilic grain disease as it is a pure
tauopathy, to the best of our knowledge at this time. It remains unclear, however,
whether the degree of abnormal tau accumulation within the microscopic grains will
be sufficient to allow detection with such methodology. Fluid and structural imaging
biomarkers that can distinguish argyrophilic grain disease from other forms of
degenerative disease, such as AD and hippocampal sclerosis of aging, have not been
developed. Early attempts at identifying argyrophilic grain disease–specific
biomarkers are in development based on biochemical analyses that show not
only the preponderance of 4-repeat tau but also a lack of tau acetylation in
argyrophilic grain disease.54,56,57,74 At present, argyrophilic grain disease remains
a diagnosis that can only be made and confirmed at autopsy.
Implications for Treatment

As yet, no specific treatments for argyrophilic grain disease have been developed.
The absolute reliance on postmortem examination for determination of the presence
or absence of argyrophilic grain disease has precluded clinical trial development
224 FEBRUARY 2019

and confounded retrospective analysis of any potential benefit for symptomatic KEY POINTS
treatment. The advent of anti-tau therapies that have been developed for AD and
● Biochemical differences
FTLD-tau hold much promise for the treatment of argyrophilic grain disease if stemming from discoveries
antemortem clinical or biomarker-based diagnostic criteria can be developed. in postmortem brain tissue
Until such time, treatment for argyrophilic grain disease should focus on targeting have not yet been translated
the symptomatic expression of disease empirically rather than basing treatment into antemortem serum or
CSF biomarkers for
paradigms on rational strategies that may be specific for the disease state.
argyrophilic grain disease.
At present, argyrophilic
PRIMARY AGE-RELATED TAUOPATHY grain disease remains a
PART is a relatively recently recognized pathology that is common in old age.5 In diagnosis that can only
be made and confirmed
brains with PART pathology, neuritic amyloid plaques are not detected, but tau
at autopsy.
neurofibrillary tangles are observed. The presence of age-related tauopathy in
the absence of substantial amyloid-β (Aβ) plaques has long been appreciated,75–77 ● In brains with primary
but we are now far more aware of the pathology’s prevalence and public health age-related tauopathy
impact. For example, hippocampal neurofibrillary tangles are practically pathology, neuritic amyloid
plaques are not detected,
universal in the 20% to 30% of centenarians whose brains lack detectable but tau neurofibrillary
Aβ plaques.78,79 Interindividual variation is seen in the severity of PART-type tangles are observed.
pathology,5 but the mechanism(s) responsible for this variation are mostly
unknown. By definition, the neurofibrillary tangles of PART are not associated ● By definition, the
neurofibrillary tangles of
with underlying FTLD or chronic traumatic encephalopathy, differentiating this
primary age-related
entity from other degenerative disease states characterized by predominant tauopathy are not
tau-related pathology.5 In addition, unlike many cases of tau-related FTLD, Pick associated with underlying
disease, and argyrophilic grain disease, which are characterized by tau inclusions frontotemporal lobar
degeneration or chronic
that may only include either 3-repeat or 4-repeat isoforms of tau, the tangles seen
traumatic encephalopathy,
in PART are composed of both isoforms, with comparable phosphorylation differentiating this entity
patterns and ultrastructural properties (paired helical filaments) that are from other degenerative
virtually identical to those seen in AD.5 disease states characterized
Although it has become a recognized disease entity, PART has generated some by predominant tau-related
pathology.
controversy among experts in the field, and divergent opinions have been
expressed.80–82 Despite the near-identical molecular and structural nature and ● Despite the near-identical
anatomic distribution of neurofibrillary tangles between PART and early AD, the molecular and structural
neuroanatomic extent of neurofibrillary tangle pathology in PART appears nature and anatomic
distribution of
largely restricted to the temporal lobes, unlike in AD, in which the distribution of neurofibrillary tangles
neurofibrillary tangles can be more widespread cortically (FIGURE 10-4). between primary age-
These areas of overlap and yet restricted distribution have led some to argue that related tauopathy and early
PART is a unique pathologic disease entity,5,82,83 while others have convincingly Alzheimer disease, the
neuroanatomic extent of
argued that PART may simply be part of the spectrum of pathology inherent
neurofibrillary tangle
in many cases of AD.76,81 Much remains unknown about the disease, including pathology in primary
how it can best be operationalized for research84,85 and how we should define the age-related tauopathy
“border zones” between AD and PART in theory and in diagnostic practice. appears largely restricted
to the temporal lobes,
unlike in Alzheimer disease,
Clinical Features in which the distribution
In large autopsy series, the distribution of PART pathology has been shown of neurofibrillary tangles
to be associated with antemortem cognitive impairment,5,86 and PART is also can be more widespread
implicated in subjective memory symptoms87 and MCI.88 PART may be more cortically.
common in those of advanced age, similar to hippocampal sclerosis of aging and

argyrophilic grain disease, differing in this respect from typical AD, which can
have an earlier mean age of onset.5,78,82,83,85 In addition, the severity of Braak
stage is highly correlated with the degree of cognitive impairment, which is quite
similar to what is seen in AD.5,86

FIGURE 10-4
Comparison of primary age-related tauopathy and Alzheimer disease. A, B, Analogous sections
from hippocampal-level regions stained with hematoxylin and eosin (H&E) at 1× magnification.
C, D, Immunohistochemistry for phosphorylated tau (p-tau) at 20× magnification. E, F,
Immunohistochemistry for amyloid-β (Aβ) at 10× magnification. Note that the appearances of
the stained sections are very similar for p-tau (C, D); by contrast, the neocortical regions lack
Aβ in primary age-related tauopathy (E) but show many Aβ plaques in Alzheimer disease (F).
CA1 = cornu ammonis 1; IHC = immunohistochemistry; NeoCx = neocortex.
A 2017 study using the National Alzheimer’s Coordinating Center cohort

compared asymptomatic and symptomatic persons with PART diagnosed at
autopsy, based on the classifications of PART-definite (no amyloid deposition,
Consortium to Establish a Registry for Alzheimer’s Disease [CERAD] stage 0)
and PART-probable (sparse amyloid, CERAD stage 1).89 The symptomatic
expression of cognitive decline was more common in those with even mild
cerebral amyloidosis (PART-probable, 80% symptomatic) compared to those
with a complete absence of cerebral amyloidosis (PART-definite, 58%
symptomatic), suggesting a potential exacerbation of PART symptomatology
with even the earliest AD-like changes.89 This study also found that PART-
definite subjects with cognitive decline were more likely to have higher
Braak stages and evidence for comorbid depression than their asymptomatic
counterparts.89 In a 2017 study, the cognitive tests showing decline most closely
associated with Braak stage were the Wechsler Adult Intelligence Scale Block
Design and Trail Making Test Part B, adjusted for age and education using the
Mayo Older Americans Normative Studies scores.86 These results would not be
226 FEBRUARY 2019

predicted on the basis of the anatomic distribution of neurofibrillary tangles in KEY POINTS
PART but were presumed due to an influence of PART on general cognitive
● In large autopsy series,
slowing as these are both timed tests.86 the distribution of primary
Clearly, a more complete understanding of the differences in clinical phenotype age-related tauopathy
between PART, AD, and other AD mimics such as hippocampal sclerosis of pathology has been shown
aging and argyrophilic grain disease is needed before such antemortem clinical to be associated with
antemortem cognitive
information may be used to accurately identify PART as a distinct clinical entity.
impairment, and primary
age-related tauopathy is
Imaging and Fluid Biomarkers also implicated in subjective
While further elucidation of the clinical phenotype of PART is awaited, evidence memory symptoms and mild
cognitive impairment.
of the ability to detect PART in living individuals using readily available
biomarker approaches is mounting.90,91 As understanding the postmortem ● Prospective testing of
pathology of PART requires evidence for tau-related neurodegeneration multimodal use of
(molecularly similar to that seen in AD and in the same early neuroanatomic antemortem biomarkers
distribution) in the absence of cerebral amyloidosis,5 studies of antemortem remains to be confirmed but
holds much promise for the
biomarker detection of PART have focused on using the absence of positive antemortem detection of
biomarkers of cerebral amyloidosis (amyloid PET and CSF amyloid levels) to rule pathologic diseases such as
out AD. Such evidence in combination with markers of tau pathology (tau primary age-related
PET and CSF tau and phosphorylated tau levels) and markers of medial temporal tauopathy.
lobe neuronal injury (MRI volumetrics and FDG-PET) may allow a more specific
antemortem multimodal characterization of PART.5,48,82,83,85
The cornerstone for such characterization includes the absence of detectable
cerebral amyloid levels by amyloid PET or CSF analyses.5,47,48,85,90–93 Such
cases, however, may also comprise a host of other degenerative disease states,
including vascular dementia, DLB, FTD, hippocampal sclerosis of aging, and
argyrophilic grain disease. Exclusion of subjects with DLB or FTD phenotypes
and of subjects with vascular dementia based on clinical and imaging evidence of
cerebrovascular disease leads to increased specificity for PART. Focusing on
medial temporal lobe involvement with the use of MRI volumetrics and
FDG-PET further restricts the pathologic entities to PART, FTD-tau (medial
temporal lobe predominant), hippocampal sclerosis of aging, and argyrophilic
grain disease. Some preliminary evidence indicates that certain tau PET imaging
ligands may bind preferentially to tau inclusions with mixed repeat isoforms,
which may help to further identify PART-specific tauopathy once AD is
excluded.94 Additionally, biochemical analyses of CSF tau levels can help identify
phosphorylated species and mixed tau isoform composition that could reliably
predict PART.5,45,47,54–57,67,93 Prospective testing of such multimodal use of
antemortem biomarkers remains to be confirmed but holds much promise for
the antemortem detection of pathologic diseases such as PART.48,90
Genetics
Given the arguable overlap between PART and AD, links between the known
genetic associations in AD have been explored in PART. Despite widespread
investigations, no associations between common AD genetic risks and PART
have been found, and evidence for any association between APOE status and
PART is lacking.5,69,82,89,95 A linkage to other isoforms of APOE, such as the
*2 allele that is postulated to play a role in influencing the development of
argyrophilic grain disease, has not been found for PART.69–71 This lack of
genetic overlap reinforces the current thinking that PART and AD are distinct
pathologically described degenerative processes.5,80,82,83,86,93

Given the discovery of mutations in the MAPT gene on chromosome 17 linked

to FTLD-tau and the linkages of other tauopathies such as PSP and argyrophilic
grain disease to the expression of specific MAPT haplotypes, it is only natural
that genetic associations with PART have been explored.61,66–69,74 To date, no
specific tau mutations have been linked to PART, although at least one study
found a strong association indicating the presence of the MAPT H1 haplotype
as a risk factor for PART.95 This association is not unique, however; the haplotype
is also a risk factor for the development of both PSP and argyrophilic grain
disease (4-repeat tauopathies), suggesting that the H1 haplotype increases the
likelihood of developing late-life tau-related neurodegeneration but is not
specific regarding genetic influences on any specific tau-related pathway or
mechanism.68,69,74,95 Further work confirming this finding and exploring the
mechanistic pathways whereby the MAPT haplotype influences the development
of distinct tauopathic disease states is needed.
Implications for Treatment

The unique involvement of tau-related pathology in PART makes it an ideal
candidate for therapeutic intervention with anti-tau strategies that have been
developed for AD, FTLD-tau, and other tau-related disorders such as PSP. The
attractiveness of a single molecular target, however, is offset by the current lack
of a reliable clinical and biomarker-based rubric for the identification of PART in
the antemortem setting. It is hoped that as more data are collected and more
validated methods for accurately identifying PART are developed in the
antemortem setting, the field will be poised to apply the myriad of anti-tau
therapies under development to the treatment of PART.
CONCLUSION
This article focused on three common AD mimics (hippocampal sclerosis of
aging, argyrophilic grain disease, and PART) that are frequently found at autopsy
in individuals who had been given the clinical diagnosis of AD or other
degenerative disorders. Recognition of these entities may help explain the lack of
specificity for the diagnosis of AD when based solely on clinical phenotype or
anatomic involvement of medial temporal lobe structures. These three diseases,
hippocampal sclerosis of aging, argyrophilic grain disease, and PART, all have
a predilection for medial temporal lobe and hippocampal involvement, present
in a common phenotype as an early amnestic syndrome, and can be associated
with medial temporal lobe atrophy. These clinical characteristics make them
indistinguishable from AD using routine clinical diagnostic tests and MRI. All
three of these entities can be found in “pure” forms that lack associated amyloid
deposition, allowing the use of CSF amyloid and amyloid PET measures to at least
suggest an underlying disease state distinct from AD.
It is intriguing that both hippocampal sclerosis of aging and argyrophilic grain
disease (but not PART) have strong associations with the genetic, biochemical,
neuroanatomic, and clinical presentations of FTLD syndromes. These data
suggest that FTLD-associated features are common in the aging population.
Differences in clinical phenotype between early-onset and late-onset diseases
associated with hippocampal sclerosis and argyrophilic grain disease deserve
further investigation. Clearly, behavioral and language features predominate in
early-onset disease, whereas a stronger amnestic component is seen in late-onset
228 FEBRUARY 2019

cases. Rethinking conceptions about how the clinical and pathologic features KEY POINTS
interrelate is a worthwhile endeavor. It is hoped that ongoing research in the field
● Hippocampal sclerosis of
will further contribute to the development of clinical diagnostic criteria for aging, argyrophilic grain
hippocampal sclerosis of aging and argyrophilic grain disease. disease, and primary
Significant overlap with the neuropathologic features of AD and other age-related tauopathy all
degenerative disease states has proved problematic in the development of have a predilection for
medial temporal lobe and
antemortem clinical diagnostic and biomarker criteria specific for these disease
hippocampal involvement,
states. These challenges have, to date, hampered the development of specific present in a common
therapeutic strategies. Understanding the presence and significant prevalence of phenotype as an early
these diseases in the aging population with cognitive decline may help to explain amnestic syndrome, and can
be associated with medial
why some patients are less responsive to traditional AD medications than others,
temporal lobe atrophy.
as many of the mimics of AD described herein are likely to not show cholinergic These clinical
deficiency or to have pathology affecting the glutaminergic circuitry as we see in characteristics make them
AD. Data acquired over the past decade have advanced our understanding of indistinguishable from
these diseases and may begin to allow the development of clinical trials for both Alzheimer disease using
routine clinical diagnostic
symptomatic therapeutics and disease-modifying agents. tests and MRI.
● Hippocampal sclerosis of
ACKNOWLEDGMENT aging and argyrophilic grain
disease (but not primary
This work was supported by a grant from the National Institutes of Health age-related tauopathy) have
(P30 AG028383). strong associations with the
genetic, biochemical,
neuroanatomic, and clinical
presentations of
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REVIEW ARTICLE

Reversible Dementias
C O N T I N UU M A UD I O By Gregory S. Day, MD, MSc
ONLINE
ABSTRACT
PURPOSE OF REVIEW: This
article describes the clinical features that suggest a
reversible cause of dementia.
RECENT FINDINGS: Substantial variability exists in the presenting features and

clinical course of patients with common neurodegenerative causes of
dementia, but the response to available therapies and eventual outcomes
are often poor. This realization has influenced the evaluation of patients
with dementia, with diagnostic approaches emphasizing routine screening
for a short list of potentially modifiable disorders that may exacerbate
dementia symptoms or severity but rarely influence long-term outcomes.
Although a standard approach to the assessment of dementia is
appropriate in the vast majority of cases, neurologists involved in the
CITE AS:
CONTINUUM (MINNEAP MINN) assessment of patients with dementia must recognize those rare patients
2019;25(1, DEMENTIA):234–253. with reversible causes of dementia, coordinate additional investigations
when required, and ensure expedited access to treatments that may
Dr Gregory S. Day, Charles F.
reverse decline and optimize long-term outcomes.
and Joanne Knight Alzheimer
Disease Research Center, SUMMARY: The potential to improve the outcome of patients with reversible
Washington University School of
Medicine, 4488 Forest Park Ave,
dementias exemplifies the need to recognize these patients in clinical
Ste 160, St Louis, MO 63108, practice. Dedicated efforts to screen for symptoms and signs associated
gday@wustl.edu. with reversible causes of dementia may improve management and
outcomes of these rare patients when encountered in busy clinical practices.
Dr Day has served as a topic
editor on dementia for DynaMed
Plus (EBSCO Industries, Inc) and
as clinical director for the INTRODUCTION
T
Anti-NMDA Receptor he vast majority of dementia cases encountered in North American
Encephalitis Foundation. Dr Day
clinics are attributable to neurodegenerative diseases, including
receives research/grant support
from Avid Radiopharmaceuticals, Alzheimer disease (AD), Lewy body disease, frontotemporal lobar
the Foundation for Barnes Jewish degeneration, and cerebrovascular disease. Although the clinical
Hospital, and the National
Institutes of Health (P01AG03991,
presentation and longitudinal course of these disorders varies, the
R56AG057195) and holds stock in long-term prognosis is uniform: cognitive deficits, disability, and functional
ANI Pharmaceuticals, Inc. Dr Day impairment gradually progress, leading to death. Accordingly, the standard
has provided record review and
expert medical testimony on diagnostic assessment focuses on screening for common, potentially modifiable
legal cases pertaining to comorbidities and disorders that may worsen or cause cognitive impairment (ie,
management of Wernicke depression, vitamin B12 deficiency, and hypothyroidism), and rare structural
encephalopathy.
causes that may necessitate alternative treatment (eg, subdural hematomas,
UNLABELED USE OF primary or secondary brain tumors).1 Although this standard approach to
PRODUCTS/INVESTIGATIONAL USE
DISCLOSURE:
assessment is appropriate in the majority of cases, neurologists involved in the
Dr Day reports no disclosure. diagnosis and management of patients with dementia must recognize the
symptoms and signs that suggest a reversible cause of dementia, coordinate
additional investigations when required, and ensure expedited access to
of Neurology. treatments that may reverse decline and optimize long-term outcomes.
234 FEBRUARY 2019

Although truly reversible causes of dementia account for a small proportion of KEY POINTS
cases in outpatient clinics,2,3 the potential to dramatically improve the outcome
● Neurologists involved in
of even a small number of patients justifies the development of diagnostic the diagnosis and
strategies that promote detection of these rare patients. Even when diagnosis and management of patients
treatment do not result in complete resolution of symptoms, the potential to with dementia should
modify disease progression and improve quality of life for patients and family recognize the symptoms
and signs that suggest
members warrants screening for reversible causes of dementia. But how can
a reversible cause
these patients be identified? of dementia.
FINDING THE NEEDLE IN THE HAYSTACK ● Truly reversible causes of

For the busy clinician managing a full clinic schedule, the challenge of identifying dementia account for a
small proportion of cases in
the rare patient with a reversible dementia may bring to mind any number of outpatient clinics.
tired analogies connoting futility. Clearly, strategies are needed to promote
recognition of patients with potentially treatable causes of dementia. In the ● Patients with rapidly
clinic, this can be accomplished by implementing a universal approach to progressive dementia
warrant an expedited
dementia assessment that relies upon standard testing1 and active monitoring for assessment, with the goal of
atypical features on history, examination, and investigations that may point to a rapidly identifying and
reversible cause of dementia. Atypical features that may indicate a reversible remedying reversible causes
cause of dementia include the following: of and contributors to
dementia.
u Rapid unexplained decline in function ● Younger than expected

u Younger than expected age at symptom onset age at symptomatic onset is
a well-recognized marker of
u Prominent fluctuations secondary causes of
u Acute or chronic high-risk exposures dementia, warranting
careful evaluation and
u A history of high-risk behaviors (past or present) screening for reversible
u Unexplained or unanticipated findings on the neurologic examination causes.
u Performance on neurocognitive testing that is incongruent with the clinical history
These “red flags” that suggest a reversible dementia are illustrated here
through a review of selected cases featuring patients with well-characterized
causes of reversible dementia. These representative cases were selected to
familiarize the reader with the clinical features and test results that point to a
reversible cause of dementia.3–5
Red Flag 1: Rapid Unexplained Decline

Potentially reversible causes of rapidly progressive dementia are well recognized
in retrospective case series,6–9 with the prevalence of specific causes varying with
patient (eg, age, risk factors7,10) and clinic-specific factors (eg, level of care,
academic affiliations11,12). Accordingly, patients with rapidly progressive
dementia warrant an expedited assessment, with the goal of rapidly identifying
and remedying reversible causes of and contributors to dementia. Core testing
should be obtained in all patients with rapidly progressive dementia, including
screening serum studies, neuroimaging (favoring MRI), routine CSF analyses,
and EEG. Findings on history and examination and the results of initial testing
may justify further testing,8 or repeat testing, as illustrated in CASE 11-1.
Red Flag 2: Younger Than Expected Age at Symptom Onset

Younger than expected age at symptom onset is a well-recognized marker of
secondary causes of dementia,6–8,15 warranting careful evaluation and screening

REVERSIBLE DEMENTIAS
CASE 11-1 A 57-year-old woman presented to an outpatient tertiary care clinic for
the evaluation of rapid cognitive decline developing over 9 months. She
was a retired engineer. Her history was notable for long-standing daily
stabbing headaches, which were initially intermittent and refractory to a
trial of indomethacin. Titration of topiramate coincided with the
emergence of cognitive symptoms, including mild forgetfulness and
disorientation to date, and increasing fatigue, which persisted despite
stopping the medication. Six months before assessment, the patient
reported increasing imbalance. A subsequent fall resulted in a right arm
fracture, complicated by a pneumothorax, which necessitated hospital
admission and surgical management. Serum studies on admission were
normal, including thyroid stimulating hormone (TSH), vitamin B12 level,
and rapid plasma regain (RPR) testing. Brain MRI and EEG were performed
to evaluate contributors to cognitive decline; they were considered
“normal.” Diagnostic lumbar puncture was bland (2 white blood cells/mm3,
protein 32 mg/dL, glucose 67 mg/dL, negative oligoclonal bands, negative
infectious studies, negative autoimmune encephalitis panel, and negative
cytology).
The patient’s headaches and cognitive status improved over the
course of her hospital admission, with the patient returning to 80% to 90%
of her baseline functioning. However, shortly following discharge, her
cognition rapidly declined, resulting in an inability to manage
instrumental activities of daily living (ie, bill paying and medication
management). The emergence of new dysphagia, with decreasing oral
intake, prompted percutaneous enterogastric tube placement. A
diagnosis of rapidly progressive dementia of unclear cause was provided,
and the patient was encouraged to seek a second opinion concerning
the cause.
At the time of her second opinion in a tertiary care memory clinic
(3 months following discharge from the hospital), the patient and her
husband reported that she had progressive short-term memory loss,
fatigue, imbalance, dysphagia, and increasing urinary incontinence
requiring a suprapubic catheter. She had no history of trauma, recent
international travel, infectious exposures, hallucinations/psychoses, or
depressive symptoms.
Performance on the Short Test of Mental Status13 demonstrated
marked impairment in delayed verbal recall (0/4 items) and orientation
(3/8 items). On examination, the patient was drowsy and even fell asleep
during the evaluation. She had mild hypokinetic dysarthria, with reduced
voluntary elevation of the palate and an absent gag reflex. She had no
focal signs on motor examination; however, toes were upgoing
bilaterally. Reflexes and sensation were intact. She had marked truncal
ataxia, impairing independent ambulation.
236 FEBRUARY 2019

Given the apparent progression of neurologic deficits, diagnostic brain
MRI was repeated (FIGURE 11-1), demonstrating “brain sag,” with loss of the
suprasellar, quadrigeminal,
and prepontine cisterns,
flattening of the pons, and
slight inferior displacement
of the cerebellar tonsils
consistent with intracranial
hypotension without
associated pachymeningeal
enhancement. The cause of
her rapidly progressive
dementia was attributed FIGURE 11-1
to an occult CSF leak.14 Imaging of the patient in CASE 11-1 with rapidly
The patient underwent an progressive cognitive decline and daily
headaches. Sagittal noncontrast T1-weighted (A)
empiric fluoroscopically
and axial fluid-attenuated inversion recovery
guided two-level low thoracic (FLAIR) (B) MRIs demonstrate “brain sag,” with loss
and high lumbar interlaminar of the suprasellar, quadrigeminal, and prepontine
epidural blood patch, with cisterns, flattening of the pons, and slight inferior
immediate resolution of her displacement of the cerebellar tonsils consistent
with intracranial hypotension. The pituitary gland is
headaches. One month later, prominent, with a convex superior border (arrow).
she reported being “100% Postcontrast T1-weighted images (not shown) did
back to normal.” not reveal pachymeningeal enhancement.
The patient in this case meets accepted definitions of rapidly progressive COMMENT
dementia,12,15 with cognitive impairment evolving over months. In
retrospect, the clinical history included several clues that pointed to a
reversible dementia, including the rapid unexplained progression of
symptoms and the apparent resolution of symptoms during her
hospitalization (during which she was immobilized and supine, improving
her CSF leak). Although initial testing failed to establish the diagnosis,
continued decline justified the need for repeat testing, which led to the
correct diagnosis and treatment. Diffuse pachymeningeal enhancement is
commonly reported in association with spontaneous intracranial
hypotension. However, as this case illustrates, the finding is not required
for the diagnosis. In a cross-sectional study enrolling 99 patients with
spontaneous hypotension, pachymeningeal enhancement was detected in
83% of cases.16 In the absence of such findings, the clinical diagnosis may
be supported by detection of radiologic features of “brain sagging”
(downward sloping of the third ventricular floor, observed in 61%), venous
distension (convex inferior border of the dominant transverse venous sinus
at its midportion, observed in 75%), or myelographic evidence of a CSF leak
(in 55% of cases).

for reversible causes (even more so when younger age at symptomatic onset
occurs together with rapidly progressive deficits). Although more likely in
younger women (particularly women of childbearing age), autoimmune
encephalitis is recognized in patients of all ages and both sexes.17,18 In addition
to “core testing,” as noted earlier, the high potential for reversibility justifies
testing the CSF and blood for autoantibodies known to associate with
autoimmune encephalitis. Autoantibody testing should be considered in all
patients meeting criteria for possible autoimmune encephalitis (eg, subacute
onset of memory deficits, mental status change, or psychiatric symptoms, with
at least one of the following: new focal central nervous system findings,
unexplained seizures, CSF pleocytosis, or MRI features suggestive of
encephalitis).18 Testing should likewise be considered in patients 60 years of age
or older with characteristic central nervous system syndromes (including
unexplained faciobrachial dystonic seizures; gait instability, brainstem
dysfunction, and sleep disorder; or subacute confusion, memory loss, and
behavioral change), even if neuroimaging and CSF findings do not suggest an
underlying autoimmune disease.19 In the United States, testing is available via
several commercial laboratories.
As patients age, detection of reversible causes of dementia may be challenged
by the rising prevalence of more typical neurodegenerative dementing illnesses,
including primary progressive aphasia20 and Creutzfeldt-Jakob disease (CJD)
(CASE 11-2).21 In such situations, the astute clinician is advised to weigh all
available evidence in pursuit of the most accurate and appropriate diagnosis.
When diagnostic uncertainty persists, additional disease-specific biomarkers
may help to clarify the diagnosis (eg, CJD-specific biomarkers22–25). In a similar
fashion, empiric treatment of autoimmune encephalitis may be considered when
appropriate, with close monitoring for a sustained objective response. Many
causes of autoimmune encephalitis are treatment responsive, with long-term
outcomes largely dependent upon early recognition and timely provision of
appropriate immunosuppressant treatments.18,26–28
Red Flag 3: Prominent Fluctuations

Prominent fluctuations can be seen in dementia with Lewy bodies but can
also be a manifestation of reversible dementias, as illustrated in CASE 11-1 and
CASE 11-2. Beyond the reversible dementias highlighted in these cases,
toxic-metabolic disturbances,30 medications,31 untreated sleep disorders
(including obstructive sleep apnea),32 and psychiatric illnesses may all present
with prominent fluctuations in cognition.
Rarer reversible causes of dementia may also warrant consideration when
supported by history and examination, including transient epileptic amnesia.
Transient epileptic amnesia is associated with acute and transient memory
disruptions lasting minutes (typically less than an hour) that are often
accompanied by fluctuations in attention and amnesia.33 Although the
symptomatic expression may lead to an initial diagnosis of transient global
amnesia, the frequency of attacks (recurrent attacks occurring a median of 12
times per year) and brief duration (median duration 30 to 60 minutes)
commonly distinguish patients with transient epileptic amnesia.34,35 Also unique
to transient epileptic amnesia, patients may experience unusual forms of
interictal memory impairment, including accelerated loss of newly acquired
memories over days to weeks despite normal retention at standard (ie, about
238 FEBRUARY 2019

30-minute) intervals (sometimes called accelerated long-term forgetting),36 and KEY POINTS
autobiographical amnesia.37 The most important indicators to the epileptic origin
● Autoantibody testing
of acute memory impairment are the frequency of occurrence and the short should be considered in all
duration of the attacks.38 Transitory sleep states remain a high-risk period for patients meeting criteria for
seizures39; accordingly, a history of rhythmic nocturnal movements (not possible autoimmune
suggestive of dream enactment behaviors) or tongue biting, particularly encephalitis and in patients
60 years of age or older with
following sleep onset or waking, should prompt consideration of an epileptic
characteristic central
etiology. EEG may be helpful in establishing the diagnosis of transient epileptic nervous system syndromes,
amnesia, with epileptiform abnormalities or nonspecific focal slow waves detected even if neuroimaging and
in many affected patients.35 However, a normal EEG does not exclude the diagnosis. CSF findings do not suggest
an underlying autoimmune
In such cases, prolonged EEG may increase the diagnostic yield (CASE 11-3),
disease.
particularly when sufficient sleep-wake periods are captured. Episodes of
transient epileptic amnesia (ie, seizures) usually respond promptly to treatment ● Toxic-metabolic
with drugs used for the treatment of focal epilepsies, although interictal disturbances, medications,
impairment may persist.33,35,38 untreated sleep disorders
(including obstructive sleep
apnea), and psychiatric
Red Flag 4: High-risk Exposures illnesses may all present
Careful screening for high-risk medications (including over-the-counter with prominent fluctuations
medications31), drugs, and toxins is imperative when making a new diagnosis in cognition.
of dementia. Narcotic, benzodiazepine, and anticholinergic medications are
● Transient epileptic
common precipitants of cognitive decline. Patients with other active health amnesia is associated with
issues may be particularly susceptible to the cognition-impairing effects of acute and transient memory
medications. Anticholinergic medications may be especially problematic in disruptions lasting minutes
(typically less than an hour)
patients with AD-associated degeneration of acetylcholine-producing basal
that are often accompanied
forebrain cells (CASE 11-4).41 Anticholinergic medications may even contribute by fluctuations in attention.
to the progression of neurodegenerative pathology, raising concerns about their
continued use in at-risk patient populations.42 ● Anticholinergic
Excessive alcohol consumption represents another prevalent high-risk medications may be
especially problematic in
exposure, with an established relationship with malnutrition in general and patients with Alzheimer
thiamine (ie, vitamin B1) deficiency in particular, leading to Wernicke disease–associated
encephalopathy. Accordingly, patients with an active or recent history of alcohol degeneration of
abuse should be considered at risk for the acute and chronic sequelae of excessive acetylcholine-producing
basal forebrain cells.
consumption. Thiamine is an essential vitamin critical to glucose metabolism
and, by extension, brain function. Without thiamine, glucose is metabolized ● If promptly recognized,
through less efficient anaerobic pathways, leading to acidosis of periventricular the life-threatening effects
structures (ie, thalami, mammillary bodies, ocular motor nuclei, cerebellar of thiamine deficiency may
be counteracted by
vermis) and to the cardinal manifestations of Wernicke encephalopathy: altered
administration of high doses
mental status (eg, confusion, encephalopathy), ocular abnormalities (eg, of parenteral thiamine.
nystagmus, ophthalmoplegia), and cerebellar dysfunction (eg, gait disturbance,
ataxia).43–46 If promptly recognized, the life-threatening effects of thiamine ● The high potential for
deficiency may be counteracted by administration of high doses of parenteral response to appropriate
treatment, high cost of
thiamine (CASE 11-5).47,48 It is especially critical that thiamine be provided before delayed diagnosis, and low
refeeding or parenteral administration of glucose-containing substances, as risk of complications
carbohydrate loading may increase thiamine utilization, provoking or associated with parenteral
exacerbating clinical manifestations of Wernicke encephalopathy.49 If thiamine supplementation
justify expedited treatment
overlooked, the consequences of thiamine deficiency may become irreversible, in all patients with possible
leading to death or severe cognitive impairment (ie, Korsakoff syndrome).43,50 nutritional deficiency and
The high potential for response to appropriate treatment, high cost of features consistent with
delayed diagnosis, and low risk of complications associated with parenteral Wernicke encephalopathy.
thiamine supplementation justify expedited treatment in all patients with

CASE 11-2 A 48-year-old woman with a history of degenerative disk disease causing
chronic back pain and remote menometrorrhagia (managed with
hysterectomy and bilateral salpingo-oophorectomy), presented with
gradual-onset progressive word-finding difficulty. Despite her
symptoms, she continued to maintain function at home, including bill
paying, home maintenance, and cooking. Two months after symptom
onset, she reported “not feeling well,” with unexplained “anxiety and
worry” and new frontal headaches. Her husband noted increasing
paraphasic errors, with intermittent confusion of word meaning and
object use. Three months after the first symptoms appeared, her level
of consciousness began to fluctuate, with periods of profound
disorientation. One morning, her husband found her unable to speak,
necessitating emergent assessment and admission to her local hospital
under her primary care physician. At that time, extensive serologic testing
was normal. Brain MRI demonstrated normal parenchyma, with
extracranial findings suggestive of sinusitis. Routine CSF studies
confirmed a lymphocytic pleocytosis (20 nucleated cells/mm3), without
evidence of viral or bacterial infection. Her primary care physician
diagnosed the patient with chronic sinusitis, despite the absence of
typical symptoms or signs attributable to sinusitis. Subsequently she was
discharged home on oral antibiotics and a prednisone taper (40 mg/d,
tapering over several weeks).
Two weeks following discharge, she had resumed many of her
activities. Her headaches, anxiety, and mood symptoms had improved.
The word-finding difficulties persisted but were less bothersome.
Unfortunately, 3 months later (6 months from symptom onset), she
experienced new-onset dysarthria and right-hand clumsiness. She began
to forget to take her medications and pay the bills. She lost the ability to
write checks, appearing as though she had forgotten how to hold a pen.
She presented to the emergency department of an academic hospital
and was promptly admitted to the neurology service. Comprehension
was intact at the time of admission, with impaired fluency and mild
dysarthria. Her speech was agrammatic, with frequent phonemic
paraphasias, and repetition was impaired. Cranial nerves were normal.
Mild pyramidal pattern weakness was evident in the right upper
extremity, with slowing of rapid alternating movements and pronator
drift. Primary sensation was normal; however, she was unable to identify
a ring when placed in her right hand (astereognosis). There was mild
ideomotor apraxia in her right hand. She had no ataxia, gait imbalance, or
involuntary movements. Bedside cognitive testing confirmed deficits in
short-term memory (4/10 recall of a 10-word list after 5-minute delay),
verbal fluency (impaired animal naming), and performance on speeded
tasks (eg, unable to complete Trail Making Test Part B in the 180 seconds
allotted).
240 FEBRUARY 2019

Diagnostic tests were repeated, including brain MRI, and revealed
increased T2 signal within the cortical ribbon of the left hemisphere, with
associated diffusion restriction in a pattern suggestive of possible
sporadic Creutzfeldt-Jakob disease (CJD) (FIGURE 11-2).29 CSF studies again
showed evidence of inflammation, with 35 nucleated cells/mm3 (87%
lymphocytes) and 10 CSF-specific oligoclonal bands. Testing for
disease-associated autoantibodies was performed in blood and CSF
(autoimmune encephalitis panel). IgG autoantibodies against central
N-methyl-D-aspartate
(NMDA) receptors were
identified in the CSF
(titer of 1:32), establishing
the diagnosis of NMDA
receptor encephalitis.
No tumor was identified
on whole-body
fludeoxyglucose positron
emission tomography
(FDG-PET).
Pulse methylprednisolone
(250 mg IV 4 times a day FIGURE 11-2
Imaging of the patient in CASE 11-2 with progressive
for 5 days) and IV aphasia and increasing confusion. A, Axial
immunoglobulin (IVIg; 2 g/kg fluid-attenuated inversion recovery (FLAIR) MRI
divided over 5 days) were shows increased signal throughout the cortical
administered, with an excellent ribbon of the left frontal and parietal areas
(arrows) associated with mild cortical edema. B,
response. The patient was Axial diffusion-weighted MRI shows diffusion
discharged home following restriction corresponding to the areas of
completion of her treatment. increased FLAIR signal (arrows).
This patient presented with progressive expressive aphasia and right-sided COMMENT
apraxia and astereognosis, implicating left-sided cortical dysfunction. The
brain MRI demonstrated corresponding T2-hyperintense changes within
the cortical ribbon, concerning for sporadic CJD. While primary progressive
aphasia and CJD may manifest in the fifth decade of life, other etiologies,
including autoimmune encephalitis, are more common in this age group and
better explain the overall presentation and findings (including CSF
leukocytosis) in this case. Ultimately, detection of CSF NMDA receptor IgG
autoantibodies confirmed the clinical diagnosis of NMDA receptor
encephalitis and ensured timely provision of appropriate
immunomodulatory treatments. Two months later, she had resumed all her
normal daily activities, with residual symptoms of mild difficulties with
verbal articulation. Five months later, she was cognitively normal, with
improved performance on cognitive testing.

possible nutritional deficiency and features consistent with Wernicke

encephalopathy.47,48
Red Flag 5: High-risk Behaviors (Past and Present)

Before 2001, testing for neurosyphilis was routinely recommended in patients
with a new diagnosis of dementia, recognizing the potential for latent infection
to manifest with reversible cognitive impairment.51 The recommendation not
to routinely screen for syphilis in more recent guidelines acknowledges the
CASE 11-3 A 59-year-old man with hypertension and coronary artery disease
presented with a 2-year history of intermittent forgetfulness and
inattentiveness, culminating in lapses in bill paying, occasional
way-finding difficulty, and job loss. The patient’s wife affirmed the
inconsistent nature of symptoms, with no identified triggers or
exacerbating/alleviating factors. The patient had no symptoms of
excessive daytime sleepiness, changes in personality, or low mood.
Medications were limited to an antiplatelet drug, a statin, and an
antihypertensive agent.
Neurologic examination and performance on bedside cognitive testing
(Mini-Mental State Examination [MMSE]40 score of 30) were normal.
Serum vitamin B12 and thyroid function tests were normal. Brain MRI
confirmed mild global atrophy, with associated periventricular T2
hyperintensity and a chronic infarct within the right corona radiata
(FIGURE 11-3A).
One year later, he reported progression of forgetfulness with
increasing geographic disorientation, word-finding difficulty, and
difficulty operating devices and appliances (eg, dialing the phone,
programming the microwave). His wife described two distinct episodes
associated with confusion (blank staring, decreased responsiveness) and
incoherent speech that lasted 5 minutes without associated motor
abnormalities. Neurologic examination was again normal. Performance
on the MMSE declined (28/30) but remained within the normal range.
Given the progression of deficits, he was diagnosed with very mild
dementia and started on donepezil. A routine EEG was normal.
His cognitive symptoms continued over successive years, with short-
term memory loss, word-finding difficulty, and way-finding difficulty
beginning to interfere with activities of daily living. His wife described him
as an unsafe driver who frequently missed red lights and stop signs. Driving
cessation was recommended following an at-fault accident. Seven years
following initial symptom onset (at age 65), he returned to clinic for the
assessment of recurrent “spells,” characterized by abrupt-onset memory
loss and confusion, now lasting 20 to 30 minutes each and occurring
several times per week. His wife also reported he had severe nightmares,
with rhythmic movements while sleeping and tongue biting. Neurologic
examination was again normal, with comparable performance on the
MMSE (27/30). Brain MRI was unchanged. Prolonged video-EEG
242 FEBRUARY 2019

decreasing prevalence of this disease in patients without traditional risk
factors.1 Syphilis testing should still be considered in patients with dementia from
endemic regions within and beyond the United States52 and in those with a
past or present history of high-risk behaviors, including individuals with
multiple sexual partners, men who have sex with men, IV drug users, and
persons with other sexually transmitted infections. Even a remote history of
high-risk behaviors may place a patient at risk and justify further evaluation
(CASE 11-6).
demonstrated occasional epileptiform potentials over the right temporal

leads (FIGURE 11-3B).
FIGURE 11-3
Imaging of the patient in CASE 11-3 with intermittent memory problems. A, Axial
fluid-attenuated inversion recovery (FLAIR) MRI demonstrates mild diffuse volume loss with
increased periventricular hyperintense signal (bottom arrow) and a well-demarcated area of
established infarction (top arrow), consistent with small vessel ischemic disease.
B, Spike-and-wave discharges were captured during a routine awake EEG (bipolar montage;
70-Hz high-frequency filter, 1.6-Hz low-frequency filter), with phase reversal over the right
temporal leads (arrow), suggestive of a focal epileptiform discharge. Bar graph (lower right)
indicates recording amplitude and time scales.
The detection of prominent fluctuations in symptoms and performance on COMMENT

cognitive tests in this case raise the possibility of a potentially reversible
cause of dementia. Although initial EEG did not show epileptiform
potentials, extended monitoring confirmed intermittent epileptiform
discharges, supporting the diagnosis of transient epileptic amnesia and
enabling effective treatment. Levetiracetam was titrated to 1000 mg orally
2 times a day, with complete resolution of spells and improvement in cognition.

An immunocompromised state, whether inherited or acquired, represents

an additional high-risk “exposure,” increasing the chances of reactivation of
latent infection in previously exposed patients. Accordingly, testing for
neurosyphilis (along with other opportunistic infections) should be performed
in any patient with dementia with a new or established diagnosis of
human immunodeficiency virus (HIV) and in individuals on chronic
immunosuppressant therapies. Neuroimaging findings consistent with cerebral
gummas and CSF profiles showing unexplained mononuclear pleocytosis,
CASE 11-4 A 71-year-old woman returned to clinic for follow-up of logopenic

variant primary progressive aphasia. Five years earlier, she had presented
with gradually progressive difficulties with verbal expression,
necessitating retirement from her position as an administrative assistant.
One year ago, she had reported very mild short-term memory deficits.
She scored 27/30 on the Mini-Mental State Examination (MMSE),40 with
3/3 delayed verbal recall. An amyloid positron emission tomography (PET)
scan (completed as part of a study protocol) demonstrated diffuse
cortical tracer retention, supporting a diagnosis of Alzheimer disease as
the cause of her dementia. She was maintained on donepezil (10 mg orally
every morning) and escitalopram (5 mg orally every morning) for low
mood, with appropriate management of comorbid vascular risk factors. In
the 6 months preceding her reassessment, the patient’s husband
reported a precipitous decline in her verbal output, with worsening
memory deficits and gait instability leading to multiple falls.
Neurologic examination revealed mild length-dependent sensory loss
in the lower extremities and a broad-based unsteady gait, without focal
deficits. She scored 23/30 on the MMSE with 1/3 delayed verbal recall,
impaired repetition, and difficulty spelling the word world backward. A
comprehensive review of medications uncovered prescriptions for
amitriptyline (for neuropathic pain) and oxybutynin (for urge
incontinence), both initiated within the past 6 months. Both
anticholinergic medications were stopped. Gabapentin was prescribed
for the management of mild neuropathic pain, and the patient was
referred to urology for intravesicular botulinum toxin injections to
manage urge incontinence.
COMMENT The patient in this case had biomarker (amyloid PET) evidence supportive of
cerebral amyloidosis and a corresponding clinical diagnosis of logopenic
variant primary progressive aphasia due to Alzheimer disease. Despite the
diagnosis of an irreversible neurodegenerative dementia, additional
changes in clinical status warranted assessment for potential reversible
contributors to cognitive decline, including anticholinergic medications.
One month following cessation of the offending medications, the patient’s
gait, postural stability, performance on cognitive testing (MMSE score of
27/30, with 3/3 on delayed verbal recall), and overall quality of life had
substantially improved.
244 FEBRUARY 2019

elevated protein, and elevated oligoclonal bands should prompt consideration KEY POINTS
of neurosyphilis.54,55 Further screening for other sexually transmitted or
● Syphilis testing should be
opportunistic infections (eg, HIV, cryptococcal meningitis, and JC virus) considered in patients with
should also be considered in any patient with an active or past history of dementia from endemic
neurosyphilis. regions within and beyond
the United States and in
those with a past or present
Red Flag 6: Unexplained/Unanticipated Findings on the history of high-risk
Neurologic Examination behaviors.
The insidious onset and slow progression of short-term memory deficits in
● A thorough history,
an older patient most commonly connote a diagnosis of symptomatic AD.56 including screening for past
However, the neurologic examination should be largely normal in patients or present high-risk
with amnestic AD, owing to early sparing of homotopic (motor/sensory) behaviors, is imperative
cortices by AD neuropathologic change.57 By extension, therefore, the when investigating patients
with unusual presentations
discovery of abnormal neurologic findings—whether subtle or pronounced—
of cognitive impairment.
warrants consideration of atypical causes of dementia, including reversible
causes. ● The discovery of
The detection of progressive memory loss, gait apraxia, and urinary abnormal neurologic
findings—whether subtle or
incontinence may be associated with a diagnosis of normal pressure
pronounced—warrants
hydrocephalus (NPH), justifying further evaluation. It is important to note, consideration of atypical
however, that the detection of the triad of features is neither required nor causes of dementia,
sufficient to establish the diagnosis of NPH; NPH may occur in patients with including reversible causes.
one or two features of the triad, or findings associated with NPH may arise ● Detection of features of
secondary to any condition leading to stretching/damage of the frontal the triad of progressive
periventricular white matter fibers (regardless of intraventricular pressure). memory loss, gait apraxia,
Accordingly, detection of features of the triad warrants screening for and urinary incontinence
warrants screening for
secondary causes of NPH (eg, history of subarachnoid hemorrhage, traumatic causes of normal pressure
brain injury, or meningitis) in addition to high-pressure hydrocephalus hydrocephalus and high-
(eg, ventricular outflow obstruction, ventricular entrapment) and other pressure hydrocephalus.
relevant etiologies (eg, dorsal midbrain or thalamic lesions, strategic
● Performance on cognitive
infarctions, moderate to severe periventricular leukoencephalopathy testing that is substantially
owing to small vessel ischemia). For more information, refer to the article better or worse than
“Normal Pressure Hydrocephalus” by Neill R. Graff-Radford, MBBCH, expected from the clinical
FRCP, FAAN, and David T. Jones, MD,58 in this issue of Continuum. history should trigger
investigations for reversible
Other abnormalities that would necessitate an urgent evaluation include
causes of dementia.
localizing signs implicating an underlying focal lesion, whether vascular,
neoplastic, demyelinating/inflammatory, or other (eg, subdural hematoma). ● Sleep dysfunction,
attributable to obstructive
sleep apnea or other causes,
Red Flag 7: Incongruent Cognitive Testing is increasingly identified as a
Performance on cognitive testing that is substantially better or worse than contributor to cognitive
expected from the clinical history should trigger investigations for reversible impairment.
causes of dementia. Initial screening should focus on detection of conditions
known to compromise encoding and recall of learned information, resulting in
inconsistent or widely fluctuating performance on tasks or subjective symptoms.
Special attention should be paid to screening for mood disorders, sleep
dysfunction, medication use (including medications reviewed in the section
Red Flag 4: High-risk Exposures), and sensory impairment (especially hearing
loss), owing to the high prevalence of each of these disorders, their potential to
interfere or disrupt sustained attention, and their potential treatment
responsiveness.

Sleep dysfunction, attributable to obstructive sleep apnea or other causes,

is increasingly identified as a contributor to cognitive impairment. Recent
studies even suggest that sleep disruption may affect amyloid homeostasis,
with implications for the development of AD.59,60 These associations
emphasize the importance of routinely evaluating patients with cognitive
symptoms for comorbid sleep pathology. Particular attention should be
paid to patients with physical attributes that place them at the highest risk
of clinically significant obstructive sleep pathology, including increased
neck circumference (>40 cm), body mass index greater than 35 kg/m2,
CASE 11-5 A 47-year-old woman presented to the emergency department with

new seizures and altered mental status. Her past medical history was
notable for excessive daily alcohol consumption and poor nutritional
status, with an 18-kg (40-lb) weight loss over the preceding year. Her
family affirmed a 3-month history of increasing forgetfulness, resulting in
missed appointments and an inability to manage bill paying. The week
before her presentation, she had enrolled in a medically supervised
alcohol cessation program, initiated chlordiazepoxide and disulfiram,
and abruptly stopped consuming alcohol. On the day of admission, she
was involved in a minor motor vehicle accident. Immediately following
the accident, she had a witnessed loss of consciousness, with
convulsions. Emergency medical services were called, and she was
transferred to the hospital.
On arrival, the patient was alert and oriented, and her general physical
examination was normal. Her speech was pressured and tangential.
Neurologic examination showed bilateral end-gaze nystagmus, with
hypometric saccades in all directions. Motor bulk, tone, and power were
normal. Reflexes were normal, and toes were downgoing. Ataxia was
noted on finger-to-nose and heel-to-shin testing. Gait was broad-based
and unsteady. Bedside cognitive testing confirmed impaired orientation
(oriented to person only), attention (eg, unable to complete Trail Making
Test Part A in the 180 seconds allotted), and short-term recall (2/10 recall
of a 10-word list after 5-minute delay). Clock drawing was markedly
impaired (FIGURE 11-4A). Standard hematologic and electrolyte measures
were in the normal range, with the exception of low-normal serum
sodium (134 mmol/L; normal >135 mmol/L). Blood alcohol level was
undetectable. A noncontrast brain CT demonstrated diffuse atrophy
(involving the cerebellum) without acute findings. CSF was acellular, with
normal protein and glucose levels.
The patient was admitted to the neurology service with a presumptive
diagnosis of Wernicke encephalopathy and alcohol withdrawal seizures.
High-dose thiamine (500 mg IV 3 times a day) was started in the
emergency department and continued on admission. Brain MRI was
completed the following day (FIGURE 11-4B) and showed increased signal
within the medial thalami bilaterally, consistent with the clinical diagnosis
of Wernicke encephalopathy.
246 FEBRUARY 2019

retrognathia, and an “apple-shaped” body habitus (a marker of central
obesity).61–63 In these patients, it may be reasonable to consider referral for
sleep consultation and polysomnography (or other formal measures of sleep
function), particularly with a history of witnessed snoring or apneas
(CASE 11-7) or symptoms of excessive daytime sleepiness, recognizing that the
clinical manifestations of obstructive sleep apnea are all too often
underreported.68
Behavioral variant frontotemporal dementia (bvFTD) represents an
important irreversible cause of incongruent findings on history and test
FIGURE 11-4
Clock drawing and brain MRI of the patient in CASE 11-5 presenting with seizure and abrupt
decline in mental status. A, Patient rendering of a clock indicating the time “20 past 8.” B,
Fluid-attenuated inversion recovery (FLAIR) MRI shows increased signal within the bilateral
medial thalami (arrow), supporting the clinical diagnosis of Wernicke encephalopathy due to
vitamin B1 deficiency.
Wernicke encephalopathy is a medical emergency warranting prompt COMMENT

treatment with high doses of parenteral thiamine while investigating for
other causes of impairment. Following appropriate thiamine repletion,
neurologic symptoms and signs improved in this patient. She also had no
seizure recurrence and was discharged to home with recommendations to
continue counseling for alcohol cessation. One month later, cognition had
markedly improved.

performance that is worthy of special mention. Disparity in reported symptoms

and objective performance on cognitive testing is common in patients with
bvFTD, owing to the early loss of social judgment, empathy, and respect of
social norms, with relative preservation of memory and visuospatial function.
Reasonably sensitive and specific diagnostic criteria for bvFTD are available to
assist with diagnosis in the outpatient environment and should be applied
to relevant patients.69
CONCLUSION
The standard dementia assessment emphasizes routine screening for common
medical comorbidities or less common structural causes that may necessitate
further evaluation or management; it is meant to be applied to routine
CASE 11-6 A 54-year-old businessman with essential hypertension and psoriatic

arthritis managed with infliximab developed new holocephalic
headaches while vacationing in the Caribbean. Shortly after returning
to the United States, he presented to the emergency department of
his local hospital with sudden-onset alexia and aphasia. Stroke
protocol head CT was normal, and his deficits improved before initiation
of acute stroke therapies. The patient was admitted for further
evaluation and management. Brain MRI, completed the next day,
demonstrated nonspecific T2 hyperintensity in the left frontal
parafalcine gyrus, without restricted diffusion (consistent with
chronic sequelae of small vessel disease). Erythrocyte sedimentation
rate was elevated at 73 mm/h, although serum markers of connective
tissue disease were normal. Subsequent diagnostic lumbar puncture
revealed increased opening pressure (33 cm H2O), with 104 nucleated
cells/mm3 (69% lymphocytes, 31% monocytes). CSF protein was
elevated (91 mg/dL); CSF glucose was normal. Four CSF-specific
oligoclonal bands were detected, with an elevated IgG synthesis
rate. Bacterial, fungal, and mycoplasma cultures; Herpesviridae
polymerase chain reaction (PCR); and testing for West Nile virus and
human immunodeficiency virus (HIV) antibodies were negative.
Histiocytes and polyclonal atypical lymphocytes (T-cell predominant)
were identified on CSF cytology. The patient was diagnosed
with aseptic meningitis, infliximab was stopped, and he was
discharged home.
Mild word-finding difficulty persisted over months, with interval
development of short-term memory impairment, which interfered with
his ability to run his business. He also reported drenching night sweats,
associated with a 6.8-kg (15-lb) weight loss. Subsequently, he was
referred to a tertiary care center for further evaluation. Neurologic
examination at the time of assessment was normal, except for
impaired verbal fluency with rare phonemic paraphasic errors.
Global cognitive function was assessed using the Montreal
248 FEBRUARY 2019

patients with probable neurodegenerative dementing illnesses. Reversible
dementias are rare in clinical practice, with causes that span the gamut of
neurologic disease. As a result, the clinician must prioritize detection of rare
reversible causes of dementia while efficiently evaluating and treating patients
with more typical (neurodegenerative) causes of dementia. The detection of red
flags on history, examination, or investigations should trigger additional
investigations, as appropriate. Neuroimaging (favoring MRI) is critically
important in many cases, with additional consideration of EEG, CSF analyses,
and other measures when atypical features necessitate further investigation. The
continued development of disease-specific biomarkers may improve detection of
rare patients with potentially reversible dementias. However, no checklist or
diagnostic protocol is expected to outperform the neurologist who remains
committed to identifying and treating patients with reversible dementia.
Cognitive Assessment (MoCA), with points lost for impaired fluency,

repetition, and delayed recall (3/5). His final score of 22/30 was
consistent with cognitive impairment.53
Relevant investigations were repeated, including brain MRI (which
was unchanged) and a diagnostic lumbar puncture. CSF demonstrated
persistent leukocytosis (29 nucleated cells/mm3) and elevated protein
(89 mg/dL), CSF-specific oligoclonal bands (13), and elevated IgG
synthesis rate. Venereal Disease Research Laboratory (VDRL) testing,
not performed on his initial evaluation, was reactive (titer of 1:8); serum
rapid plasmin reagin (RPR; titer of 1:1024) and treponemal antibodies were
similarly reactive.
The patient was diagnosed with neurosyphilis. Urgent treatment
with IV penicillin G (4 million units every 4 hours) for 14 days was
provided, followed by IM penicillin G (2.4 million units in one dose).
The patient affirmed his commitment to his wife but did acknowledge
having another partner over a decade ago. He denied other potential
exposures.
A thorough history, including screening for past or present high-risk COMMENT

behaviors, is imperative when investigating patients with unusual
presentations of cognitive impairment. As this case illustrates, dementia
may emerge as a late complication of Treponema pallidum infection, with
the potential to respond to appropriate treatment with penicillin. Four
weeks following treatment, this patient’s word-finding difficulties had
completely resolved. His family reported that he was “brighter” and more
engaged. His follow-up plans included repeat CSF analyses and VDRL
testing 6 months following initial treatment.

CASE 11-7 A 56-year-old man with a paternal history of early-onset Alzheimer

disease dementia (age at onset 55 years) was referred for evaluation of
short-term memory deficits. His past medical history was notable for
depression (managed with a selective serotonin reuptake inhibitor
[SSRI]), type 2 diabetes mellitus, dyslipidemia, hypertension, and
obesity. The patient endorsed difficulty recalling his schedule, resulting
in several missed appointments over the past 6 months. He also
acknowledged several missed bill payments over the preceding year and
frequent forgetfulness of work-related passwords. Despite these
difficulties, he continued to work full time and to meet his employer’s
expectations. Review of systems was notable for symptoms of low mood
and poor sleep, ongoing for 2 years, which were associated with mild
headaches on awakening and excessive daytime sleepiness. His wife
described frequent snoring and nocturnal apneas.
His performance on cognitive testing suggested moderate severity
impairment in all domains (episodic memory, language, processing
speed), with a score of 20/30 on the Mini-Mental State Examination
(MMSE); the remainder of his neurologic examination was normal. On
further screening, he indicated a positive response to 6/8 questions on an
abbreviated version of the Geriatric Depression Scale,64 consistent with
active depression, and 18/22 questions on the Epworth Sleepiness
Scale,65 indicating abnormally increased sleepiness. The dose of his SSRI
was increased, and he was referred for an outpatient sleep assessment,
including polysomnography.
Overnight polysomnography with standard respiratory monitoring
confirmed an apnea-hypopnea index of 61 per hour of sleep, associated
with desaturations to an SaO2 of 83% and 5.8 respiratory effort–related
arousals per hour of sleep, meeting criteria for severe obstructive sleep
apnea.66,67 Continuous positive airway pressure of 12 cm H2O effectively
eliminated apneas, with the appearance of consolidated sleep and an
apnea-hypopnea index of 0.
COMMENT This patient’s cognitive symptoms completely resolved with sustained use
of nocturnal continuous positive airway pressure, exemplifying the
importance of screening for and treating sleep pathology in at-risk patients
with cognitive symptoms. Six months later, he reported overall
improvement in sleep quality and mood symptoms, with complete
resolution of cognitive symptoms.
250 FEBRUARY 2019

ACKNOWLEDGMENTS
The author would like to thank the many patients whose stories and experiences
inform and elevate his clinical practice as well as Dr Jonathan Graff-Radford
(Mayo Clinic; Rochester, MN) and Drs Robert C Bucelli, Ed Hogan, and John C
Morris (Washington University in St. Louis; Saint Louis, MO), whose acumen,
clinical insights, and expertise made this manuscript possible.
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doi:10.1093/brain/awx148.

MEDICOLEGAL ISSUES

Prescribing
ONLINE
Antipsychotic
Medications to Patients
With Dementia: Boxed
Warnings and Mitigation
of Legal Liability
By Rachel V. Rose, JD, MBA; Joseph S. Kass, MD, JD, FAAN
ABSTRACT
CITE AS:
Clinicians caring for patients with dementia are often at a loss when trying
CONTINUUM (MINNEAP MINN) to manage dementia-related behavioral disturbances pharmacologically
2019;25(1, DEMENTIA):254–259.
because no drugs have been proven effective for this indication.
Antipsychotics are commonly prescribed for these patients despite a US
Dr Joseph S. Kass, Baylor College Food and Drug Administration (FDA)–mandated boxed warning about the
of Medicine, One Baylor Plaza heightened risk of death in patients with dementia treated with
M-210, Houston, TX 77030,
kass@bcm.edu.
antipsychotic drugs. This boxed warning does not prevent clinicians from
prescribing antipsychotics to patients with dementia. However, it serves as
RELATIONSHIP DISCLOSURE: a heightened warning to prescribers to include the specific risks
Ms Rose serves on the editorial
board of BC Advantage and mentioned in the boxed warning in their discussion of risks and benefits of
receives book royalties from the proposed therapy with their patients or their patients’ health care
the American Bar Association. proxy and to document this informed consent conversation in the medical
Dr Kass serves as associate
editor of medicolegal issues record. By documenting that the risks of the treatment, including those the
for Continuum, as an associate FDA has deemed serious enough to include in a boxed warning, were
editor for Continuum Audio,
as a neurology section editor
discussed and accepted by the medical decision maker, the prescriber
of Ferri’s Clinical Advisor for also reduces the risk of liability should an adverse event ensue.
Elsevier, and as co-editor of
Neurology Secrets, Sixth Edition.
Dr Kass has received personal
compensation for CME lectures
from Pri-Med Medical Group and
has received personal CASE
compensation as a medicolegal Note: This is a hypothetical case.
consultant in legal cases
involving criminal proceedings,
A 78-year-old woman with a 6-year history of Alzheimer disease
malpractice, and personal injury. presented with frequent episodes of agitation. She lived with her adult
daughter, who cared for her with the help of a live-in home health aide.
UNLABELED USE OF
When the patient was first diagnosed with Alzheimer disease, she made her
USE DISCLOSURE: daughter promise never to put her into a nursing home. The daughter was
Ms Rose and Dr Kass report no committed to fulfilling her promise to her mother but had increasingly
disclosure.
struggled to safely care for her mother over the previous few months as her
© 2019 American Academy mother had developed behavioral symptoms of dementia, characterized
of Neurology. by a combination of agitation, visual hallucinations, paranoid delusions,
254 FEBRUARY 2019

apathy, and nighttime wandering. Initially, the patient’s neurologist
recommended nonpharmacologic interventions for managing her
symptoms, such as memory training, social stimulation, and physical
exercise.1 However, as her symptoms worsened, she became less and less
amenable to these interventions. Her daughter therefore brought her
mother for reevaluation earlier than anticipated and expressed her
frustration and concern over her mother’s safety. The patient’s neurologist
recommended quetiapine, an atypical antipsychotic commonly prescribed
for patients experiencing behavioral symptoms of dementia, and
instructed the daughter on how to titrate the dose to the intended clinical
effect.
DISCUSSION
T
he US Food and Drug Administration (FDA) has approved
quetiapine, whether in its immediate-release or extended-release
formulation, to treat schizophrenia and bipolar disorder in both adults
and adolescents and in its extended release form to treat major
depressive disorder in adults as an adjunct to antidepressant
medication.2 However, neither quetiapine nor any other antipsychotic is FDA
approved to treat any of the behavioral symptoms of dementia. In fact, the
prescriber information found with all antipsychotics, including quetiapine,
contains a boxed warning about the potential risks of using the medication in
elderly patients with dementia-related psychosis, including an increased risk
of death.2
In addition to the boxed warning, the FDA-mandated quetiapine label
mentions two additional significant side effects with heightened risk in patients
with Alzheimer disease: dysphagia, which can lead to aspiration pneumonia,
and seizures.2
Neurologists have few pharmacologic options in their armamentarium for
patients with behavioral symptoms of dementia, so they are often faced with the
dilemma of whether to prescribe a medication that has no better than anecdotal
evidence of efficacy but has enough evidence of harm to warrant an FDA
boxed warning or to leave the patient and caregivers without any pharmacologic
intervention despite the failure of nonpharmacologic interventions.
This case raises two interrelated issues:
u What are the legal risks for prescribing a pharmacologic therapy with an FDA boxed
warning, especially when the indication is off-label?
u How can legal risk be mitigated in situations in which the available therapy carries an FDA
safety warning?
Prescribing Risks When a Boxed Warning Is Present

The FDA requires a drug’s package insert to contain safety information for
prescribers. A drug package insert, which is found on either the FDA’s or the
manufacturer’s website or in the Physicians’ Desk Reference, is part of the
FDA-approved labeling that details information about the drug (eg, chemical
composition, indications, dosages, warnings, and drug interactions).3
A boxed warning, previously called a black box warning, is a special type of
safety information that is found on a prescription drug’s package insert

BOXED WARNINGS AND MITIGATION OF LIABILITY
specifically to call attention to serious or life-threatening risks.4 The FDA

requires a drug to carry a boxed warning under one of three circumstances:
u There is an adverse reaction so serious in proportion to the potential benefit from the
drug (eg, a fatal, life-threatening, or permanently disabling adverse reaction) that it is
essential that it be considered in assessing the risks and benefits of using the drug
OR
u There is a serious adverse reaction that can be prevented or reduced in frequency or
severity by appropriate use of the drug (eg, patient selection, careful monitoring, avoiding
certain concomitant therapy, addition of another drug or managing patients in a
specific manner, avoiding use in a specific clinical situation)
OR
u The FDA approved the drug with restrictions to ensure safe use because the FDA
concluded that the drug can be safely used only if distribution or use is restricted5
Medications with a boxed warning are still considered safe enough to stay
on the US market, but prescribers are asked to weigh the special conditions
prompting the warning against the anticipated benefits when prescribing the
medication. The boxed warning on antipsychotics arises because two of the three
conditions for a boxed warning are met: the potential for serious adverse events
from the medication when used in patients with dementia-related psychosis is
disproportionate to the drug’s evidence of efficacy in this population, and the
overall risk profile of antipsychotics can be reduced if these drugs are not
prescribed to patients with dementia.
Risks associated with medications are often identified through clinical trials,
the FDA Adverse Event Reporting System, and the FDA Office of Surveillance
and Epidemiology, which evaluates postmarket safety information.6 Examples of
warnings include the necessity to weigh potential side effects against the
potential benefit, proper dosing, required monitoring (ie, pregnancy), and
interactions with other drugs.6 Physicians and patients alike are encouraged to
report drug-related adverse events to the FDA Adverse Event Reporting System
by accessing the online public dashboard.7
In the case of antipsychotics prescribed for patients with dementia, physicians
are faced with not only a boxed warning about the increased risk of death but also
two troubling side effects: an increased risk of aspiration pneumonia and an
increased risk of seizures. Additionally, prescribing an antipsychotic to a patient
with dementia is off-label (not an FDA-approved indication). Given the
heightened scrutiny of a boxed warning, physicians may be reasonably
concerned that prescribing an antipsychotic increases their exposure to legal
liability for professional negligence (malpractice), especially since the use of an
antipsychotic in dementia is an off-label use.
The FDA does not restrict the prescribing of off-label drugs, but it does
regulate corporate marketing of a medication for nonapproved indications.8
Despite the restrictions on corporate marketing for off-label indications, off-label
use of medications is extremely common. For example, in 2001, 47% of
anticonvulsant prescriptions were written for off-label indications.8 However,
off-label use may be problematic because it is often not supported by high-
quality evidence, especially in recently FDA-approved medications that have not
been on the market for an extended period of time. Nonetheless, off-label use
makes its way into daily clinical practice for a variety of reasons. Prescribers may
256 FEBRUARY 2019

presume the existence of a drug class effect. They may believe the medication
will help treat different forms of an approved indication or different conditions
sharing either a physiologic connection or symptom overlap with an approved
indication.8 As clinicians lack pharmacologic alternatives in treating patients
with dementia-related psychosis, they have understandably looked to
antipsychotics approved for the treatment of schizophrenia to treat psychotic
symptoms in their patients with dementia. However, when evidence of harm due
to an off-label use accumulates, as occurred with antipsychotic drugs, the FDA
may require drug manufacturers to add warnings related to a common off-label
use to the medication’s label. Yet when off-label use does accumulate evidence of
efficacy, drug manufacturers rarely pursue the costly and risky clinical trials
process required to expand the FDA indication.8
Mitigating Legal Risks Associated With a Boxed Warning

How can legal risk be mitigated when prescribing an off-label medication for
behavioral symptoms of dementia, as in this patient? To understand how
prescription decisions impact potential liability exposure, the basic anatomy
of a professional negligence lawsuit (medical malpractice suit) should be
considered. A plaintiff (either the patient, the patient’s estate, or someone
acting on behalf of a legally incompetent patient) may allege professional
negligence due to a wide variety of physician actions. These actions can include
allegations of a misdiagnosis or a delay in diagnosis, improper treatment,
improper performance of a medical procedure, or even failure to provide
appropriate informed consent. If a neurologist were to face a lawsuit based on
prescribing an antipsychotic for behavioral symptoms of dementia, the likely
allegations would include improper treatment and failure to provide adequate
informed consent.
To find a physician liable of professional negligence, the plaintiff must
establish to the trier of fact (eg, the jury) that the preponderance of the evidence
(“more likely than not” or 51% likely) supports all four of the following
conditions: (1) the physician had a duty, based on the existence of a
patient-physician relationship, to care for the patient at the nationally accepted
standard of care for the physician’s specialty; (2) the physician breached that
duty by failing to provide care at the accepted standard; (3) the physician’s
actions were the cause of the plaintiff’s injury; and (4) the injury resulted in the
plaintiff’s suffering of damages.9–11 Often, the crux of the litigation involves
medical experts from both sides presenting conflicting opinions about whether
the physician’s actions met or failed to meet the nationally accepted standard of
care for the specialty.12 Given how widespread the practice of off-label use is,
writing a prescription for an off-label indication is not in itself evidence of
breaching the standard of care. Prescribing a medication with a boxed warning is
also not in itself evidence of breaching the standard of care, since the medication
is still manufactured and sold for human use. Many reputable expert witnesses
can be found to testify to the widespread use of quetiapine and other
antipsychotics to treat patients with behavioral symptoms of dementia.
However, the physician may be particularly vulnerable to liability depending on
the adequacy of the documented informed consent process.
Although informed consent is typically thought of as the process of signing
forms before an invasive procedure, the informed consent process is, in some
form, actually part of every medical encounter that involves prescribing a

BOXED WARNINGS AND MITIGATION OF LIABILITY
therapeutic intervention, whether or not consent forms are signed. For example,
before prescribing a medication, prescribers typically review the common side
effects or complications of a proposed therapy with patients or their health care
proxies and await concurrence before proceeding with the intervention. Not
every potential risk or side effect must be discussed, but physicians are typically
held to a reasonable patient or reasonable physician standard, depending on the
jurisdiction. A reasonable patient would like to know, and a reasonable physician
would disclose, the most common and the most serious risks associated with the
proposed intervention. Additionally, the more the recommended intervention
veers from evidence-based medicine or the higher the risk of the proposed
intervention, the more detailed should be the discussion and subsequent
documentation of the practitioner’s rationale for recommending the proposed
intervention over lower-risk alternatives. In this case, since the patient’s
neurologist is recommending quetiapine to treat the behavioral symptoms of
dementia despite the boxed warning, she should explicitly inform the patient’s
daughter (the patient’s health care proxy) that the FDA requires a boxed warning
on the quetiapine label and explain the actual contents of that safety warning.
The neurologist should also review the other risks associated with quetiapine
that are not included in the boxed warning, such as the most commonly
experienced side effects, in particular those that may limit limit tolerability or
adherence and, although typically rare, the most serious side effects, including an
appropriate recommendation to seek medical attention should a serious side
effect occur. Next, the neurologist should explain why, in her clinical judgment,
using the quetiapine is still warranted despite the risk of harm and only anecdotal
evidence of efficacy. The neurologist should then ensure that the patient’s
daughter understands risks and benefits of the medication and ask for the
daughter’s explicit verbal consent. The neurologist should also warn the patient’s
daughter about symptoms that should prompt medication discontinuation or the
seeking of emergency medical attention.13 Of course, all these details must be
recorded in the medical record contemporaneously with the discussion and,
should litigation arise, in sufficient detail for a jury to be able to reconstruct the
details of the conversation years after the event.
CONCLUSION
The decision to prescribe quetiapine for this patient with dementia-related
behavioral disturbance is ultimately an issue of medical judgment. Although the
neurologist must decide whether or not to prescribe quetiapine for this patient,
the patient’s daughter must consent to administer this medication to her mother.
To make the best possible decision for her mother, the daughter should
understand the risks and benefits of quetiapine, including the boxed warning, as
well as the neurologist’s rationale for this particular intervention, despite
evidence of serious risk and low-quality evidence of benefit. The neurologist
should also discuss alternative interventions and explain why she believes
quetiapine to be the most appropriate one. This informed consent conversation is
proper medical practice from both an ethical and medicolegal perspective. The
neurologist should document the details of this conversation in the patient’s
medical record and specifically record such details as the discussion of the risks
and benefits of the medication, the rationale for the off-label use of this
medication despite the boxed warning, the alternatives to the proposed
258 FEBRUARY 2019

intervention, and the health care proxy’s verbal consent to administer the
medication as prescribed to the patient.
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Program of the Royal College of Physicians and Surgeons
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Medical Education and Professional Development,
University of Calgary, on April 1, 2017. Refer to the CME 17 A B C D E 37 A B C D E
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(credits are automatically calculated).
For all questions regarding Continuum CME, email 20 A B C D E 40 A B C D E

ContinuumCME@aan.com or call (612) 928-6161.

Postreading
SELF-ASSESSMENT
AND CME
Self-Assessment
and CME Test
By D. Joanne Lynn, MD, FAAN; Allyson R. Zazulia, MD
DEMENTIA
The Continuum Postreading Self-Assessment and CME Test is an integral
part of the issue that is intended to stimulate thought and help participants
assess general understanding of the material presented in this issue. The
Postreading Self-Assessment and CME Test is also approved by the
American Board of Psychiatry and Neurology (ABPN) to meet the Lifelong
Learning (CME), Self-Assessment (SA) (part 2) component for Maintenance
of Certification.
For each item, select the single best response. A tally sheet is provided
with this issue to allow the option of marking answers before entering them
online at continpub.com/CME. Nonsubscribers who have purchased single
back issues should email ContinuumCME@aan.com for instructions to
complete this test online.
US PARTICIPANTS: Upon the completion of the Postreading Self-Assessment

and CME Test and issue evaluation online at continpub.com/CME,
participants may earn up to 20 AMA PRA Category 1 CreditsTM toward
SA-CME. US participants have up to 3 years from the date of publication to
earn SA-CME credits. No SA-CME will be awarded for this issue after
February 28, 2022.
CANADIAN PARTICIPANTS: This program is an Accredited Self-Assessment

Program (Section 3) as defined by the Maintenance of Certification
Program of the Royal College of Physicians and Surgeons of Canada and
approved by the Office of Continuing Medical Education and Professional
Development, University of Calgary, on April 1, 2017. Refer to the CME
tab on ContinuumJournal.com for dates of accreditation. Canadian
participants should visit MAINPORT (mainport.org) to record learning and
outcomes. Canadian participants can claim a maximum of 20 hours (credits
are automatically calculated).

POSTREADING TEST
ARTICLE 1: LATE-ONSET ALZHEIMER DISEASE
1 In what brain region do amyloid-β plaques first appear in patients with

Alzheimer disease dementia?
A diencephalon
B hippocampus
C limbic structures
D neocortex
E striatum
2 Which of the following APOE genotypes is most protective against

late-onset Alzheimer disease?
A ε2/ε2
B ε2/ε4
C ε3/ε3
D ε3/ε4
E ε4/ε4
3 Acetylcholinesterase inhibitors should be used with caution in patients

with Alzheimer disease who have a history of which of the following
comorbidities?
A bradycardia
B constipation
C depression
D glaucoma
E hypertension
4 An 85-year-old man with Alzheimer disease who is being treated with

donepezil and memantine is experiencing anxiety, anger, and aggressive
behavior. If nonpharmacologic interventions are unsuccessful, which of
the following pharmacologic treatments represents first-line therapy
for his behavioral symptoms?
A atypical neuroleptic
B benzodiazepine
C conventional neuroleptic
D selective serotonin reuptake inhibitor (SSRI)
E tricyclic antidepressant
264 FEBRUARY 2019

ARTICLE 2: EARLY-ONSET ALZHEIMER DISEASE AND ITS VARIANTS
5 Which of the following is the most common cause of neurodegenerative

dementia with onset before the age of 65 years?
A autoimmune encephalitis
B cerebrovascular disease
C early-onset Alzheimer disease
D frontotemporal dementia
E Lewy body disease
6 Which of the following is more characteristic of early-onset Alzheimer

disease than of late-onset Alzheimer disease?
A higher rate of antecedent traumatic brain injury

B higher rate of diabetes mellitus
C lower age-controlled mortality rate
D lower genetic predisposition
E shorter duration of disease before diagnosis
7 Patients with early-onset Alzheimer disease will typically perform better

in which of the following cognitive functions compared with similarly
impaired patients with late-onset Alzheimer disease?
A attention
B executive function
C ideomotor praxis
D semantic memory
E visuospatial skills
8 Which of the following is the most common phenotypic variant of

early-onset Alzheimer disease?
A acalculia variant
B corticobasal syndrome
C frontal/executive variant
D logopenic variant primary progressive aphasia
E posterior cortical atrophy

POSTREADING TEST
9 Which of the following is the hallmark finding of logopenic variant

primary progressive aphasia?
A agraphia
B decreased comprehension for words but not complex sentences
C disproportionately decreased sentence repetition
D impaired motor articulation
E intact digit span
ARTICLE 3: POSTERIOR CORTICAL ATROPHY
10 Which of the following is the typical initial presentation of posterior

cortical atrophy?
A anterograde memory impairment

B poor judgment and insight
C socially inappropriate behavior
D speech impairment without aphasia
E visuospatial deficits
11 Impairment on which of the following cognitive tests is most likely to be

seen in patients with early to midstage posterior cortical atrophy?
A clock drawing
B orientation
C recall
D repetition
E verbal IQ
12 Which of the following patterns of amyloid deposition typifies

posterior cortical atrophy?
A global cortical deposition

B marked deposition in striate cortex, lateral geniculate nucleus, and
inferior pulvinar
C no appreciable deposition
D predominant neostriatal deposition
E striking deposition in parietal and occipital cortex
266 FEBRUARY 2019

ARTICLE 4: BEHAVIORAL VARIANT FRONTOTEMPORAL DEMENTIA
13 Which of the following is one of the central features of behavioral variant

frontotemporal dementia that often leads to the early manifestations of
the disease, which may include recurrent job loss and marital discord?
A disinhibition
B language impairment
C memory loss
D prosopagnosia
E pseudobulbar affect
14 Which of the following is the most common genetic variant that causes
behavioral variant frontotemporal dementia?
A C9orf72
B FUS
C GRN
D MAPT
E VCP
15 Apathy in behavioral variant frontotemporal dementia is associated

with pathology in which of the following areas?
A anterior cingulate cortex

B dorsolateral prefrontal cortex
C hypothalamus
D lateral parietal cortex
E orbitofrontal cortex

POSTREADING TEST
ARTICLE 5 PRIMARY PROGRESSIVE APHASIAS AND APRAXIA OF SPEECH
16 A 64-year-old man is seen in the office for a 2-year history of difficulty

“getting the words out right” that has progressed such that he
increasingly relies on written communication at work. He denies
difficulties with memory, reading, writing, or following conversations
and has had no changes in motor skills, gait, or behavior. On
examination, he scores within the normal range on the Mini-Mental
State Examination (MMSE). His speech is slow with multiple articulatory
errors, including false starts, groping, and distorted sounds resulting in
poor intelligibility. A sample of conversational speech reveals normal
grammar, and he has normal naming, reading, and verbal and written
comprehension. His neurologic examination is otherwise significant only
for mildly decreased finger tapping. Which of the following pathologies
is most likely to underlie this patient’s condition?
A Alzheimer disease
B corticobasal degeneration
C frontotemporal lobar degeneration with transactive response
DNA-binding protein 43 (TDP-43)
D Lewy body disease
E spongiform changes in gray matter
17 A 61-year-old right-handed woman reports word-finding difficulty

for the past year. Her husband reports that over the past 6 months,
she has become less talkative, leaves words out, and often says “no”
when she means to say “yes.” She has had no cognitive or motor
difficulties. On examination, she has reduced spontaneous verbal
output. When presented with the Cookie Theft Picture and asked to
describe what she sees, she says, “The boy is…boy…take cookie…
girl…stool fall…water spilling…dishes.” She has intact single-word
comprehension but impaired comprehension of complex
instructions. Naming is mildly impaired. Repetition and word and
object knowledge are normal. The remainder of the examination is
normal. Which of the following diagnoses is most likely?
A behavioral variant frontotemporal dementia

B logopenic variant primary progressive aphasia
C nonfluent/agrammatic variant primary progressive aphasia
D primary progressive apraxia of speech
E semantic variant primary progressive aphasia
268 FEBRUARY 2019

18 A patient with semantic variant primary progressive aphasia would
likely have the most trouble reading and writing which of the following
sets of words?
A across, calendar, tattoo

B argument, forty, sense
C bizarre, existence, further
D cough, sure, two
E forward, lollipop, until
19 A 64-year-old woman is evaluated for progressive difficulty in

retrieving words over the past 18 months. She frequently substitutes
the words thing and person for the more specific word of the
object/person she is describing. She recognizes her husband and knows
that his name is Alan but does not know what “husband” is. Grammar,
repetition, and sentence comprehension are normal. She has severe
difficulty with naming that improves only slightly with cuing. She has
difficulty matching related pictures (eg, when presented with a picture
of a camel, she matches it with a picture of a rose rather than a cactus).
Brain MRI in this patient is most likely to show atrophy in which of the
following regions?
A bilateral anterior temporal pole

B bilateral supplementary motor area
C left dorsolateral premotor cortex
D left inferior frontal lobe
E right anterior insula and superior temporal gyrus
ARTICLE 6: LEWY BODY DEMENTIAS
20 A 67-year-old man with a 3-year history of Parkinson disease has

had increasingly distressing problems with visual and auditory
hallucinations and very severe and disturbing delusions. Which of the
following medications is US Food and Drug Administration (FDA)
approved for treatment of these symptoms in Parkinson disease?
A clozapine
B lurasidone
C pimavanserin
D quetiapine
E ziprasidone

POSTREADING TEST
21 A 71-year-old woman is brought by her daughter for evaluation of

cognitive impairment. Her history includes significant fluctuations in
attention and alertness. Examination and cognitive testing are
remarkable for evidence of deficits in attention, executive function,
and visuoperceptual ability. She also has mild memory impairment.
Which of the following additional features, if present, would allow a
diagnosis of probable dementia with Lewy bodies?
A hyposmia
B recurrent visual hallucinations
C repeated falls
D severe autonomic dysfunction
E syncope
22 Which of the following is the first-line treatment for rapid eye movement
(REM) sleep behavior disorder in the context of Lewy body dementia?
A carbamazepine
B melatonin
C pramipexole
D quetiapine
E triazolam
ARTICLE 7: VASCULAR COGNITIVE IMPAIRMENT
23 As a group, patients with vascular cognitive impairment tend to perform

worst on tests of which of the following neuropsychological domains?
A emotion
B executive function
C intellect
D language
E memory
24 Lacunar infarcts in which of the following locations are associated

with the greatest negative impact on cognitive performance?
A internal capsule
B lobar white matter
C medulla
D pons
E thalamus
270 FEBRUARY 2019

25 Which of the following neuroimaging manifestations of cerebral
amyloid angiopathy is most likely to present as recurrent transient
episodes of unilateral upper extremity numbness and tingling
spreading from the fingers to the shoulder in an elderly patient?
A convexity subarachnoid hemorrhage

B cortical microinfarct
C enlarged perivascular spaces in the centrum semiovale
D lobar cerebral microbleed
E lobar intracerebral hemorrhage
26 A 45-year-old man with a history of migraine is admitted to the

hospital with acute-onset right hemiparesis and dysarthria. MRI
demonstrates an acute infarct in the left centrum semiovale and T2
hyperintensities involving periventricular regions, deep white matter,
anterior temporal poles, and external capsules. His mother and
maternal sister both had strokes in their fifties and have dementia.
Which of the following diagnostic tests is most likely to confirm the
diagnosis in this patient?
A fludeoxyglucose positron emission tomography (FDG-PET)

B fluorescein angiography
C lumbar puncture with CSF analysis
D serum lactate-to-pyruvate ratio
E skin biopsy with examination by electron microscope
27 Which of the following subtypes of vascular cognitive impairment is

most associated with stepwise neurologic decline with focal neurologic
findings on examination?
A hereditary vascular dementia

B hypoperfusion dementia
C mixed dementia
D multi-infarct dementia
E small vessel dementia

POSTREADING TEST
ARTICLE 8: NORMAL PRESSURE HYDROCEPHALUS
28 A 67-year-old woman presents for evaluation of a 6-month history of

cognitive impairment associated with frequent urinary incontinence
and a mild slowing of gait with decreased stride length. Which of the
following findings on cognitive testing would most suggest a disorder
other than normal pressure hydrocephalus?
A anomia
B apathy
C decreased attention
D impaired executive function
E psychomotor slowing
29 Which of the following clinical features of normal pressure

hydrocephalus should be present for consideration of intervention
with shunt surgery?
A gait abnormality
B impaired executive functions
C incontinence
D psychomotor slowing
E urinary urgency
30 Which of the following accurately describes the measurement of the

Evans index used for MRI assessment for ventriculomegaly?
A the ratio of the largest width of the frontal horns and the widest
measure of the inner table of the skull at that level
B the ratio of the largest width of the frontal horns to the longest
anterior-posterior dimension of the lateral ventricles
C the ratio of the largest width of the lateral ventricles at the trigone
to the width of the midpoint of the third ventricle
D the ratio of the largest width of the posterior horns and the largest
width of the frontal horns
E the ratio of the width of the zone of abnormal subependymal
signal around the lateral ventricles to the largest width of the
lateral ventricles
272 FEBRUARY 2019

31 Which of the following is a characteristic of disproportionately
enlarged subarachnoid space hydrocephalus (DESH)?
A association with poor response to shunting

B displacement of the brain by CSF accumulated in sulci
C presence of an arachnoid cyst
D slitlike appearance of sylvian fissures
E ventriculomegaly due to hydrocephalus ex vacuo
ARTICLE 9: CHRONIC TRAUMATIC ENCEPHALOPATHY
32 Which of the following neuropathologic findings is a required element

for the diagnosis of chronic traumatic encephalopathy?
A accumulation of perivascular tau at sulcal depths

B atrophy of the mammillary bodies
C dilation of the third ventricle
D septal abnormalities, atrophy of the mammillary bodies, and
contusions
E transactive response DNA-binding protein 43 (TDP-43) neuronal
inclusions in the hippocampus
33 Which of the following anatomic variants occurs at an increased

frequency among patients with chronic traumatic encephalopathy
compared to healthy individuals?
A absent recurrent artery of Heubner

B cavum septum pellucidum
C cerebellar tonsillar ectopia
D hypoplasia of the rostrum of the corpus callosum
E mega cisterna magna
34 In a patient with dementia and parkinsonism, which of the following

clinical features favors a diagnosis of chronic traumatic
encephalopathy over one of dementia with Lewy bodies?
A early presence of gait instability and tremor

B fluctuation in alertness and cognition
C presence of rapid eye movement (REM) sleep behavior disorder
D prominent disinhibition and explosivity
E recurrent visual hallucinations

POSTREADING TEST
ARTICLE 10: HIPPOCAMPAL SCLEROSIS, ARGYROPHILIC GRAIN DISEASE,

AND PRIMARY AGE-RELATED TAUOPATHY
35 In which of the following conditions is hippocampal sclerosis

accompanied by the pathologic finding of intraneuronal cytoplasmic
transactive response DNA-binding protein 43 (TDP-43) inclusions
within the hippocampal CA1 subfield, subiculum, and amygdala?
A anoxic/hypoxic injury
B chronic traumatic encephalopathy
C frontotemporal lobar degeneration
D severe obstructive sleep apnea
E temporal lobe epilepsy
36 Which of the following vascular conditions of the brain has been

demonstrated to have an association with the development of
hippocampal sclerosis of aging?
A arteriolosclerosis
B cardioembolic stroke
C cerebral amyloid angiopathy
D lacunar infarcts
E large vessel atheroembolic stroke
37 Which of the following neuropathologic changes is (are) associated

with primary age-related tauopathy?
A amyloid deposition
B ballooned neurons
C coiled bodies
D neurofibrillary tangles
E tufted astrocytes
274 FEBRUARY 2019

ARTICLE 11: REVERSIBLE DEMENTIAS
38 A 75-year-old man with Alzheimer disease dementia is brought to the

emergency department after a fall. His daughter notes that although he
has had a gradually progressive decline in cognition over the past
5 years, his memory and gait have dramatically worsened over the past
3 months since moving to a new extended-care facility. His medications
include donepezil, memantine, metformin, gabapentin, venlafaxine,
diphenhydramine, and docusate. He scores 21/30 on the Mini-Mental
State Examination (MMSE). Routine laboratory studies, urinalysis,
urine drug screen, and alcohol level are normal or negative. Which
of the following medications is most appropriate to discontinue at
this time?
A diphenhydramine
B donepezil
C gabapentin
D memantine
E venlafaxine
39 A 53-year-old woman is seen in the emergency department for a 6-week

history of nausea, vomiting, confusion, and diplopia. She underwent
gastric bypass surgery 2 years ago, after which she had intermittent
nausea and vomiting, but these symptoms intensified in the past
6 weeks. Neurologic examination demonstrates impaired orientation,
attention, and short-term recall; coarse horizontal nystagmus on gaze
to either side with bilateral lateral rectus weakness; and a wide-based,
unsteady gait. Empiric IV administration of which of the following
nutrients is immediately indicated?
A cobalamin
B niacin
C pyridoxine
D riboflavin
E thiamine

POSTREADING TEST
40 A 47-year-old man is seen in clinic for progressive memory impairment

over the past year that led to losing his job as an accountant last month.
He endorses long-standing bifrontal headaches and night sweats. He
has no history of serious medical illness. He used cocaine and heroin
30 years ago and currently smokes marijuana. General and neurologic
examinations are normal. He scores 24/30 on the Mini-Mental State
Examination (MMSE), with impaired attention, orientation, and
delayed recall. Brain MRI shows nonspecific T2 hyperintensities. CSF
demonstrates a mononuclear pleocytosis, elevated protein, and
oligoclonal bands. Testing for which of the following conditions is
most appropriate in this patient?
A Creutzfeldt-Jakob disease
B heavy metal toxicity
C neurosyphilis
D thiamine deficiency
E Wilson disease
276 FEBRUARY 2019

Postreading
SELF-ASSESSMENT
AND CME
Self-Assessment and
CME Test—Preferred
Responses
By D. Joanne Lynn, MD, FAAN; Allyson R. Zazulia, MD
DEMENTIA
Following are the preferred responses to the questions in the Postreading
Self-Assessment and CME Test in this Continuum issue. The preferred
response is followed by an explanation and a reference with which you
may seek more specific information. You are encouraged to review the
responses and explanations carefully to evaluate your general
understanding of the article topic. The comments and references included
with each question are intended to encourage independent study.
US PARTICIPANTS: Upon completion of the Postreading Self-Assessment and

CME Test and issue evaluation online at continpub.com/CME, participants
may earn up to 20 AMA PRA Category 1 Credits™ toward SA-CME. US
participants have up to 3 years from the date of publication to earn
SA-CME credits. No SA-CME will be awarded for this issue after
February 28, 2022.
CANADIAN PARTICIPANTS: This program is an Accredited Self-Assessment

Program (Section 3) as defined by the Maintenance of Certification
Program of the Royal College of Physicians and Surgeons of Canada and
approved by the Office of Continuing Medical Education and Professional
Development, University of Calgary, on April 1, 2017. Refer to the CME
tab on ContinuumJournal.com for dates of accreditation. Canadian
participants should visit MAINPORT (mainport.org) to record learning and
outcomes. Canadian participants can claim a maximum of 20 hours (credits
are automatically calculated).
ARTICLE 1: LATE-ONSET ALZHEIMER DISEASE
1 The preferred response is D (neocortex). The neuropathologic features of

Alzheimer disease dementia include senile plaques and neurofibrillary tangles.
Senile plaques are deposits of aggregated amyloid-β polypeptides. Amyloid-β
plaques first accumulate in the neocortex, followed sequentially by spread into
the hippocampus and limbic structures, striatum and diencephalon, brainstem,

POSTREADING TEST—PREFERRED RESPONSES
and cerebellum. For more information, refer to page 23 of the Continuum article
“Late-onset Alzheimer Disease.”
2 The preferred response is A (ε2/ε2). The strongest genetic risk factor for
late-onset Alzheimer disease is apolipoprotein E (APOE) genotype. APOE ε2,
which is found in approximately 8% of the population, is associated with a
reduced risk of developing Alzheimer disease (odds ratio of approximately 0.5
among homozygotes) compared to the more common ε3 allele, while APOE ε4
increases the risk (odds ratio of 8 to 12 among homozygotes). For more
information, refer to pages 15–16 of the Continuum article “Late-onset Alzheimer
Disease.”
3 The preferred response is A (bradycardia). Acetylcholinesterase inhibitors are

the mainstay of pharmacologic treatment for Alzheimer disease, although benefits
are modest and difficult to appreciate in clinical practice. Side effects reflect
actions on the parasympathetic nervous system, with the most common ones
reflecting gastrointestinal hypermotility: diarrhea, nausea, vomiting, and
anorexia. The medications may also cause bradycardia, hypotension,
bronchoconstriction, and decreased intraocular pressure. For more information,
refer to page 27 of the Continuum article “Late-onset Alzheimer Disease.”
4 The preferred response is D (selective serotonin reuptake inhibitor [SSRI]).

Nonpharmacologic interventions should always be attempted for behavioral
symptoms in Alzheimer disease since they are often more effective than
pharmacologic interventions and are not associated with the significant
morbidity and mortality that can be seen with pharmacologic therapy. If
pharmacologic therapy is deemed necessary, first-line agents include SSRIs and
serotonin norepinephrine reuptake inhibitors (SNRIs). Benzodiazepines should
be avoided because of sedating effects and the potential to worsen cognition.
Tricyclic antidepressants should be avoided because of their anticholinergic
properties. Neuroleptics—both conventional and atypical—should be avoided, if
possible, because of evidence for increased morbidity and mortality in patients
with dementia. For more information, refer to pages 29–30 of the Continuum
article “Late-onset Alzheimer Disease.”
ARTICLE 2: EARLY-ONSET ALZHEIMER DISEASE AND ITS VARIANTS
5 The preferred response is C (early-onset Alzheimer disease). Early-onset

Alzheimer disease is the most common cause of neurodegenerative dementia
with onset before the age of 65 years and accounts for at least one-third
of early-onset dementia cases. Other causes include vascular disease,
frontotemporal dementia, drug-related conditions, Lewy body disease, and
autoimmune and infectious conditions. For more information, refer to
page 35 of the Continuum article “Early-onset Alzheimer Disease and
Its Variants.”
278 FEBRUARY 2019

6 The preferred response is A (higher rate of antecedent traumatic brain injury).
Patients with early-onset Alzheimer disease (AD) are more likely to have a history
of traumatic brain injury as a risk factor for dementia than those with late-onset
AD. Early-onset AD is associated with a higher rate of genetic etiology and
a higher mortality rate than late-onset AD. Although patients with early-onset
AD have, on average, a more aggressive clinical course than those with
late-onset AD, patients with early-onset AD have a longer duration of disease
before diagnosis, probably reflecting missed or delayed diagnosis or a greater
extent of evaluation for diagnosis. The frequency of associated cerebrovascular
risk factors such as diabetes mellitus is lower in early-onset AD. For more
information, refer to page 35 of the Continuum article “Early-onset Alzheimer
Disease and Its Variants.”
7 The preferred response is D (semantic memory). Patients with early-onset

Alzheimer disease will more often present with phenotypes characterized
by impairment of attention, language, executive function, ideomotor praxis, or
visuospatial skills rather than the prominent amnestic disorder of late-onset
Alzheimer disease and therefore, in aggregate, perform better on memory
recognition scores and semantic memory. For more information, refer to page 35
of the Continuum article “Early-onset Alzheimer Disease and Its Variants.”
8 The preferred response is D (logopenic variant primary progressive aphasia).

The most common phenotypic variant of early-onset Alzheimer disease is
logopenic variant primary progressive aphasia. This form of dementia presents
with progressive aphasia and relatively spared memory and other cognitive
domains. Pathology is characterized by focal Alzheimer degenerative
changes in the dominant temporoparietal language areas, especially the
superior/midtemporal gyrus and angular gyrus as well as the midfrontal cortex.
For more information, refer to pages 39–40 of the Continuum article
“Early-onset Alzheimer Disease and Its Variants.”
9 The preferred response is C (disproportionately decreased sentence

repetition). The hallmark finding of logopenic variant primary progressive
aphasia is difficulty with repetition of sentences out of proportion to other
impairments. Comprehension is typically decreased for long sentences
but not for single words. Motor articulation is generally preserved. Other
evidence of decreased phonologic store, such as decreased digit or word span,
is generally present. Agraphia is not a component of this variant. For more
information, refer to pages 39–40 of the Continuum article “Early-onset
Alzheimer Disease and Its Variants.”

ARTICLE 3: POSTERIOR CORTICAL ATROPHY
10 The preferred response is E (visuospatial deficits). While the earliest symptoms

of posterior cortical atrophy may be a vague, nonspecific anxiety and sense that
something is wrong, the more concrete problems that bring the individual to
medical attention typically center on higher-order visuospatial and perceptual
deficits, such as dyslexia, visual agnosia, optic ataxia, and spatial disorientation.
In contrast to typical Alzheimer disease, anterograde memory is relatively
preserved at onset. In contrast to frontotemporal dementia, personality and
behavior are generally unaffected and insight is preserved. For more
information, refer to page 55 of the Continuum article “Posterior Cortical
Atrophy.”
11 The preferred response is A (clock drawing). Screening cognitive tests in

patients with posterior cortical atrophy typically reveal severe deficiencies
in performance IQ and tests of construction, with relative preservation of
orientation, recall, repetition, and verbal IQ. Patients have difficulties in parietal
and occipital tasks, such as calculation, spelling, reading, writing, copying
complex figures, clock drawing, and describing complex pictures. For
more information, refer to page 57 of the Continuum article “Posterior
Cortical Atrophy.”
12 The preferred response is A (global cortical deposition). Although symptoms

in posterior cortical atrophy are strikingly focal, amyloid binding as determined
by amyloid positron emission tomography (PET) is typically global and
indistinguishable from that of patients with more typical Alzheimer syndromes.
Tau PET scanning, on the other hand, shows striking posterior cortical
deposition of tau pathology. For more information, refer to page 62 of the
Continuum article “Posterior Cortical Atrophy.”
ARTICLE 4: BEHAVIORAL VARIANT FRONTOTEMPORAL DEMENTIA
13 The preferred response is A (disinhibition). The central features of behavioral

variant frontotemporal dementia are apathy and loss of social graces because
of disinhibition and deficits in compassion. These early manifestations are
subtle, develop insidiously, and lead to severe impairment of relationships and
social function. For more information, refer to page 77 of the Continuum article
“Behavioral Variant Frontotemporal Dementia.”
14 The preferred response is A (C9orf72). Behavioral variant frontotemporal

dementia is associated with a known pathogenic genetic variant in
approximately 15% to 20% of patients. The most common genetic cause of
behavioral variant frontotemporal dementia is hexanucleotide repeat
280 FEBRUARY 2019

expansions in C9orf72, and this variant is often associated with prominent
psychiatric features. For more information, refer to pages 81–82 of the
Continuum article “Behavioral Variant Frontotemporal Dementia.”
15 The preferred response is A (anterior cingulate cortex). The feature of apathy in

behavioral variant frontotemporal dementia is associated with pathology in the
anterior cingulate cortex. For more information, refer to Table 4-2 on page 80 of
the Continuum article “Behavioral Variant Frontotemporal Dementia.”
ARTICLE 5 PRIMARY PROGRESSIVE APHASIAS AND APRAXIA OF SPEECH
16 The preferred response is B (corticobasal degeneration). This patient with

predominantly phonetic difficulties and preserved cognition and language
meets criteria for primary progressive apraxia of speech. Subtle parkinsonian
signs may be seen, and 40% of patients develop a progressive supranuclear
palsy–corticobasal-like syndrome. The most common pathology seen at
autopsy in patients with this condition is corticobasal degeneration. For more
information, refer to pages 106–107 and 110–111 of the Continuum article “Primary
Progressive Aphasias and Apraxia of Speech.”
17 The preferred response is C (nonfluent/agrammatic variant primary

progressive aphasia). This patient has a progressive primary language disorder
characterized by agrammatic language production and effortful, halting speech
with impaired comprehension of complex instructions and spared object
knowledge, meeting criteria for nonfluent/agrammatic variant primary
progressive aphasia. For more information, refer to pages 114–115 of the
Continuum article “Primary Progressive Aphasias and Apraxia of Speech.”
18 The preferred response is D (cough, sure, two). Patients with semantic primary
progressive aphasia typically have difficulty reading and writing irregularly
spelled words (ie, words that do not conform to regular spelling or phonetic
rules). Patients may treat them as if they were regular words when reading
(eg, tuh-woe for two) and write them phonetically (eg, coff for cough). For more
information, refer to page 119 of the Continuum article “Primary Progressive
Aphasias and Apraxia of Speech.”
19 The preferred response is A (bilateral anterior temporal pole). This patient has
a progressive primary language disorder characterized by impaired word
comprehension, confrontation naming, object knowledge, and semantic
association, with spared speech production and repetition, meeting criteria for
semantic variant primary progressive aphasia. Neuroimaging in this condition
demonstrates focal atrophy of the anterior temporal pole that is typically
bilateral (though more prominent on the left in semantic variant primary

progressive aphasia and on the right in right-sided semantic dementia). For

more information, refer to pages 120–121 of the Continuum article “Primary
Progressive Aphasias and Apraxia of Speech.”
ARTICLE 6: LEWY BODY DEMENTIAS
20 The preferred response is C (pimavanserin). Pimavanserin has US Food and

Drug Administration (FDA) approval for treatment of Parkinson disease
psychosis. Pimavanserin is an atypical antipsychotic that is not a dopamine
receptor antagonist; the primary mechanism of action is as a highly selective
antagonist for the serotonin 5-HT2A receptor. Quetiapine and clozapine are also
commonly used to treat Parkinson disease–associated psychosis but do not
have specific FDA approval for this indication. For more information, refer to
pages 141, 143 of the Continuum article “Lewy Body Dementias.”
21 The preferred response is B (recurrent visual hallucinations). A diagnosis of

dementia with Lewy bodies using the fourth consensus report of the Dementia
With Lewy Bodies Consortium (2017) requires the presence of dementia, often
with prominent deficits in attention, executive function, and visuoperceptual
ability, as well as two or more core clinical features or one core clinical feature
plus at least one indicative biomarker. In this case, the patient’s significant
fluctuations in attention and alertness constitute one core clinical feature.
Additional core clinical features in the 2017 criteria are recurrent visual
hallucinations, rapid eye movement (REM) sleep behavior disorder, and
parkinsonism. The other choices represent supportive clinical features. For
more information, refer to pages 129–130 and Table 6-2 of the Continuum article
“Lewy Body Dementias.”
22 The preferred response is B (melatonin). Melatonin is considered the first-line

treatment for rapid eye movement (REM) sleep behavior disorder in the context
of Lewy body dementia and has the advantage of relatively few side effects.
Clonazepam is frequently used, but caution is advised for patients with
dementia, gait disorders, and obstructive sleep apnea, and tolerance should be
monitored. For more information, refer to page 143 of the Continuum article
“Lewy Body Dementias.”
ARTICLE 7: VASCULAR COGNITIVE IMPAIRMENT
23 The preferred response is B (executive function). Tests of executive function

and tasks requiring cognitive speed tend to be preferentially affected in
vascular cognitive impairment, although no pathognomonic neuropsychological
pattern exists that distinguishes a given individual with vascular cognitive
impairment from one with Alzheimer disease or other cause of cognitive
282 FEBRUARY 2019

impairment. For more information, refer to page 148 of the Continuum article
“Vascular Cognitive Impairment.”
24 The preferred response is E (thalamus). Lacunar infarcts are independently

associated with cognitive impairment, with increasing burden related to
deteriorating score on cognitive tests such as the Mini-Mental State
Examination (MMSE). The location of lacunar infarcts is important, with those in
the thalamus and putamen associated with worse cognitive performance. For
more information, refer to page 151 of the Continuum article “Vascular Cognitive
Impairment.”
25 The preferred response is A (convexity subarachnoid hemorrhage). A number

of neuroimaging biomarkers indicate the presence of cerebral amyloid
angiopathy, including lobar intracerebral hemorrhage and cerebral
microbleeds, convexity subarachnoid hemorrhage, cortical superficial
siderosis, microinfarction, enlarged perivascular spaces within the centrum
semiovale, and reversible white matter edema. Convexity subarachnoid
hemorrhage (ie, hemorrhage located in one or a few cortical sulci without
spread into the sylvian fissure, interhemispheric fissure, basal cisterns, or
ventricles) and cortical superficial siderosis often present with recurrent
transient spreading sensory or motor symptoms. For more information, refer to
pages 152–153 of the Continuum article “Vascular Cognitive Impairment.”
26 The preferred response is E (skin biopsy with examination by electron

microscope). The leading diagnosis in a middle-aged patient such as this one
with migraine and subcortical infarct, a family history of stroke and dementia,
and MRI evidence for leukoencephalopathy with involvement of the anterior
temporal poles and external capsules is cerebral autosomal dominant
arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).
CADASIL may be diagnosed with genetic testing confirming the pathogenic
mutation in the NOTCH3 gene or biopsy of the skin (or muscle) with
demonstration of irregular granular osmophilic deposits in the basal lamina of
vascular smooth muscle cells. Although silent retinal abnormalities are common
in CADASIL, they are not specific for the condition. For more information, refer
to pages 154–156 of the Continuum article “Vascular Cognitive Impairment.”
27 The preferred response is D (multi-infarct dementia). Patients with

multi-infarct dementia, also known as multiple cortical infarcts and dementia,
may have an abrupt symptom onset with stepwise neurologic decline in
association with new cortical strokes. For more information, refer to
pages 153–154 of the Continuum article “Vascular Cognitive Impairment.”

ARTICLE 8: NORMAL PRESSURE HYDROCEPHALUS
28 The preferred response is A (anomia). The cognitive impairment in normal

pressure hydrocephalus displays the features of a frontal lobe subcortical
dementia. Common features include psychomotor slowing, decreased
attention and concentration, impaired executive function, and apathy. An
anomia should prompt suspicion and evaluation for a cause of cortical
dementia/cognitive impairment, such as Alzheimer disease. For more
information, refer to page 170 of the Continuum article “Normal Pressure
Hydrocephalus.”
29 The preferred response is A (gait abnormality). Multiple studies have shown

that shunt surgery is not effective for patients with large ventricles but no gait
abnormality. While patients may present without the full range of normal
pressure hydrocephalus clinical features, the clinical presentation of those
who are evaluated for possible intervention with shunt surgery should include
gait abnormality, which is usually an early symptom. For more information, refer
to page 171 of the Continuum article “Normal Pressure Hydrocephalus.”
30 The preferred response is A (the ratio of the largest width of the frontal horns
and the widest measure of the inner table of the skull at that level). The Evans
index is the ratio of the largest width of the frontal horns and the widest
measure of the inner table of the skull at that level. When the Evans index is
greater than 0.3, the ventricles are considered to be enlarged. More detailed
quantitative volumetric analyses may have better correlation with speed of gait
and cognition, but the Evans index is easily measured and requires no special
techniques. For more information, refer to pages 171–172 of the Continuum
article “Normal Pressure Hydrocephalus.”
31 The preferred response is B (displacement of the brain by CSF accumulated in

sulci). Disproportionately enlarged subarachnoid space hydrocephalus (DESH)
is characterized by an MRI appearance of CSF collection with expansion of the
major fissures, such as the sylvian, calcarine, parietooccipital, and longitudinal
fissures, with secondary compression of adjacent sulci. Displacement of CSF
from sulci at the convexity gives a “tight high convexity” appearance. The
appearance can be mistaken for hydrocephalus ex vacuo and may give the
misleading impression of atrophy or of an arachnoid cyst. The DESH pattern is
associated with a good response to shunting. For more information, refer to
pages 172–174 of the Continuum article “Normal Pressure Hydrocephalus.”
284 FEBRUARY 2019

ARTICLE 9: CHRONIC TRAUMATIC ENCEPHALOPATHY
32 The preferred response is A (accumulation of perivascular tau at sulcal

depths). According to the consensus neuropathologic criteria developed
in 2015, the pathognomonic feature of chronic traumatic encephalopathy that
allows the disorder to be distinguished from other tauopathies is accumulation
of abnormal phosphorylated tau in neurons and astroglia distributed around
small blood vessels at the depths of cortical sulci. Each of the other pathologic
findings listed may be present in chronic traumatic encephalopathy but are
not required elements for the diagnosis. For more information, refer to
pages 189–190 of the Continuum article “Chronic Traumatic Encephalopathy.”
33 The preferred response is B (cavum septum pellucidum). Cavum septum

pellucidum is a persistence of the embryologic fluid-filled space between the
leaflets of the septum pellucidum and is a common anatomic variant seen in up
to 15% of healthy individuals. In autopsy studies, cavum septum pellucidum is
present in increased frequency within the chronic traumatic encephalopathy
population and may be a result of head trauma–induced fluid waves producing
fenestrations within the septum. For more information, refer to page 195 of the
Continuum article “Chronic Traumatic Encephalopathy.”
34 The preferred response is D (prominent disinhibition and explosivity). Dementia

and parkinsonism can occur in chronic traumatic encephalopathy and dementia
with Lewy bodies, but these conditions can usually be distinguished by the
prominence of disinhibition and explosivity in chronic traumatic encephalopathy
and the early prominence of parkinsonism, presence of rapid eye movement
(REM) behavior disorder, fluctuation in alertness and cognition, and recurrent
visual hallucinations in dementia with Lewy bodies. For more information, refer
to page 198 of the Continuum article “Chronic Traumatic Encephalopathy.”
ARTICLE 10: HIPPOCAMPAL SCLEROSIS, ARGYROPHILIC GRAIN DISEASE,

AND PRIMARY AGE-RELATED TAUOPATHY
35 The preferred response is C (frontotemporal lobar degeneration). Selective

hippocampal neuronal loss and gliosis may be seen in all the above conditions
that may be associated with hippocampal sclerosis. However, only
hippocampal sclerosis associated with frontotemporal lobar degeneration is
associated with abnormal accumulations of transactive response DNA-binding
protein 43 (TDP-43) within the affected regions of the hippocampus, subiculum,
and amygdala. For more information, refer to pages 213–214 of the Continuum
article “Hippocampal Sclerosis, Argyrophilic Grain Disease, and Primary
Age-Related Tauopathy.”

36 The preferred response is A (arteriolosclerosis). Investigations of multiple

large autopsy series have demonstrated a specific association between
cerebral arteriolosclerosis and hippocampal sclerosis of aging. The
hippocampus is a vulnerable watershed area, and it is hypothesized that
chronic reduction in blood flow may play a role in hippocampal sclerosis of
aging. For more information, refer to pages 215–216 of the Continuum article
“Hippocampal Sclerosis, Argyrophilic Grain Disease, and Primary Age-Related
Tauopathy” and the following reference.
Neltner JH, Abner EL, Baker S, et al. Arteriolosclerosis that affects multiple brain regions is linked to
hippocampal sclerosis of ageing. Brain 2014;137(pt 1):255–267. doi:10.1093/brain/awt318.
37 The preferred response is D (neurofibrillary tangles). Primary age-related

tauopathy is a common pathology of old age in which tau neurofibrillary tangles
are observed in the absence of the neuritic amyloid plaques typically seen in
Alzheimer disease. “Coiled bodies,” “ballooned neurons,” and “tufted
astrocytes” are pathologic changes related to accumulation of phosphorylated
tau protein seen in argyrophilic grain disease. For more information, refer to
pages 220 and 225 of the Continuum article “Hippocampal Sclerosis,
Argyrophilic Grain Disease, and Primary Age-Related Tauopathy.”
ARTICLE 11: REVERSIBLE DEMENTIAS
38 The preferred response is A (diphenhydramine). Precipitous worsening of

clinical status in a patient with dementia warrants assessment for potentially
reversible contributors to cognitive decline, most notably exposure to high-risk
medications, drugs, or toxins. Among the high-risk medications, those with
strong anticholinergic properties are especially problematic for patients
with Alzheimer disease and may even contribute to the progression of
neurodegenerative pathology. Diphenhydramine is strongly anticholinergic and
should be discontinued in this patient. Venlafaxine’s anticholinergic properties
are weak, so it is reasonable to continue this medication at this time. For
more information, refer to page 239 of the Continuum article “Reversible
Dementias.”
39 The preferred response is E (thiamine). This patient has encephalopathy,

ophthalmoparesis, and cerebellar dysfunction, the cardinal manifestations of
Wernicke encephalopathy due to thiamine deficiency. Although Wernicke
encephalopathy is classically described in the setting of excessive alcohol
consumption, it may occur with malnutrition of any cause, such as in this patient
with protracted vomiting associated with gastric bypass surgery. Since
untreated thiamine deficiency can lead to irreversible cognitive impairment
and death, empiric treatment with high-dose parenteral thiamine is warranted
in this case. For more information, refer to pages 239 and 242 of the Continuum
article “Reversible Dementias.”
286 FEBRUARY 2019

40 The preferred response is C (neurosyphilis). Testing for neurosyphilis is
recommended in patients with dementia who are from endemic regions
or have a history of high-risk behaviors (even a remote history, as in this patient)
or immunocompromised state. This patient’s history of headaches and night
sweats and CSF profile are also consistent with the diagnosis. In addition to
CSF Venereal Disease Research Laboratory (VDRL) and serum rapid plasma
reagin (RPR), this patient should be screened for other sexually transmitted or
opportunistic infections. For more information, refer to pages 242–245 of the
Continuum article “Reversible Dementias.”

LEARNING OBJECTIVES AND CORE COMPETENCIES
Learning Objectives ◆ Describe the pathologic entities commonly found in

the aging population that can mimic Alzheimer disease
Upon completion of this Continuum: Lifelong and understand the clinical, biomarker-based, and
Learning in Neurology Dementia issue, genetic features that may distinguish these entities
participants will be able to: from the dementia and cognitive decline caused by
Alzheimer disease pathology
◆ Describe the epidemiology, genetic and
environmental risk factors, clinical diagnosis, ◆ Identify clinical features that distinguish patients
biomarkers, and treatment of late-onset with reversible causes of dementia
Alzheimer disease
◆ Discuss the reasons medications carry a boxed
◆ Discuss the clinical, neuropathologic, and warning as well as the importance of disclosing (and
management aspects of early-onset Alzheimer documenting the discussion of) the risks and benefits
disease that differentiate it from the more common of any high-risk medications to patients or patients’
health care proxies
late-onset Alzheimer disease
◆ Describe the clinical features, molecular

underpinnings, relevant investigation findings,
diagnostic criteria, and management of patients Core Competencies
with posterior cortical atrophy This Continuum: Lifelong Learning in Neurology
Dementia issue covers the following
◆ Define the core clinical features of behavioral variant
frontotemporal dementia (bvFTD), distinguish it from
core competencies:
other forms of mid- to late-life behavioral change,
formulate a pathologic differential diagnosis for ◆ Patient Care
individual patients with bvFTD, and identify key
aspects of management ◆ Medical Knowledge
◆ Discuss the classification and distinguishing clinical ◆ Practice-Based Learning and Improvement
and imaging features of primary progressive apraxia
and aphasia ◆ Interpersonal and Communication Skills
◆ Describe the diseases included under the Lewy ◆ Professionalism

body dementia umbrella and current strategies
for evaluating and treating them ◆ Systems-Based Practice
◆ Describe the diseases included under the vascular

cognitive impairment umbrella and current strategies
for evaluating and treating them
◆ Develop a practical clinical approach to the diagnosis

and management of idiopathic normal pressure
hydrocephalus and recognize when overlapping
diseases are present
◆ Describe the current chronic traumatic

encephalopathy neuropathologic and
research-based diagnostic criteria and the
emerging understanding of chronic traumatic
encephalopathy risk factors and biomarkers
4 F EB R UA R Y 2 0 1 9

LIST OF ABBREVIATIONS
Dementia LP Lumbar puncture

MCI Mild cognitive impairment
MMSE Mini-Mental State Evaluation
MoCA Montreal Cognitive Assessment
Aβ Amyloid β
AAN American Academy of Neurology MRI Magnetic resonance imaging
AChEI Acetylcholinesterase inhibitor mRNA Messenger ribonucleic acid
AD Alzheimer disease mRS Modified Rankin Scale
ALS Amyotrophic lateral sclerosis NFL National Football League
bvFTD Behavioral variant frontotemporal dementia NIBIB National Institute of Biomedical Imaging
CAA Cerebral amyloid angiopathy and Bioengineering
NINDS National Institute of Neurological Disorders and Stroke
CADASIL Cerebral autosomal dominant arteriopathy with
subcortical infarcts and leukoencephalopathy NINDS-AIREN National Institute of Neurological Disorders and Stroke
and the Association Internationale pour la Recherche
CARASIL Cerebral autosomal recessive arteriopathy with
et l’Enseignement en Neurosciences
subcortical infarcts and leukoencephalopathy
CBD Corticobasal degeneration NMDA N-methyl-D-aspartate
CJD Creutzfeldt-Jakob disease NPH Normal pressure hydrocephalus
CSF Cerebrospinal fluid p-tau Hyperphosphorylated tau
CT Computed tomography PART Primary age-related tauopathy
CTE Chronic traumatic encephalopathy PCA Posterior cortical atrophy
DESH Disproportionately enlarged subarachnoid PCR Polymerase chain reaction
space hydrocephalus PD Parkinson disease
DLB Dementia with Lewy bodies PD-CRS Parkinson’s Disease-Cognitive Rating Scale
DNA Deoxyribonucleic acid PD-MCI Parkinson disease mild cognitive impairment
DSM-5 Diagnostic and Statistical Manual of Mental PET Positron emission tomography
Disorders, Fifth Edition PPA Primary progressive aphasia
DWI Diffusion-weighted imaging PSP Progressive supranuclear palsy
EEG Electroencephalogram PTSD Posttraumatic stress disorder
FDA US Food and Drug Administration
REM Rapid eye movement
FDG Fludeoxyglucose
RBD Rapid eye movement sleep behavior disorder
FDG-PET Fludeoxyglucose positron emission tomography
RNA Ribonucleic acid
FIESTA-C Fast imaging employing steady state acquisition C
RPR Rapid plasma reagin
FLAIR Fluid-attenuated inversion recovery
SNRI Serotonin norepinephrine reuptake inhibitor
fMRI Functional magnetic resonance imaging
SPECT Single-photon emission computed tomography
FTD Frontotemporal dementia
SSRI Selective serotonin reuptake inhibitor
FTLD Frontotemporal lobar degeneration
SWI Susceptibility-weighted imaging
GRE Gradient recalled echo
H&E Hematoxylin and eosin t-tau Total tau
HIV Human immunodeficiency virus TBI Traumatic brain injury
IgG Immunoglobulin G TDP-43 Transactive response DNA-binding protein 43
IM Intramuscular TES Traumatic encephalopathy syndrome
IQ Intelligence quotient TSH Thyroid-stimulating hormone
IV Intravenous VA-BU-CLF Veterans Affairs-Boston University-Concussion Legacy
IVIg Intravenous immunoglobulin Foundation [brain bank]
LOVA Long-standing overt ventriculomegaly in adults VDRL Venereal Disease Research Laboratory

Dementia
Article 1: Late-onset Alzheimer Disease
Gil D. Rabinovici, MD. Continuum (Minneap Minn). February 2019; 25 (1 Dementia):14–33.
ABSTRACT
PURPOSE OF REVIEW:
Alzheimer disease (AD) is the most common cause of late-onset dementia. This article describes
the epidemiology, genetic and environmental risk factors, clinical diagnosis, biomarkers, and
treatment of late-onset AD, defined by age of onset of 65 years or older.
RECENT FINDINGS:
An estimated 5.7 million Americans are living with AD dementia, with the number of affected
individuals growing rapidly because of an aging population. Vascular risk factors, sleep
disorders, and traumatic brain injury are associated with an increased risk of AD, while increased
cognitive and physical activity throughout the lifespan reduce the risk of disease. The primary
genetic risk factor for late-onset AD is the apolipoprotein E (APOE) ε4 allele. AD typically
presents with early and prominent episodic memory loss, although this clinical syndrome is
neither sensitive nor specific for underlying AD neuropathology. Emerging CSF and imaging
biomarkers can now detect the key neuropathologic features of the disease (amyloid plaques,
neurofibrillary tangles, and neurodegeneration) in living people, allowing for characterization of
patients based on biological measures. A comprehensive treatment plan for AD includes use
of symptomatic medications, optimal treatment of comorbid conditions and neuropsychiatric
symptoms, counseling about safety and future planning, and referrals to community resources.
SUMMARY:
AD is very common in older neurologic patients. Neurologists should set the standard for the
diagnosis and care of patients with AD and should be familiar with emerging biomarkers that
have transformed AD research and are primed to enter the clinical arena.
KEY POINTS
• Alzheimer disease is the most common cause of dementia, affecting an estimated 5.7 million Americans. The
number of affected individuals is expected to triple by 2050 because of an aging population.
• Vascular risk factors, sleep disturbances, and traumatic brain injury increase the risk of Alzheimer disease.
Increased years of education and greater cognitive and physical activity throughout the lifespan decrease the
risk of Alzheimer disease.
• The estimated heritability of late-onset Alzheimer disease is approximately 60% to 80%. The primary genetic
risk factor for sporadic late-onset Alzheimer disease is the apolipoprotein E (APOE) ε4 allele.

• The clinical evaluation of patients with cognitive symptoms should first and foremost exclude reversible
causes based on history, examination, and laboratory testing.
• Mild cognitive impairment is defined as objectively confirmed cognitive decline that does not interfere with
independent function. When cognitive decline interferes with independent function, patients meet criteria
for dementia.
• Late-onset Alzheimer disease typically presents with progressive decline in episodic memory, with variable
involvement of other cognitive domains. Progressive memory impairment can also be caused by other
neurodegenerative processes affecting the medial temporal lobes.
• Common neuropsychiatric symptoms in Alzheimer disease include depression, anxiety, mild apathy,
irritability, and sleep disturbances.
• MRI findings in Alzheimer disease include medial temporal lobe and posterior-predominant cortical atrophy.
Iron-sensitive sequences should be performed to assess for hemorrhages associated with cerebral
amyloid angiopathy.
• The neuropathology of Alzheimer disease is defined by the presence of senile amyloid plaques and tau
neurofibrillary tangles. The burden and distribution of these two lesions define the degree of Alzheimer
disease neuropathologic changes.
• Late-life dementia is often associated with multiple brain pathologies. The most common are Alzheimer
disease, Lewy bodies, vascular brain injury, hippocampal sclerosis, and TDP-43 inclusions.
• Amyloid plaques and tau tangles can be detected in living people based on changes in CSF levels of amyloid-
β and phosphorylated tau or by using positron emission tomography radiotracers that selectively bind
amyloid-β or tau aggregates.
• A comprehensive care plan for patients with Alzheimer disease includes treatment with Alzheimer
disease–specific medications, treatment of relevant comorbid conditions, counseling about safety and
future planning, and referrals to community resources.
• Acetylcholinesterase inhibitors are approved for the treatment of mild to severe Alzheimer disease
dementia. Memantine is approved for the treatment of moderate to severe Alzheimer disease dementia.
• Difficult behaviors in Alzheimer disease should be addressed primarily with nonpharmacologic approaches,
use of Alzheimer disease symptomatic drugs, and judicious use of antidepressants. Use of neuroleptics
should be avoided, if possible, because of increased morbidity and mortality.
Article 2: Early-onset Alzheimer Disease

and Its Variants
Mario F. Mendez, MD, PhD, FAAN. Continuum (Minneap Minn). February 2019; 25 (1
Dementia):34–51.
ABSTRACT
PURPOSE OF REVIEW:
Early-onset Alzheimer disease (AD) is defined as having an age of onset younger than 65 years.
While early-onset AD is often overshadowed by the more common late-onset AD, recognition of
the differences between early- and late-onset AD is important for clinicians.
RECENT FINDINGS:
Early-onset AD comprises about 5% to 6% of cases of AD and includes a substantial percentage
of phenotypic variants that differ from the usual amnestic presentation of typical AD.
Characteristics of early-onset AD in comparison to late-onset AD include a larger genetic
predisposition (familial mutations and summed polygenic risk), more aggressive course, more

frequent delay in diagnosis, higher prevalence of traumatic brain injury, less memory impairment
and greater involvement of other cognitive domains on presentation, and greater psychosocial
difficulties. Neuroimaging features of early-onset AD in comparison to late-onset AD include
greater frequency of hippocampal sparing and posterior neocortical atrophy, increased tau
burden, and greater connectomic changes affecting frontoparietal networks rather than the
default mode network.
SUMMARY:
Early-onset AD differs substantially from late-onset AD, with different phenotypic
presentations, greater genetic predisposition, and differences in neuropathologic burden and
topography. Early-onset AD more often presents with nonamnestic phenotypic variants that
spare the hippocampi and with greater tau burden in posterior neocortices. The early-onset AD
phenotypic variants involve different neural networks than typical AD. The management of
early-onset AD is similar to that of late-onset AD but with special emphasis on targeting specific
cognitive areas and more age-appropriate psychosocial support and education.
KEY POINTS
• Early-onset Alzheimer disease, which makes up about 5% to 6% of all cases of Alzheimer disease, is
distinct from late-onset Alzheimer disease in a number of clinical, genetic, neurobiological, and management
features.
• Early-onset Alzheimer disease is the most common cause of early-onset neurodegenerative dementia.
• Many clinical, neuropathologic, and management differences exist between early-onset and late-onset
Alzheimer disease.
• One major difference between early-onset and late-onset Alzheimer disease is that one-third or more of
patients with early-onset Alzheimer disease present with language, visuospatial, or other phenotypes rather
than the usual amnestic disorder seen in late-onset Alzheimer disease.
• MRI of patients with early-onset Alzheimer disease shows more widespread cortical atrophy, particularly in
the parietal cortex, compared to the more limited atrophy affecting temporal regions in patients with
late-onset Alzheimer disease.
• Fludeoxyglucose positron emission tomography shows greater parietal hypometabolism in early-onset
Alzheimer disease compared to greater bilateral temporal hypometabolism in late-onset Alzheimer disease.
• Amyloid positron emission tomography is positive in most patients with early-onset Alzheimer disease who
would not be expected to have age-associated brain amyloid deposition and can be useful in diagnosis of
the disorder.
• Tau positron emission tomography has promise for future use in early-onset Alzheimer disease, particularly in
correlating localization of changes with clinical symptoms.
• CSF analysis in early-onset Alzheimer disease is similar to late-onset Alzheimer disease, showing the
characteristic low amyloid-β1-42 and high total tau and phosphorylated tau levels but with some variations.
• The vast majority of patients with early-onset Alzheimer disease have a nonfamilial, or sporadic, form.
• Only 11% or less of those with early-onset Alzheimer disease (about 0.6% of the total of all patients with
Alzheimer disease of any age) have familial Alzheimer disease associated with one of the three known
autosomal dominant mutations in APP, PSEN1, or PSEN2.
• An active area of genetic research is the recognition of a polygenic risk for sporadic early-onset Alzheimer
disease from a number of susceptibility genes.
• On neuropathology, patients with early-onset Alzheimer disease (especially with the variants) are more likely
to have hippocampal sparing with increased neocortical tau pathology, particularly in the parietal cortex
and, to a lesser extent, the frontal cortex, than patients with late-onset Alzheimer disease.
• On neuropathology, tau and neurofibrillary tangles, more than amyloid-b1-42 and neuritic plaques,
correspond with the features of early-onset Alzheimer disease, with a relatively greater tau burden in
early-onset Alzheimer disease than in late-onset Alzheimer disease.

• Phenotypic variants of early-onset Alzheimer disease include those that present with language impairment
(known as logopenic variant primary progressive aphasia), those that present with visuospatial or
visuoperceptual impairments (known as posterior cortical atrophy), frontal or behavioral/executive variants,
a number of parietal syndromes (such as the acalculia variant of early-onset Alzheimer disease), and a
subgroup of patients with corticobasal syndrome.
• Phenotypic variants of early-onset Alzheimer disease may involve alternative frontoparietal neural networks
rather than the posterior default mode network implicated in late-onset Alzheimer disease.
• Logopenic variant primary progressive aphasia, the most common nonamnestic phenotypic variant of
early-onset Alzheimer disease, presents with a progressive decline in language with relatively spared
memory and cognition due to focal Alzheimer neuropathology in temporoparietal language areas in the left
hemisphere, especially the superior/midtemporal gyrus, angular gyrus, and midfrontal cortex.
• In logopenic variant primary progressive aphasia, neuroimaging and CSF studies usually reveal abnormalities
consistent with early-onset Alzheimer disease, including focal atrophy and decreased metabolism in the
left temporoparietal junction.
• Posterior cortical atrophy, the second most common early-onset Alzheimer disease variant, presents with
progressive and disproportionate loss of visuospatial or visuoperceptual functions, usually due to Alzheimer
neurodegeneration of posterior visual cortical regions.
• The frontal variant of Alzheimer disease, now known as behavioral/dysexecutive Alzheimer disease, presents
with features suggestive of frontotemporal lobar degeneration but most commonly with apathy or abulia.
• Less common phenotypic variants of early-onset Alzheimer disease may have prominent parietal lobe
symptoms and signs, exemplified by the acalculia variant from early Alzheimer neuropathology in the left
inferior parietal lobule, particularly the intraparietal sulcus.
• Acetylcholinesterase inhibitors, such as donepezil, galantamine, and rivastigmine, are indicated in the
management of patients with early-onset Alzheimer disease, with the usual precautions and titration schedules.
• The management of early-onset Alzheimer disease may differ from late-onset Alzheimer disease when
targeting the management of specific cognitive and behavioral deficits.
• Management of patients with early-onset Alzheimer disease must also consider providing genetic counseling
if patients are to be evaluated for familial Alzheimer disease when the family history is suggestive of an
autosomal dominant disorder.
• The provision of age-appropriate psychosocial support is important in the management of early-onset
Alzheimer disease.
Article 3: Posterior Cortical Atrophy

Jonathan M. Schott, BSc, MD, FRCP, FEAN, SFHEA; Sebastian J. Crutch, PhD, CPsych.
Continuum (Minneap Minn). February 2019; 25 (1 Dementia):52–75.
ABSTRACT
PURPOSE OF REVIEW:
This article presents an overview of the clinical syndrome of posterior cortical atrophy (PCA),
including its pathologic underpinnings, clinical presentation, investigation findings, diagnostic
criteria, and management.
RECENT FINDINGS:
PCA is usually an atypical form of Alzheimer disease with relatively young age at onset. New
diagnostic criteria allow patients to be diagnosed on a syndromic basis as having a primary visual
(pure) form or more complex (plus) form of PCA and, when possible, on a disease-specific basis
using biomarkers or underlying pathology. Imaging techniques have demonstrated that some

pathologic processes are concordant (atrophy, hypometabolism, tau deposition) with clinical
symptoms and some are discordant (widespread amyloid deposition). International efforts are
under way to establish the genetic underpinnings of this typically sporadic form of Alzheimer
disease. In the absence of specific disease-modifying therapies, a number of practical
suggestions can be offered to patients and their families to facilitate reading and activities of
daily living, promote independence, and improve quality of life
SUMMARY:
While rare, PCA is an important diagnostic entity for neurologists, ophthalmologists, and
optometrists to recognize to allow for early accurate diagnosis and appropriate patient
management. PCA provides an important opportunity to investigate the causes of selective
vulnerability in Alzheimer disease.
KEY POINTS
• A striking feature of posterior cortical atrophy is that the majority of affected individuals have an unusually
early age at disease onset, typically presenting between 50 and 65 years of age.
• Most patients with posterior cortical atrophy have underlying Alzheimer disease.
• The core features of posterior cortical atrophy include visuospatial and perceptual deficits as well as
features of Gerstmann syndrome (acalculia, left-right disorientation, finger agnosia, and agraphia), Balint
syndrome (ocular motor apraxia, optic ataxia, and simultanagnosia), alexia, and apraxia.
• Patients with posterior cortical atrophy may have a history of repeated visits to optometrists and
ophthalmologists and multiple unsuccessful changes in eyeglasses or surgical procedures in an attempt to
correct acuity.
• Over time, difficulties with reading emerge in the vast majority of patients with posterior cortical atrophy.
• Patients with posterior cortical atrophy often become anxious about riding on escalators, particularly when
going down; can be cautious when crossing the road because of difficulties in judging the speed of traffic;
and can have difficulty with revolving doors.
• Combinations of visual problems and dyspraxia in patients with posterior cortical atrophy have significant
functional consequences, including difficulty in getting dressed; cooking; and using cell phones, remote
controls, and computers.
• Simultanagnosia (the inability to interpret the entirety of a visual scene) can often be demonstrated by asking
an individual to describe a complex picture; rather than describing it in its entirety, individuals with posterior
cortical atrophy will often hone in on specific features and fail to see the picture as a whole.
• A particularly striking and very common feature of posterior cortical atrophy is the presence of an
apperceptive agnosia.
• Visual disorientation (likely reflecting combinations of simultanagnosia and optic ataxia), when present, is a
striking sign in patients with posterior cortical atrophy.
• When performing neuropsychological testing in posterior cortical atrophy, it is important that the testing
psychologist is aware of the patient’s difficulties with vision, ensuring that test material is, whenever
possible, presented in verbal rather than visual form.
• In the presence of a typical history for posterior cortical atrophy, the absence of marked parietooccipital
volume loss should not exclude the diagnosis.
• Fludeoxyglucose positron emission tomography may be extremely valuable in demonstrating
hypometabolism within the parietooccipital cortices.
• While amyloid positron emission tomography has a role in confirming the presence or absence of amyloid
pathology, it is not useful in distinguishing between Alzheimer disease syndromes.
• Tau positron emission tomography, which is currently only available in a research setting, often shows very
striking posterior cortical deposition of tau pathology.
• Posterior cortical atrophy due to Alzheimer disease is a sporadic condition, and routine testing for the
autosomal dominant forms of the disease is not usually indicated.

• For most patients with posterior cortical atrophy due to Alzheimer disease, treatment with
acetylcholinesterase inhibitors or memantine, as would be standard treatment for Alzheimer disease, is
appropriate.
• The mainstay of management of patients with posterior cortical atrophy (as with typical Alzheimer disease) is
the provision of practical and psychological support to affected patients and their caregivers.
• Most patients with posterior cortical atrophy will not be fit to drive. Establishing driving safety is of
paramount importance.
Article 4: Behavioral Variant

Frontotemporal Dementia
William W. Seeley, MD. Continuum (Minneap Minn). February 2019; 25 (1 Dementia):76–100.
ABSTRACT
PURPOSE OF REVIEW:
This article describes the clinical, anatomic, genetic, and pathologic features of behavioral
variant frontotemporal dementia (bvFTD) and discusses strategies to improve diagnostic
accuracy, emphasizing common pitfalls to avoid. Key aspects of management and the future of
diagnosis and care for the disorder are highlighted.
RECENT FINDINGS:
BvFTD is a clinical syndrome, not a disease. Patients with the syndrome share core symptoms
that reflect degeneration within the most consistently affected brain regions, but accompanying
features vary and reflect the precise topography of regional degeneration. The clinician must
distinguish a bvFTD syndrome from psychiatric illness and other neurodegenerative syndromes
that feature a prominent behavioral component. Antemortem prediction of pathologic diagnosis
remains imperfect but improves with careful attention to the clinical details. Management
should emphasize prevention of caregiver distress, behavioral and environmental strategies,
symptom-based psychopharmacology, and genetic counseling.
SUMMARY:
BvFTD is an important and challenging dementia syndrome. Although disease-modifying
treatments are lacking, clinicians can have a profound impact on a family coping with this
disorder. Treatment trials are under way for some genetic forms of bvFTD. For sporadic disease,
pathologic heterogeneity remains a major challenge, and ongoing research seeks to improve
antemortem molecular diagnosis to facilitate therapeutic discovery.
KEY POINTS
• Behavioral variant frontotemporal dementia (bvFTD) is an important disorder than can be difficult to
recognize, in part because of the wide normative variation in social-emotional functions and the long list of
disorders that affect those functions.
• BvFTD is a syndrome, not a disease, and clinicians who diagnose bvFTD should generate a differential
diagnosis.
• BvFTD presents with slowly progressive decline in social and emotional functions.
• BvFTD core diagnostic features reflect degeneration of networked structures, typically including the anterior
insula, anterior cingulate and adjacent medial prefrontal cortices, amygdala, striatum, and thalamus.
• Features that develop less frequently in patients with bvFTD reflect variable involvement of additional brain
regions.

• Patients with bvFTD often develop prominent motor deficits of various types later in the course of the
syndrome.
• BvFTD is the result of a known pathogenic variant in 15% to 20% of patients.
• Expansions in C9orf72 are the most common genetic cause of bvFTD and are commonly accompanied by
motor neuron disease.
• BvFTD results from a diverse array of neuropathologic entities, most of which are classified as
frontotemporal lobar degeneration.
• Accurate bvFTD diagnosis requires a methodical stepwise approach that relies heavily on the clinical history.
• Both neurodegenerative and non-neurodegenerative causes should be considered in all patients with bvFTD.
• Structural MRI and, increasingly, molecular biomarkers play a key role in predicting pathology in patients
with a bvFTD syndrome.
• Occasionally, patients with bvFTD have severe early memory loss or a normal MRI.
• Executive dysfunction is common in bvFTD but also in other disorders and should not be used as an indicator
of bvFTD unless accompanied by signature social-emotional features.
• Model care for bvFTD involves contributions from a multidisciplinary team that supports both patient and
caregiver.
• BvFTD caregivers are at high risk for burnout.
• Nonpharmacologic approaches are often the best way to manage troublesome behavioral symptoms in
bvFTD.
• Pharmacologic management of bvFTD should target specific symptoms, such as overeating, compulsivity,
severe agitation, or psychosis.
• Selective serotonin reuptake inhibitors are first-line therapy for overeating and compulsivity symptoms in
bvFTD.
• Acetylcholinesterase inhibitors have shown no benefit in bvFTD and may worsen behavioral symptoms.
Article 5: Primary Progressive Aphasias

and Apraxia of Speech
Hugo Botha, MBChB; Keith A. Josephs, MD, MST, MSc. Continuum (Minneap Minn).
February 2019; 25 (1 Dementia):101–127.
ABSTRACT
PURPOSE OF REVIEW:
This article reviews two of the primary progressive aphasias (PPAs), disorders characterized
by the early and predominant impairment of language, and primary progressive apraxia of
speech, a degenerative motor speech disorder that is closely related to PPA. An outline of the
history and controversy surrounding how these disorders are classified is provided before the
article focuses on each disorder’s clinical and imaging features.
RECENT FINDINGS:
Over the past decade, the classification of degenerative speech and language disorders has
been refined. Clinical, imaging, and pathologic evidence suggests that primary progressive
apraxia of speech is a distinct degenerative disorder. Furthermore, multiple lines of evidence
have highlighted issues with nonfluent/agrammatic variant PPA, which complicates the
diagnosis, prognosis, and study of this disorder. Semantic variant PPA, while not without
controversy, remains one of the most well-defined disorders, with good clinicopathologic
correlation.

SUMMARY:
Accurate classification and diagnosis of these degenerative speech and language disorders is
crucial in clinical practice and ongoing research efforts. For nonfluent/agrammatic variant PPA,
the authors suggest emphasizing agrammatism as the core inclusion criterion and taking care not
to include patients with isolated or predominant apraxia of speech. Isolated apraxia of speech
can be the manifestation of a degenerative disease and, based on the different prognosis,
should be recognized as distinct from PPA. Finally, it is important to recognize that some
patients with semantic dementia, despite sharing the same pathologic associations, may not
meet criteria for PPA.
KEY POINTS
• Primary progressive aphasia refers to a group of neurodegenerative diseases characterized by early and
prominent language impairment occurring in the relative absence of cognitive impairment, behavioral
disturbance, or motor symptoms.
• Three canonical variants of primary progressive aphasia (PPA) are recognized, of which two
(nonfluent/agrammatic variant PPA and semantic variant PPA) are classified as frontotemporal dementia
syndromes while the other (logopenic variant PPA) is most commonly viewed as an atypical variant of
Alzheimer disease.
• Apraxia of speech is a motor speech disorder thought to result from impaired planning and programming of
the movements required for speech production.
• The most widely accepted current classification scheme and diagnostic criteria for primary progressive
aphasia consists of two stages. First, a root diagnosis of primary progressive aphasia is considered.
Second, criteria for the three main variants are considered, each with a set of mandatory and supportive
features.
• While motor speech disorders such as dysarthria and apraxia of speech often co-occur with aphasia, these
are clearly not language impairments that would, on their own, qualify a patient for a diagnosis of primary
progressive aphasia.
• The relative dominance of phonetic impairment (sound level errors, such as distorted substitutions or
additions) or prosodic impairment (such as slow rate or segmented speech) is the primary source of
heterogeneity in apraxia of speech.
• Primary progressive apraxia of speech refers to cases in which apraxia of speech is the sole initial
manifestation of a neurodegenerative disease.
• In primary progressive apraxia of speech, it is crucial to ask about writing or typing, as preservation of these
forms of communication is often striking despite severe speech impairment.
• Cases in which apraxia of speech dominates over aphasia appear to have clinical and imaging features that
are more like those seen in primary progressive apraxia of speech than nonfluent/agrammatic variant
primary progressive aphasia.
• Patients with primary progressive apraxia of speech typically score well within the normal range on bedside
cognitive testing and may continue to do so in the later disease stages, provided written responses are
allowed.
• The most helpful parts of the speech examination for primary progressive apraxia of speech are those
that demand the production of motorically complex utterances: conversational or narrative speech,
alternating motion rates, sequential motor rates, and repetition of increasingly complex words and
sentences.
• About two-thirds of patients with primary progressive apraxia of speech have a coexisting nonverbal oral
apraxia, which can be assessed at the bedside by asking the patient to perform simple movements such as
smacking their lips, clicking their tongue, coughing, or blowing.
• Gray and white matter atrophy of the motor, premotor, and supplementary motor areas bilaterally has been
reported in primary progressive apraxia of speech at group level, but it is worth noting that this may be
fairly asymmetric at the single patient level.

• Approximately 40% of patients with primary progressive apraxia of speech develop a progressive
supranuclear palsy/corticobasal syndrome–like disorder, which has been termed progressive supranuclear
palsy–apraxia of speech, approximately 5 years into their illness.
• The overwhelming majority of autopsied cases of primary progressive apraxia of speech reported in the
literature were found to have an underlying 4-repeat tauopathy, with corticobasal degeneration pathology
being the most common.
• While some patients or informants may volunteer examples of impaired grammar or syntax, focused
questioning is often necessary to reveal early problems.
• When assessing language ability, it is important to bear in mind that aphasia typically involves all aspects
of language to varying degrees, and thus the primary progressive aphasia classification depends on the
relative impairment.
• When evaluating patients for nonfluent/agrammatic variant primary progressive aphasia, it is helpful to
review samples of written language, such as emails, as they frequently contain errors involving word order or
functional morphemes.
• The rest of the neurologic examination is typically unrevealing in nonfluent/agrammatic variant primary
progressive aphasia, although mild ideomotor apraxia and parkinsonism are possible.
• The anterior portions of the language network appear to be most vulnerable in nonfluent/agrammatic variant
primary progressive aphasia, including Broca areas 44 and 45.
• The subset of nonfluent/agrammatic variant primary progressive aphasia cases with apraxia of speech are
more likely to have underlying 4-repeat tau.
• Semantic dementia results from a breakdown in semantic memory, the amodal and time-independent
knowledge store, in contrast to the episodic memory system, which is involved with recall of specific events
or experiences.
• About 70% of cases of semantic dementia have predominant left-sided involvement (ie, would be viewed
as semantic variant primary progressive aphasia), while the remaining 30% present with predominant
right-sided involvement.
• Nouns are typically most difficult for patients with semantic variant primary progressive aphasia, which may
result in circumlocution, the use of a more general or category label, or the use of nonspecific filler words.
• Testing for prosopagnosia is usually done by showing patients pictures of celebrities or other famous people
and asking them to either identify the famous face among distractors or to provide some information to
prove that they have correctly recognized the person.
• Whereas patients with nonfluent/agrammatic variant or logopenic variant primary progressive aphasia
typically benefit greatly from cueing on unnamed items, patients with semantic variant primary progressive
aphasia often fail to choose the correct word from a small list.
• A supportive, albeit not specific, feature of semantic variant primary progressive aphasia is trouble with
reading (surface dyslexia) and writing {surface dysgraphia) of irregularly spelled words, such as yacht,
colonel, and debt.
• Focal anterior temporal pole involvement is characteristic of semantic dementia.
• Semantic dementia appears to be the frontotemporal dementia syndrome with the lowest risk of an
underlying genetic cause.
• The majority (>80%) of semantic dementia cases are associated with the accumulation of TDP-43 Type C.
• Even in unclassified or mixed cases of primary progressive aphasia, the presence of certain features (eg,
apraxia of speech) may still influence management and can still be predictive of the underlying pathology.
• The lack of pharmacologic options to treat speech and language disorders should not dissuade the physician
or patient from seeking therapeutic options, and referral to a speech and language pathologist is highly
recommended when a degenerative speech and language disorder is considered.

Article 6: Lewy Body Dementias
Melissa J. Armstrong, MD, MSc, FAAN. Continuum (Minneap Minn). February 2019; 25 (1
Dementia):128–146.
ABSTRACT
PURPOSE OF REVIEW:
This article describes current diagnostic criteria relating to the diagnosis of Lewy body dementia,
highlights diagnostic controversies, and reviews treatment approaches.
RECENT FINDINGS:
Clinical diagnostic criteria for both Parkinson disease and dementia with Lewy bodies have been
recently updated. These criteria result in overlap between individuals diagnosed with Parkinson
disease and those with dementia with Lewy bodies. Although clinical features and symptomatic
treatment overlap, differences remain in epidemiology and expected progression. The high
prevalence of cognitive impairment in Parkinson disease supports regular screening for cognitive
changes and counseling patients and families regarding what to expect. Treatment for Lewy
body dementia involves avoiding medications that may cause or exacerbate symptoms;
prescribing pharmacologic agents to address bothersome cognitive, behavioral, movement, and
other nonmotor symptoms; recommending physical exercise and therapy; and providing
education, counseling, caregiver support, and palliative care.
SUMMARY:
Lewy body dementia includes both dementia with Lewy bodies and Parkinson disease dementia,
overlapping clinicopathologic entities with differences relating to diagnosis and expected
progression. Treatment is symptomatic and thus largely overlapping for the two conditions.
KEY POINTS
• Lewy body dementia is an umbrella term that includes the clinical diagnoses of both Parkinson disease
dementia and dementia with Lewy bodies.
• According to current diagnostic criteria from the Dementia With Lewy Bodies Consortium, probable dementia
with Lewy bodies is diagnosed in the context of a dementia consistent with the dementia with Lewy
bodies phenotype and either two or more core clinical features or the presence of one core clinical feature
and at least one indicative biomarker.
• In dementia with Lewy bodies, visual processing, attention, and executive functioning are typically more
impaired than memory and naming.
• Individuals with a history of rapid eye movement sleep behavior disorder are 6 times more likely to have
autopsy-confirmed dementia with Lewy bodies than other neurodegenerative dementias.
• Parkinson disease psychosis includes a broad range of experiences, including hallucinations in various
modalities, sense of presence or passage, illusions, and delusions.
• The American Academy of Neurology Parkinson disease quality measurement set includes a measure
identifying the percentage of patients with Parkinson disease who were assessed for cognitive
dysfunction in the past 12 months using a recommended screening tool or neuropsychological
assessment.
• The diagnosis of Parkinson disease-mild cognitive impairment should prompt clinicians to identify potentially
modifiable risk factors for cognitive impairment, perform serial evaluations to monitor for changes in
cognitive status, assess functional capabilities, and counsel patients and families to discuss long-term
planning topics.

• In a 2016 study examining cause of death in Lewy body dementia, dementia was described as a contributor to
death 71% of the time, followed by circulatory (45%) and respiratory (38%) contributors, consistent with
reports that pneumonia is the most common cause of death in Parkinson disease dementia (25%).
• Treating individuals with Lewy body dementia and their families should include querying safety concerns and
driving safety, assessing pain, screening for and managing behavioral and psychiatric symptoms, discussing
pharmacologic and nonpharmacologic treatment approaches, encouraging advance care planning, and
providing palliative care counseling and caregiver education and support.
• The first step in successfully treating an individual with Lewy body dementia is to identify medications that
could contribute to symptoms or are best avoided in older adults with dementia.
• Cognitive symptoms in Lewy body dementia are treated with cholinesterase inhibitors, with use supported by
multiple systematic reviews and meta-analyses.
• Pimavanserin was approved by the US Food and Drug Administration for Parkinson disease psychosis in 2016
based on a single randomized controlled trial, and it is the only approved treatment for this indication.
While high-level efficacy data are lacking, quetiapine and clozapine are also commonly used to treat
psychosis in the context of Parkinson disease and Lewy body dementia as these are safer than alternative
antipsychotics. All antipsychotic agents have a boxed warning regarding increased risk of death in patients
with dementia-related psychosis.
• Melatonin is first-line treatment for rapid eye movement sleep behavior disorder in the context of Lewy body
dementia, but clonazepam is often cautiously tried if melatonin is not sufficiently helpful.
• Physical therapy, occupational therapy, and speech-language pathology assessments (addressing both
speech and swallowing) are important interdisciplinary considerations for care of patients with Lewy body
dementia. Therapy sessions will usually include both patients and caregivers to compensate for patients’
cognitive limitations and also to teach caregiver-specific skills (eg, assistance in transfers and fall reduction).
Article 7: Vascular Cognitive Impairment

Jonathan Graff-Radford, MD. Continuum (Minneap Minn). February 2019; 25 (1
Dementia):147–164.
ABSTRACT
PURPOSE OF REVIEW:
This article provides an overview of vascular cognitive impairment; discusses its epidemiology,
subtypes, and associations with other neurodegenerative diseases; and reviews the diagnostic
evaluation and management of these disorders.
RECENT FINDINGS:
Cerebrovascular disease is a common cause of dementia and frequently coexists with
neurodegenerative causes. The heterogeneity of mechanisms leading to vascular cognitive
impairment makes developing unifying clinical and research criteria difficult. Recognizing the
neuroimaging hallmarks of different forms of vascular cognitive impairment can allow for
individualized treatment and management. In individuals with mild vascular cognitive impairment,
aerobic exercise appears to be a promising treatment but requires further investigation.
SUMMARY:
Vascular cognitive impairment can be caused by several mechanisms. While treating vascular
risk factors is rational to prevent worsening of cognitive impairment, well-designed studies are
needed to demonstrate efficacy.
KEY POINTS
• Vascular cognitive impairment represents a spectrum of vascular disorders that cause cognitive impairment.

• No single neuropsychological pattern distinguishes vascular cognitive impairment from other etiologies of
cognitive impairment; however, patients with vascular cognitive impairment tend to perform worse on tests
of executive function compared to memory function.
• In the community setting, cerebrovascular disease commonly occurs with neurodegenerative diseases.
• Both clinical and so-called “silent” strokes are significant risk factors for the development of dementia.
• Neuroimaging biomarkers may allow for identification of different mechanisms leading to small vessel
disease. For example, deep cerebral microbleeds are suggestive of hypertensive arteriopathy, and lobar
cerebral microbleeds are suggestive of cerebral amyloid angiopathy.
• Several strategic brain regions have been associated with the development of dementia after an infarct,
including the angular gyrus, thalamus, caudate and putamen, basal forebrain, posterior cerebral artery (ie,
hippocampus), and anterior cerebral artery territories.
• While multi-infarct dementia was once considered synonymous with vascular dementia, it is now recognized
that multi-infarct dementia represents a subset of individuals with vascular cognitive impairment.
• Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a
genetic cerebral small vessel disease caused by mutations in the NOTCH3 gene. Cognitive impairment is
common in CADASIL, as are migraine headaches and stroke.
• T2 hyperintensity involvement of the anterior temporal lobes on MRI may suggest CADASIL as a possible
diagnosis.
• Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL)
occurs due to mutations in the HTRA1 gene and is associated with alopecia and spondylosis in addition to the
cerebral small vessel disease.
• Microinfarcts are increasingly recognized as an important contributor to cognitive decline. Recent advances
in MRI techniques have allowed a subset to be imaged in vivo.
• Treatment of vascular risk factors in midlife, aerobic exercise, and a Mediterranean diet are promising
treatments to prevent and treat vascular cognitive impairment but require further investigation.
Article 8: Normal Pressure

Hydrocephalus
Neill R. Graff-Radford, MBBCH, FRCP, FAAN; David T. Jones, MD. Continuum (Minneap
Minn). February 2019; 25 (1 Dementia):165–186.
ABSTRACT
PURPOSE OF REVIEW:
Since it was first described in 1965, normal pressure hydrocephalus (NPH) has been a
controversial subject. New studies have shed light on its epidemiology and pathogenesis and
provided objective ways to measure outcome in patients with NPH. Neuroimaging has improved
and allows better recognition of both NPH and the presence of overlapping diseases
RECENT FINDINGS:
Several recent epidemiologic studies confirm that NPH is a rare disease, but the presence of
large ventricles is a common finding with aging. NPH may be multifactorial, including congenital
causes, vascular disease, and impaired CSF absorption. MRI features of NPH include enlarged
ventricular size and CSF fluid collection outside the ventricles not due to atrophy. The term
disproportionately enlarged subarachnoid space hydrocephalus (DESH) has been used to
describe prognostic MRI features in NPH, including a “tight high convexity” and enlargement of
CSF spaces in the sylvian fissure. DESH has been included in the Japanese guideline for the

diagnosis and treatment of NPH. A new NPH scale has been published that provides an objective
framework for evaluating patients with NPH before and after shunt placement. Programmable
shunts can noninvasively manage overdrainage complications. Surgical outcome has been
improving over time. Recent studies have led to improved recognition of overlapping diseases
such as Alzheimer pathology, which co-occurs in about 30% of NPH cases. Fludeoxyglucose
positron emission tomography (FDG-PET) is a promising imaging modality for diagnosing NPH and
detecting concomitant degenerative disease.
SUMMARY:
A systematic approach to patients with possible NPH allows recognition of the subset of patients
whowill respond to shunt surgery and identification of those with alternative diagnoses.
KEY POINTS
• Hydrocephalus can occur as fluid accumulation both inside and outside the ventricles.
• Factors associated with so-called idiopathic normal pressure hydrocephalus include impaired CSF
absorption, vascular disease, and congenital hydrocephalus. All these factors may alter CSF dynamics in a
way that can lead to increased CSF content in the cranial vault while maintaining a relatively normal average
CSF pressure.
• Normal pressure hydrocephalus is an uncommon disease, but large ventricles are commonly seen in persons
older than 70 years of age.
• No pathognomonic individual or combination of clinical features exists for normal pressure hydrocephalus.
Comorbid diseases are common and should be evaluated.
• The triad of gait abnormality, incontinence, and cognitive impairment seen in normal pressure hydrocephalus
may possibly be related to periventricular frontal cortical–basal ganglia–thalamocortical circuitry. Most
often, patients with normal pressure hydrocephalus do not have the full triad of symptoms, and gait
abnormality usually presents first.
• Cognitive features of normal pressure hydrocephalus include psychomotor slowing, decreased attention and
concentration, impaired executive functions, and apathy. Anomia suggests the presence of a cortical
dementia and is a poor prognostic factor when deciding about shunt placement.
• The differential diagnosis of gait abnormalities in the elderly is broad and should be reviewed in detail when
evaluating patients for normal pressure hydrocephalus.
• A focused history and examination should be performed looking for diseases that can co-occur or mimic the
symptoms of normal pressure hydrocephalus and looking for factors that may influence management.
• In the assessment of patients for NPH, establish that there is ventriculomegaly; look for congenital factors
such as aqueductal stenosis or webbing; and recognize the features of disproportionately enlarged
subarachnoid space hydrocephalus (DESH), not mistaking DESH for atrophy.
• The two best diagnostic tests for normal pressure hydrocephalus are evaluating the MRI for the
characteristic features, and performance of a high-volume lumbar puncture, measuring gait features
objectively before and within 30 minutes after the lumbar puncture.
• Overlapping chronic diseases are common in persons being considered for shunt surgery because their
average age is about 74 years. At this age, 30% of cognitively normal persons have Alzheimer disease
pathology. Fludeoxyglucose positron emission tomography may help reveal a concomitant degenerative
disease.
• In idiopathic normal pressure hydrocephalus, most metabolic proteins are low in the CSF, so Alzheimer
biomarkers (eg, amyloid-β1-42 and phosphorylated tau) are also low and are not helpful in distinguishing
Alzheimer disease from idiopathic normal pressure hydrocephalus.
• Surgical complications following shunt surgery are common but have decreased over the decades.
Adjustable shunts allow treatment of overdrainage without surgical intervention.
• Objective measurements to assess patient change with shunt placement are very helpful in management.

• Surgical outcome is improving, and patients who are seen in follow-up 3 years after shunt surgery have a good
chance of remaining improved.
Article 9: Chronic Traumatic

Encephalopathy
Katherine W. Turk, MD; Andrew E. Budson, MD. Continuum (Minneap Minn). February
2019; 25 (1 Dementia):187–207.
ABSTRACT
PURPOSE OF REVIEW:
This article provides a discussion on the current state of knowledge of chronic traumatic
encephalopathy (CTE), with an emphasis on clinical features and emerging biomarkers of the
condition.
RECENT FINDINGS:
The results of several large brain bank case series among subjects with a history of contact
sports or repetitive head trauma have indicated that a high frequency of CTE may exist in this
population. However, the true prevalence of CTE among individuals with a history of head
trauma remains unknown, given that individuals who experienced cognitive, behavioral, and
mood symptoms during life are more likely to have their brains donated for autopsy at death and
epidemiologic studies of the condition are lacking. Neuropathologic consensus criteria have
been published. Research-based clinical criteria have been proposed and are beginning to be
applied, but the definitive diagnosis of CTE in a living patient remains impossible without
effective biomarkers for the condition, which is an active area of study.
SUMMARY:
The field of CTE research is rapidly growing and parallels many of the advances seen for other
neurodegenerative conditions, such as Alzheimer disease decades ago.
KEY POINTS
• Chronic traumatic encephalopathy is a pathologically defined neurodegenerative disorder associated with
repetitive concussive or subconcussive head injury.
• The frequency, severity, and total exposure to head trauma and the exact pathophysiologic mechanism by
which blows to the head result in chronic traumatic encephalopathy are active areas of research.
• Head injury is an important but nonsufficient risk factor in the development of chronic traumatic
encephalopathy; other exposure and genetic risk factors are under investigation.
• Currently, no validated clinical diagnostic criteria for chronic traumatic encephalopathy exist, although
research diagnostic criteria have been developed.
• Concussion is a clinical syndrome of impaired brain function, typically impacting memory and orientation,
with or without loss of consciousness that results from head injury.
• Chronic traumatic encephalopathy is defined by neuropathology: perivascular aggregation of
phosphorylated tau protein within neurons and astrocytes that begins in the depths of sulci and progresses
to involve the medial temporal lobes and other parts of the brain.
• Chronic traumatic encephalopathy deficits involve progressive cognitive, behavior, and mood changes as
well as possible motor deficits.
• The most common cognitive difficulties in patients with chronic traumatic encephalopathy involve memory
and executive function.

• Four traumatic encephalopathy syndrome subtypes have been described: (1) a behavioral/mood variant,
occurring in younger patients; (2) a cognitive variant, which occurs later in life; (3) a mixed variant; and (4)
a dementia form.
• The classification of patients into the diagnostic categories probable, possible, and unlikely chronic
traumatic encephalopathy relies, in part, on results of potential research-based biomarker findings, thus
diagnoses are for use in research, not clinical settings.
• The evaluation for possible chronic traumatic encephalopathy should include asking about a history of
repetitive head trauma, with or without concussion, including exposures during contact sports, military
service, domestic abuse, assault, and motor vehicle accidents.
• The differential diagnosis for chronic traumatic encephalopathy often includes frontotemporal dementia and
Alzheimer disease.
• No disease-modifying or symptomatic treatments for chronic traumatic encephalopathy are US Food and
Drug Administration approved. All medication management is off-label and symptom-based, and can include
acetylcholinesterase inhibitors, selective serotonin reuptake inhibitors, and memantine.
• The incidence and prevalence of chronic traumatic encephalopathy is unknown because of a lack of
epidemiologic data. However, the frequency of chronic traumatic encephalopathy is potentially increased
within the professional contact sports community and others exposed to head trauma.
• The age of clinical onset of traumatic encephalopathy syndrome/chronic traumatic encephalopathy
symptoms is delayed by several years or decades following exposure to head injuries and is currently
estimated to be between 30 and 65 years of age.
• Posttraumatic stress disorder and traumatic brain injury often co-occur in military veterans and may share a
common pathophysiology.
• Posttraumatic stress disorder, postconcussive disorder, and chronic traumatic encephalopathy share many
common symptoms, including difficulty with concentration, changes in mood, memory problems, irritability,
and sleep disturbances.
• Chronic traumatic encephalopathy frequently involves TDP-43 pathology, but TDP-43 is not necessary for
pathologic confirmation.
• Chronic traumatic encephalopathy can co-occur pathologically with other neurodegenerative conditions,
including motor neuron disease, Alzheimer disease, Lewy body disease, and frontotemporal dementia.
• The main genetic risk factor investigated in association with head injury and chronic traumatic
encephalopathy is the APOE ε4 allele.
• The APOE ε4 allele may lower the threshold for an individual to develop cognitive deficits following repeated
head injury.
• Nongenetic potential risk factors for chronic traumatic encephalopathy include cognitive reserve, age of first
exposure, and cumulative exposure to head injuries.
• Serum tau concentration elevations may indicate the existence of prior head injury but have not been found
to correlate with cognitive function.
Article 10: Hippocampal Sclerosis,

Argyrophilic Grain Disease, and Primary
Age-Related Tauopathy
Gregory A. Jicha, MD, PhD; Peter T. Nelson, MD, PhD. Continuum (Minneap Minn).
February 2019; 25 (1 Dementia):208–233.

ABSTRACT
PURPOSE OF REVIEW:
Hippocampal sclerosis, argyrophilic grain disease, and primary age-related tauopathy are
common Alzheimer disease mimics that currently lack clinical diagnostic criteria. Increased
understanding of these pathologic entities is important for the neurologist who may encounter
patients with an unusually slowly progressive degenerative dementia that may appear to meet
criteria for Alzheimer disease but who progress to develop symptoms that are unusual for classic
Alzheimer disease
RECENT FINDINGS:
Hippocampal sclerosis has traditionally been associated with hypoxic/ischemic injury and
poorly controlled epilepsy, but it is now recognized that hippocampal sclerosis may also be
associated with a unique degenerative disease of aging or may be an associated pathologic
finding in many cases of frontotemporal lobar degeneration. Argyrophilic grain disease has been
recognized as an enigma in the field of pathology for over 30 years, but recent discoveries
suggest that it may overlap with other tau-related disorders within the spectrum of
frontotemporal lobar degeneration. Primary age-related tauopathy has long been recognized as
a distinct clinical entity that lies on the Alzheimer pathologic spectrum, with the presence of
neurofibrillary tangles that lack the coexistent Alzheimer plaque development; thus, it is thought
to represent a distinct pathologic entity.
SUMMARY:
Despite advances in dementia diagnosis that suggest that we have identified and unlocked the
mysteries of the major degenerative disease states responsible for cognitive decline and
dementia in the elderly, diseases such as hippocampal sclerosis, argyrophilic grain disease, and
primary age-related tauopathy demonstrate that we remain on the frontier of discovery and that
our diagnostic repertoire of diseases responsible for such clinical symptoms remains in its
infancy. Understanding such diagnostic confounds is important for the neurologist in assigning
appropriate diagnoses and selecting appropriate therapeutic management strategies for
patients with mild cognitive impairment and dementia.
KEY POINTS
• Several clinically uncharacterized neuropathologic disease states are found at high frequency in the elderly
population and may contribute to the observed inaccuracy of clinical diagnostic criteria in clinicopathologic
correlation studies in dementia.
• Recent and ongoing work over the past several decades has brought to light the importance and high
prevalence of diseases such as hippocampal sclerosis, argyrophilic grain disease, and primary age-related
tauopathy as common mimics of Alzheimer disease and other dementing disorders, largely because their own
clinical phenotype has been poorly elucidated to date.
• The prevalence of diseases such as hippocampal sclerosis, argyrophilic grain disease, and primary age-related
tauopathy can be as high as 20% of normal controls and higher than 50% in individuals with clinical dementia.
• It is now recognized that hippocampal sclerosis occurs not only in “pure” or isolated forms but is frequently
found to be a comorbid process, coexisting with other neurodegenerative pathologies such as Alzheimer
disease, dementia with Lewy bodies, progressive supranuclear palsy, and amyotrophic lateral sclerosis.
• The presence of hippocampal sclerosis should always be suspected in patients diagnosed with
frontotemporal dementia who demonstrate appreciable anterograde amnestic signs and symptoms,
irrespective of other associated clinical features or diagnoses.
• The extent of TDP-43 pathology seen in hippocampal sclerosis of aging can frequently extend well beyond
the medial temporal lobe to include neighboring regions of the frontal and temporal cortices as well as
subcortical regions, demonstrating that hippocampal sclerosis of aging is not confined to the medial
temporal lobe structures but instead can be associated with more widespread pathology.

• The “coiled bodies,” “ballooned” neurons, and “tufted” or “thorny” astrocytes seen in argyrophilic grain
disease all involve accumulation of phosphorylated tau protein, suggesting its central role in the
pathogenesis of the disease. At the time of their original description, it was understood that they were
associated with an increased frequency of clinical dementia, but their presence is not an absolute
determinant of clinical dementia.
• Biochemical differences stemming from discoveries in postmortem brain tissue have not yet been translated
into antemortem serum or CSF biomarkers for argyrophilic grain disease. At present, argyrophilic grain
disease remains a diagnosis that can only be made and confirmed at autopsy.
• In brains with primary age-related tauopathy pathology, neuritic amyloid plaques are not detected, but tau
neurofibrillary tangles are observed.
• By definition, the neurofibrillary tangles of primary age-related tauopathy are not associated with underlying
frontotemporal lobar degeneration or chronic traumatic encephalopathy, differentiating this entity from
other degenerative disease states characterized by predominant tau-related pathology.
• Despite the near-identical molecular and structural nature and anatomic distribution of neurofibrillary
tangles between primary age-related tauopathy and early Alzheimer disease, the neuroanatomic extent of
neurofibrillary tangle pathology in primary age-related tauopathy appears largely restricted to the temporal
lobes, unlike in Alzheimer disease, in which the distribution of neurofibrillary tangles can be more
widespread cortically.
• In large autopsy series, the distribution of primary age-related tauopathy pathology has been shown to be
associated with antemortem cognitive impairment, and primary age-related tauopathy is also implicated in
subjective memory symptoms and mild cognitive impairment.
• Prospective testing of multimodal use of antemortem biomarkers remains to be confirmed but holds much
promise for the antemortem detection of pathologic diseases such as primary age-related tauopathy.
• Hippocampal sclerosis of aging, argyrophilic grain disease, and primary age-related tauopathy all have a
predilection for medial temporal lobe and hippocampal involvement, present in a common phenotype as an
early amnestic syndrome, and can be associated with medial temporal lobe atrophy. These clinical
characteristics make them indistinguishable from Alzheimer disease using routine clinical diagnostic tests
and MRI.
• Hippocampal sclerosis of aging and argyrophilic grain disease (but not primary age-related tauopathy) have
strong associations with the genetic, biochemical, neuroanatomic, and clinical presentations of
frontotemporal lobar degeneration syndromes. These data suggest that frontotemporal lobar
degeneration–associated features are common in the aging population.
• Data acquired over the past decade have advanced our understanding of hippocampal sclerosis of aging,
argyrophilic grain disease, and primary age-related tauopathy and may begin to allow the development of
clinical trials for both symptomatic therapeutics and disease-modifying agents.
Article 11: Reversible Dementias

Gregory S. Day, MD, MSc. Continuum (Minneap Minn). February 2019; 25 (1 Dementia):
234–253.
ABSTRACT
PURPOSE OF REVIEW:
This article describes the clinical features that suggest a reversible cause of dementia.
RECENT FINDINGS:
Substantial variability exists in the presenting features and clinical course of patients with
common neurodegenerative causes of dementia, but the response to available therapies and

eventual outcomes are often poor. This realization has influenced the evaluation of patients with
dementia, with diagnostic approaches emphasizing routine screening for a short list of
potentially modifiable disorders that may exacerbate dementia symptoms or severity but rarely
influence long-term outcomes. Although a standard approach to the assessment of dementia is
appropriate in the vast majority of cases, neurologists involved in the assessment of patients
with dementia must recognize those rare patients with reversible causes of dementia,
coordinate additional investigations when required, and ensure expedited access to treatments
that may reverse decline and optimize long-term outcomes.
SUMMARY:
The potential to improve the outcome of patients with reversible dementias exemplifies the
need to recognize these patients in clinical practice. Dedicated efforts to screen for symptoms
and signs associated with reversible causes of dementia may improve management and
outcomes of these rare patients when encountered in busy clinical practices.
KEY POINTS
• Neurologists involved in the diagnosis and management of patients with dementia should recognize the
symptoms and signs that suggest a reversible cause of dementia.
• Truly reversible causes of dementia account for a small proportion of cases in outpatient clinics.
• Patients with rapidly progressive dementia warrant an expedited assessment, with the goal of rapidly
identifying and remedying reversible causes of and contributors to dementia.
• Younger than expected age at symptomatic onset is a well-recognized marker of secondary causes of
dementia, warranting careful evaluation and screening for reversible causes.
• Autoantibody testing should be considered in all patients meeting criteria for possible autoimmune
encephalitis and in patients 60 years of age or older with characteristic central nervous system syndromes,
even if neuroimaging and CSF findings do not suggest an underlying autoimmune disease.
• Toxic-metabolic disturbances, medications, untreated sleep disorders (including obstructive sleep apnea),
and psychiatric illnesses may all present with prominent fluctuations in cognition.
• Transient epileptic amnesia is associated with acute and transient memory disruptions lasting minutes
(typically less than an hour) that are often accompanied by fluctuations in attention.
• Anticholinergic medications may be especially problematic in patients with Alzheimer disease–associated
degeneration of acetylcholine-producing basal forebrain cells.
• If promptly recognized, the life-threatening effects of thiamine deficiency may be counteracted by
administration of high doses of parenteral thiamine.
• The high potential for response to appropriate treatment, high cost of delayed diagnosis, and low risk of
complications associated with parenteral thiamine supplementation justify expedited treatment in all
patients with possible nutritional deficiency and features consistent with Wernicke encephalopathy.
• Syphilis testing should be considered in patients with dementia from endemic regions within and beyond the
United States and in those with a past or present history of high-risk behaviors.
• A thorough history, including screening for past or present high-risk behaviors, is imperative when
investigating patients with unusual presentations of cognitive impairment.
• The discovery of abnormal neurologic findings—whether subtle or pronounced—warrants consideration of
atypical causes of dementia, including reversible causes.
• Detection of features of the triad of progressive memory loss, gait apraxia, and urinary incontinence warrants
screening for causes of normal pressure hydrocephalus and high-pressure hydrocephalus.
• Performance on cognitive testing that is substantially better or worse than expected from the clinical history
should trigger investigations for reversible causes of dementia.
• Sleep dysfunction, attributable to obstructive sleep apnea or other causes, is increasingly identified as a
contributor to cognitive impairment.

Issue Overview
Dementia, Volume 25, Issue 1, February 2019
Continuum: Lifelong Learning in Neurology® is designed to help practicing neurologists stay
abreast of advances in the field while simultaneously developing lifelong self-directed learning
skills.
Learning Objectives
Upon completion of this Continuum: Lifelong Learning in Neurology Dementia issue,
participants will be able to:
 Describe the epidemiology, genetic and environmental risk factors, clinical diagnosis,
biomarkers, and treatment of late-onset Alzheimer disease
 Discuss the clinical, neuropathologic, and management aspects of early-onset Alzheimer
disease that differentiate it from the more common late-onset Alzheimer disease
 Describe the clinical features, molecular underpinnings, relevant investigation findings,
diagnostic criteria, and management of patients with posterior cortical atrophy
 Define the core clinical features of behavioral variant frontotemporal dementia (bvFTD),
distinguish it from other forms of mid- to late-life behavioral change, formulate a pathologic
differential diagnosis for individual patients with bvFTD, and identify key aspects of
management
 Discuss the classification and distinguishing clinical and imaging features of primary
progressive apraxia and aphasia
 Describe the diseases included under the Lewy body dementia umbrella and current
strategies for evaluating and treating them
 Describe the diseases included under the vascular cognitive impairment umbrella and current
strategies for evaluating and treating them

 Develop a practical clinical approach to the diagnosis and management of idiopathic normal
pressure hydrocephalus and recognize when overlapping diseases are present
 Describe the current chronic traumatic encephalopathy neuropathologic and research-based
diagnostic criteria and the emerging understanding of chronic traumatic encephalopathy risk
factors and biomarkers
 Describe the pathologic entities commonly found in the aging population that can mimic
Alzheimer disease and understand the clinical, biomarker-based, and genetic features that
may distinguish these entities from the dementia and cognitive decline caused by Alzheimer
disease pathology
 Identify clinical features that distinguish patients with reversible causes of dementia
 Discuss the reasons medications carry a boxed warning as well as the importance of
disclosing (and documenting the discussion of) the risks and benefits of any high-risk
medications to patients or patients’ health care proxies
Core Competencies
This Continuum: Lifelong Learning in Neurology Dementia issue covers the following core
competencies:
 Patient Care
 Medical Knowledge
 Practice-Based Learning and Improvement
 Interpersonal and Communication Skills
 Professionalism
 Systems-Based Practice

Contributors
Jonathan Graff-Radford, MD, Guest Editor

Assistant Professor of Neurology, Mayo Clinic College of Medicine and Science, Rochester,
Minnesota
Relationship Disclosure: Dr Graff-Radford receives research/grant support from the National Institute on
Aging/National Institutes of Health (K76AG057015).
Unlabeled Use of Products/Investigational Use Disclosure: Dr Graff-Radford discusses the unlabeled/investigational

use of acetylcholinesterase inhibitors and memantine for vascular cognitive impairment.
Melissa J. Armstrong, MD, MSc, FAAN

Assistant Professor of Neurology, University of Florida College of Medicine; Director,
University of Florida Mangurian Clinical Research Headquarters for Lewy Body Dementia,
Gainesville, Florida
Relationship Disclosure: Dr Armstrong serves on the evidence review board of Neurology journals and as a
guideline consultant for the American Academy of Neurology and has received personal compensation for speaking
engagements from the American Academy of Neurology and Medscape CME. Dr Armstrong receives research/grant
support from the Agency for Healthcare Research and Quality (K08HS24159), 1Florida Alzheimer’s Disease
Research Center (AG047266), and the Lewy Body Dementia Association Research Center of Excellence program
and receives publishing royalties from Oxford University Press.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Armstrong discusses the unlabeled/investigational use
of biomarkers for the diagnosis of dementia with Lewy bodies and the unlabeled/investigational use of donepezil,
galantamine, and memantine for cognitive symptoms in Lewy body dementia; clozapine and quetiapine for
psychosis in Lewy body dementia; and clonazepam and melatonin for rapid eye movement sleep behavior disorder.
Hugo Botha, MBChB

Assistant Professor of Neurology, Mayo Clinic College of Medicine and Science, Rochester,
Minnesota
Relationship Disclosure: Dr Botha receives research/grant support from the National Institutes of Health (R01
DC012519-06).
Unlabeled Use of Products/Investigational Use Disclosure: Dr Botha reports no disclosure.
Andrew E. Budson, MD
Chief, Cognitive and Behavioral Neurology, VA Boston Healthcare System; Professor of
Neurology, Boston University School of Medicine, Boston, Massachusetts
Relationship Disclosure: Dr Budson has served as a consultant for Axovant Sciences, Inc, and Eli Lilly and
Company and has received personal compensation for speaking engagements from Eli Lilly and Company. Dr
Budson receives research/grant support from the US Department of Veterans Affairs (I01CX000736) and publishing
royalties from Elsevier and Oxford University Press.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Budson discusses the unlabeled/investigational use of
several classes of medications for chronic traumatic encephalopathy, including cholinesterase inhibitors for
memory-related issues, selective serotonin reuptake inhibitors for mood and behavioral issues, memantine for
attentional issues in those with advanced dementia, and atypical antipsychotics for those who are disinhibited and
violent.

Sebastian J. Crutch, PhD, CPsych
Professor of Neuropsychology, Dementia Research Centre, University College London Institute
of Neurology, University College London, London, United Kingdom
Relationship Disclosure: Dr Crutch receives research/grant support from the Alzheimer’s Society (AS-PG-14-
022), The Dunhill Medical Trust (R337/0214), the Economic and Social Research Council-National Institute of
Health Research (ES/L001810/1), and the Engineering and Physical Sciences Research Council (EP/M006093/1).
Unlabeled Use of Products/Investigational Use Disclosure: Dr Crutch reports no disclosure.
Gregory S. Day, MD, MSc

Assistant Professor of Neurology; Associate Leader, Knight Alzheimer Disease Research Center
Clinical Core, Washington University in St. Louis, St. Louis, Missouri
Relationship Disclosure: Dr Day has served as a topic editor on dementia for DynaMed Plus (EBSCO Industries,
Inc) and as clinical director for the Anti-NMDA Receptor Encephalitis Foundation. Dr Day receives research/grant
support from Avid Radiopharmaceuticals, the Foundation for Barnes Jewish Hospital, and the National Institutes of
Health (P01AG03991, R56AG057195) and holds stock in ANI Pharmaceuticals, Inc. Dr Day has provided record
review and expert medical testimony on legal cases pertaining to management of Wernicke encephalopathy.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Day reports no disclosure.
Neill R. Graff-Radford, MBBCH, FRCP, FAAN

David Eisenberg Professor, Mayo Clinic College of Medicine and Science, Jacksonville, Florida
Relationship Disclosure: Dr Graff-Radford serves on the editorial board of Alzheimer’s Research & Therapy and
receives research/grant support from AbbVie Inc; Axovant Sciences, Inc; Biogen; Eli Lilly and Company; the
National Institutes of Health (P50AG16574, 1R01AG045390-01A1, R56AG057195, UF1AG032438,
U54NS092089, U01AG24904, U01NS100620); Novartis AG; and the US Department of Defense (WEI1872).
Unlabeled Use of Products/Investigational Use Disclosure: Dr Graff-Radford reports no disclosure.
Gregory A. Jicha, MD, PhD

Professor of Neurology and Behavioral Science, University of Kentucky, Lexington, Kentucky
Relationship Disclosure: Dr Jicha serves as a consultant for the Cure Alzheimer’s Fund and provides contract
research for AbbVie Inc; Alltech; Axovant Sciences, Inc; Eli Lilly and Company; Eisai Inc; Janssen Global
Services, LLC; Novartis AG; Suven Life Sciences Limited; and VTV Therapeutics. Dr Jicha receives research/grant
support from the National Institutes of Health (UH2 NS100606, R01 AG054130, U19 AG010483, U24 AG057437,
P30 AG028383, R01 HD064993, R01 AG057187, R01 AG042419, R01 NR014189).
Unlabeled Use of Products/Investigational Use Disclosure: Dr Jicha reports no disclosure.
David T. Jones, MD
Senior Associate Consultant, Department of Neurology, Mayo Clinic; Assistant Professor of
Neurology and Radiology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota
Relationship Disclosure: Dr Jones receives research/grant support from the Minnesota Partnership for
Biotechnology and Medical Genomics (P006598701) and the National Institutes of Health (U01EB 24450-1,
R01DC14942-1, U01AG52943, U01AG45390, U19AG24904).
Unlabeled Use of Products/Investigational Use Disclosure: Dr Jones reports no disclosure.

Keith A. Josephs, MD, MST, MSc
Professor of Neuroscience and Neurology, Mayo Clinic College of Medicine and Science,
Rochester, Minnesota
Relationship Disclosure: Dr Josephs receives research/grant support from the National Institutes of Health (R01
AG37491, R01NS89757, R01 DC14942).
Unlabeled Use of Products/Investigational Use Disclosure: Dr Josephs reports no disclosure.
Joseph S. Kass, MD, JD, FAAN

Associate Dean, Office of Student Affairs; Professor of Neurology, Psychiatry, and Medical
Ethics; Director, Alzheimer’s Disease and Memory Disorders Center, Baylor College of
Medicine; Chief of Neurology, Ben Taub General Hospital, Houston, Texas
Relationship Disclosure: Dr Kass serves as associate editor of ethical and medicolegal issues for Continuum, as an
associate editor for Continuum Audio, as a neurology section editor of Ferri’s Clinical Advisor for Elsevier, and as
co-editor of Neurology Secrets, Sixth Edition. Dr Kass has received personal compensation for CME lectures from
Pri-Med Medical Group and has received personal compensation as a medicolegal consultant in legal cases
involving criminal proceedings, malpractice, and personal injury.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Kass reports no disclosure.
Mario F. Mendez, MD, PhD, FAAN

Behavioral Neurology Program Director; Professor of Neurology, Psychiatry, and Biobehavioral
Sciences, David Geffen School of Medicine at the University of California, Los Angeles;
Director of Neurobehavior, VA Greater Los Angeles Healthcare System, Los Angeles, California
Relationship Disclosure: Dr Mendez serves as a section editor for UpToDate, Inc, and as an associate editor of the
Journal of Alzheimer’s Disease. Dr Mendez has received personal compensation for speaking engagements from the
Medical Education Speakers Network and receives research/grant support from Biogen and the National Institutes of
Health/National Institute on Aging (R01AG050967). Dr Mendez receives publishing royalties from Cambridge
University Press.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Mendez reports no disclosure.
Peter T. Nelson, MD, PhD

Professor of Pathology and Laboratory Science, University of Kentucky College of Medicine,
Lexington, Kentucky
Relationship Disclosure: Dr Nelson serves on the National Institutes of Health/National Institute on Aging external
advisory boards of Mayo Clinic and Rush University and as an associate editor for Acta Neuropathologica and the
Journal of Neuropathology & Experimental Neurology.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Nelson reports no disclosure.

Gil D. Rabinovici, MD
Edward Fein and Pearl Landrith Distinguished Professor, Department of Neurology, University
of California San Francisco, San Francisco, California
Relationship Disclosure: Dr Rabinovici receives research/grant support from the National Institutes of Health (P01-
AG019724, P50-AG23501, R01 AG032289, R01-AG045611, R01-AG048234, R01 AG057204, R56-AG057195)
and the National Institute of Neurological Disorders and Stroke (R01-AG038791). Dr Rabinovici receives research
support from Avid Radiopharmaceuticals, Eli Lilly and Company, General Electric Healthcare, and Life Molecular
Imaging. Dr Rabinovici has served on scientifi c advisory boards for AXON Neuroscience SE; Eisai Co, Ltd; F.
Hoffman- La Roche Ltd; Genentech, Inc; and Merck & Co, Inc. Dr Rabinovici serves as an associate editor for
JAMA Neurology.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Rabinovici discusses the investigational use of the
positron emission tomography (PET) radiotracers [11C]Pittsburgh Compound B and [1⁸F]fl ortaucipir in the
diagnosis of Alzheimer disease.
Rachel V. Rose, JD, MBA

Attorney, Rachel V. Rose Attorney at Law PLLC; Affiliated Faculty, Baylor College of
Medicine, Houston, Texas
Relationship Disclosure: Ms Rose serves on the editorial board of BC Advantage and receives book royalties from
the American Bar Association.
Unlabeled Use of Products/Investigational Use Disclosure: Ms Rose reports no disclosure.
Jonathan M. Schott, BSc, MD, FRCP, FEAN, SFHEA

Professor of Neurology, Honorary Consultant Neurologist, University College London, London,
United Kingdom
Relationship Disclosure: Dr Schott serves on advisory boards for Biogen; Eli Lilly and Company; F Hoffman-La
Roche Ltd; and Merck & Co, Inc, and on the drug safety monitoring board for AXON Neuroscience SE. Dr Schott
has received personal compensation for speaking engagements for Biogen, Eli Lilly and Company, and GE
Healthcare Worldwide and receives research/grant support from Alzheimer’s Research UK, Avid
Radiopharmaceuticals, Brain Research UK, British Heart Foundation, Engineering and Physical Sciences Research
Council (EP/J020990/1), European Commission Horizon 2020, Medical Research Council Dementias Platform UK
(MR/L023784/1), Weston Brain Institute, and Wolfson Foundation. Dr Schott receives royalties from Henry Stewart
Talks and Oxford University Press.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Schott reports no disclosure.
Professor of Neurology and Pathology, University of California San Francisco, San Francisco,
California
Relationship Disclosure: Dr Seeley serves on the editorial boards of Acta Neuropathologica, Annals of Neurology,
and NeuroImage: Clinical and as a consultant for Biogen; Merck & Co, Inc; and Third Rock Ventures, LLC. Dr
Seeley receives research/grant support from the Bluefield Project to Cure FTD, the National Institutes of
Health/National Institute on Aging (AG023501, AG019724), and the National Institutes of Health/National Institute
of Neurological Disorders and Stroke (NS1104437, NS092474). Dr Seeley has provided expert medical testimony
on legal cases related to violence in patients with neuropsychiatric illness.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Seeley discusses the unlabeled/investigational use of
medications for the treatment of behavioral variant frontotemporal dementia, none of which are approved by the US
Food and Drug Administration.

Katherine W. Turk, MD
Cognitive and Behavioral Neurologist, VA Boston Healthcare System; Assistant Professor of
Neurology, Boston University School of Medicine, Boston, Massachusetts
Relationship Disclosure: Dr Turk receives research/grant support from the Alzheimer’s Association.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Turk discusses the unlabeled/investigational use of
several classes of medications for chronic traumatic encephalopathy, including cholinesterase inhibitors for
memory-related issues, selective serotonin reuptake inhibitors for mood and behavioral issues, memantine for
attentional issues in those with advanced dementia, and atypical antipsychotics for those who are disinhibited and
violent.
Self-Assessment and CME Test Writers

D. Joanne Lynn, MD, FAAN
Associate Dean for Student
Life, Clinical Professor
of Neurology, The Ohio
State University College of
Medicine, Columbus, Ohio
Relationship Disclosure: Dr Lynn receives book royalties from Lippincott Williams & Wilkins and holds stock in
Abbott Laboratories; AbbVie Inc; Amgen Inc; Bristol-Myers Squibb Company; CVS Health Corporation; Express
Scripts Holding Company; General Electric; Merck & Co, Inc; and Zimmer Biomet.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Lynn reports no disclosure.
Allyson R. Zazulia, MD
Professor of Neurology and Radiology, Associate Dean for Continuing Medical Education,
Washington University, St. Louis, Missouri
Relationship Disclosure: Dr Zazulia reports no disclosure.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Zazulia reports no disclosure.

Methods of Participation and Instructions for Use
Continuum: Lifelong Learning in Neurology® is designed to help practicing neurologists stay
abreast of advances in the field while simultaneously developing lifelong self-directed learning
skills. In Continuum, the process of absorbing, integrating, and applying the material presented is
as important as, if not more important than, the material itself.
The goals of Continuum include disseminating up-to-date information to the practicing
neurologist in a lively, interactive format; fostering self-assessment and lifelong study skills;
encouraging critical thinking; and, in the final analysis, strengthening and improving patient
care.
Each Continuum issue is prepared by distinguished authors who are acknowledged leaders in
their respective fields. Six issues are published annually and are composed of review articles,
case-based discussions on ethical and practice issues related to the issue topic, coding
information, and comprehensive continuing medical education (CME) and self-assessment
offerings. For detailed instructions regarding Continuum CME and self-assessment activities,
visit continpub.com/CME.
The review articles emphasize clinical issues emerging in the field in recent years. Case reports
and vignettes are used liberally, as are tables and illustrations. Audio interviews with the authors
of Continuum articles are published alongside each article, and video material relating to the
issue topic accompanies issues when applicable.
The text can be reviewed and digested most effectively by establishing a regular schedule of
study in the office or at home, either alone or in an interactive group. If subscribers use such
regular and perhaps new study habits, Continuum’s goal of establishing lifelong learning patterns
can be met.

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FEBRUARY 2019

VOL. 25 NO. 1 Dementia

14 Late-onset Alzheimer Disease

34 Early-onset Alzheimer Disease and Its Variants

52 Posterior Cortical Atrophy

76 Behavioral Variant Frontotemporal Dementia

101 Primary Progressive Aphasias and Apraxia of Speech

128 Lewy Body Dementias

147 Vascular Cognitive Impairment

165 Normal Pressure Hydrocephalus

DENOTES SUPPLEMENTAL 187 Chronic Traumatic Encephalopathy

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

234 Reversible Dementias

254 Prescribing Antipsychotic Medications to Patients With Dementia:

SELF-ASSESSMENT AND CME

4 Learning Objectives and Core Competencies

261 Instructions for Completing Postreading Self-Assessment and CME

263 Postreading Self-Assessment and CME Test

277 Postreading Self-Assessment and CME Test—Preferred Responses

List of Abbreviations (Back Cover)

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Jonathan Graff-Radford, MD, Hugo Botha, MBChB

Unlabeled Use of Products/Investigational

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Gregory A. Jicha, MD, PhD

Unlabeled Use of Products/Investigational

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

David T. Jones, MD Joseph S. Kass, MD, JD, FAAN

Unlabeled Use of Products/Investigational

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Peter T. Nelson, MD, PhD Rachel V. Rose, JD, MBA

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Jonathan M. Schott, BSc, MD, Katherine W. Turk, MD

Unlabeled Use of Products/Investigational

Unlabeled Use of Products/Investigational

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Self-Assessment and CME Test Writers

D. Joanne Lynn, MD, FAAN Allyson R. Zazulia, MD

Unlabeled Use of Products/Investigational

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

RECENT FINDINGS: An estimated 5.7 million Americans are living with AD

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

ENVIRONMENTAL RISK FACTORS

GENETIC RISK FACTORS

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

frequency in the population), ε3 (77.9%), and ε4 (13.7%).17 APOE ε4 is associated

CLINICAL APPROACH TO PATIENTS WITH COGNITIVE SYMPTOMS

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u Vascular cognitive impairment ● Late-onset Alzheimer

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TABLE 1-1 Symptoms Associated With Neurodegenerative Dementia

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

CASE 1-1 A 73-year-old woman presented for evaluation of 3 years of progressive

COMMENT This patient’s clinical presentation is highly suggestive of underlying AD,

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.