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Cognitive neurology

REVIEW

Lifting the veil: how to use clinical neuropsychology


to assess dementia
James R Burrell,1,2,3 Olivier Piguet1,2,3
1

Neuroscience Research
Australia, Sydney, New South
Wales, Australia
2
University of New South
Wales, Sydney, New South
Wales, Australia
3
ARC Centre of Excellence in
Cognition and its Disorders,
Sydney, New South Wales,
Australia
Correspondence to
Dr James R Burrell,
Neuroscience Research
Australia & University of New
South Wales, Barker Street,
Randwick, Sydney, NSW 2031,
Australia;
j.burrell@neura.edu.au
Received 1 September 2014
Revised 10 February 2015
Accepted 24 February 2015
Published Online First
26 March 2015

ABSTRACT
Neurologists often struggle to interpret the results of
neuropsychological testing, even though cognitive
assessments are an integral component of the diagnostic
process in dementia syndromes. This article reviews the
principles underlying clinical neuropsychology,
background on common neuropsychological tests, and
tips on how to interpret the results when assessing
patients with dementia. General cognitive screening
tools, appropriate for use by general neurologists and
psychiatrists, as well as specic cognitive tests examining
the main cognitive domains (attention and orientation,
memory, visuospatial function, language and executive
function) in patients with dementia are considered.
Finally, the pattern of decits, helpful in dening clinical
dementia phenotypes and sometimes in predicting the
underlying molecular pathology, are outlined. Such
clinicopathological associations will become invaluable
as disease-modifying treatments for dementia are
developed and implemented.

INTRODUCTION

To cite: Burrell JR,


Piguet O. J Neurol
Neurosurg Psychiatry
2015;86:12161224.
1216

Neurologists are trained to investigate complex


medical and personal histories and perform
detailed neurological examinations. Seamlessly, they
proceed to neurophysiological tests or engage vigorously with neuroradiologists to interpret neuroimaging. Similarly, psychiatrists deftly synthesise
complex psychiatric and behavioural histories to
determine the presence of affective and anxiety disorders, or psychosis in later life. In contrast, cognitive testing is often deferred to neuropsychologists.
Why is it that general neurologists and psychiatrists
appear to lack understanding of the benets of
neuropsychological examination? Here, we review
the principles underlying clinical neuropsychology,
background on common cognitive tests, and tips on
how to interpret cognitive test results when assessing patients with dementia (box 1). In addition,
we examine some of the more controversial areas
in dementia assessment, where clinical assessment
and neuropsychology may need to be interpreted in
a wider context.
In the right context, neuropsychological testing
provides reliable information on cognitive function.
It helps determine an individuals cognitive
strengths and weaknesses, informs functional capacity and documents progression and/or evolution
of cognitive decits over time. The pattern of cognitive decits provides insights into normal brain
function and underlying pathological processes.
Nonetheless, the interfaces between neurology,
psychiatry and neuropsychology in the assessment

of dementia are complex and an understanding of


the underpinnings of clinical neuropsychological is
valuable and will improve diagnostic accuracy.

WHAT IS NEUROPSYCHOLOGICAL TESTING?


A neuropsychological assessment encompasses a
series of different tasks designed to probe specic
aspects of cognition. Six independent, but overlapping, domains are outlined in the fth edition of
the Diagnostic and Statistical Manual of Mental
Disorders (DSM-V): complex attention, learning
and memory, perceptual/visuospatial/visuoconstructive, language, executive function and social cognition.1 Each domain can be further subdivided into
specic subdomains.
Cognitive functions have more or less precise
biological substrates, although evidence from lesion
and neuroimaging studies has demonstrated that
most involve distributed neural networks and
various brain regions. Although important for the
understanding of normal brain function, and the
mechanisms by which pathological processes can
result in specic clinical features, a review of the
neuroanatomical regions and networks underlying
specic cognitive domains is beyond the scope of
the present review.
Although cognitive dysfunction may be suspected
following a careful clinical assessment, neuropsychological testing quanties the extent and
severity of change. Furthermore, the pattern of
cognitive decits may evolve over time, prompting
revision of the syndromic diagnosis in individual
patients.

WHAT ARE THE PITFALLS IN


NEUROPSYCHOLOGICAL TESTING?
Importantly, the neuropsychological assessment is
interpreted within the broader context of the
medical and personal history (obtained from both
the patient and family), psychiatric history, neurological examination, neuroimaging and where available other investigations (eg, blood tests, genetic
testing).
A number of medical and non-medical variables
have the potential to inuence cognitive performance on testing. First, reduced or variable effort,
which may be inherent to the underlying disease
prompting the assessment, can affect capacity to
sustain concentration for long periods of time.
Comorbid physical and psychological illnesses
(eg, respiratory, renal or hepatic failure, drug
intoxication, depression, anxiety) can also affect
performance.

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Cognitive neurology
Box 1 What to look for in a neuropsychology report
1. Premorbid cognitive ability (how was it estimated?)
2. History
3. Test conditions
A. Effort
B. Medical/medication confounds
C. Comorbid depression/anxiety
D. Linguistic/cultural background
4. Cognitive screening task
A. Mini-Mental State Examination (MMSE)
B. Montreal Cognitive Assessment (MoCA), or
C. ACE-III
5. Domain-based cognitive testing (with reference to normal
performance*)
A. Attention/orientation/working memory
B. Memory
C. Language
D. Executive function
E. Visuospatial ability
F. Social cognition
6. Summary of ndings
7. Neuropsychological diagnosis
*Normal performance may be dened in reference to a
population normative value, or to the estimated cognitive ability
of the individual patient, based either on a reading task or
educational/vocational attainment

Second, most neuropsychological tests are administered using


verbal instructionsand often require a verbal or written
response. As such, ensuring that patient and examiner can communicate with each other appropriately is important. The use of
medical interpreters only partly accounts for this potential confound. Culturally biased tests and level of education are other
potential confounds. Additionally, it is important to bear in
mind that language decits are inherent to a number of dementia syndromes. Such decits may interfere with the assessment
of non-language cognitive domains, regardless of the language
used to perform testing.
Finally, performance on cognitive testing is not meaningful in
itself, and scores need to be compared to a relevant benchmark
(ie, comparative or normative scores). Normative scores are
usually derived from testing of healthy individuals, generally
controlling for such variables as age and/or education. Norms,
however, may not be able to control for all relevant variables,
for example premorbid cognitive ability in an individual patient
(more on this later). It is worth emphasising that, while people
perform better on some tests than others, healthy individuals
tend to obtain a fairly homogeneous test performance across
cognitive domains (eg, memory, language, executive function).
A disproportionate impairment in one or more cognitive
domains, while not pathognomonic in itself, may reect a disorder of cognition. It is also the pattern of decits that is most
informative diagnostically.

GENERAL COGNITIVE SCREENING TESTS


A vast array of neuropsychological tasks is available to probe
specic cognitive abilities, many of which are time-consuming
and labour intensive. Clearly, a comprehensive neuropsychological examination for every individual is not always possible

or necessary. Nonetheless, even busy clinicians can administer a


brief cognitive screening task, which provide an estimate of
overall cognitive function, and help identify patients who
require a detailed cognitive evaluation.

Mini-Mental State Examination


The Mini-Mental State Examination, or MMSE, is probably the
most recognised cognitive screening test. The MMSE was
designed to distinguish cognitive impairment due to dementia,
from apparent cognitive impairment in psychiatric illnesses.2 Its
administration usually takes less than 10 min, even in patients
with dementia and it provides a broad index of cognitive function, where a score of 25 or below, out of a possible 30 points,
is indicative of cognitive decits.
The MMSE is widely used by clinicians from all levels
(eg, junior hospital doctors, registrars, specialists) and specialties
(eg, general practitioners, neurologists, psychiatrists, geriatricians). Importantly, the MMSE was not designed to distinguish
different forms of dementia. It is heavily weighted towards the
orientation/attention and memory domains (70% of the available points). Assessments of language and visuospatial function
are very brief, and executive function is essentially ignored. As
such, the MMSE is insensitive to cognitive decits encountered
in some dementias like frontotemporal dementia (FTD). The
MMSE is now subject to copyright, making it an expensive
option for routine clinical practice.

The Montreal Cognitive Assessment


The Montreal Cognitive Assessment (MoCA) was rst published
in 2005.3 Like the MMSE, the MoCA is scored out of 30.
Unlike the MMSE, however, attention and memory make up
only half of the available points. Tests of language, executive
function and visuospatial abilities are also included.
The MoCA offers a number of advantages over the MMSE.
First, the assessment of a broader range of cognitive decits
results in a higher sensitivity of the MoCA in detecting mild
cognitive impairment, and a cut-off of 26/30 detects mild cognitive impairment with a sensitivity of 90% and specicity of
87%.3 It has been translated into, and validated in, many different languages and administration time of the MoCA is comparable to that of the MMSE.

The Addenbrookes cognitive examinationversion III


The Addenbrookes cognitive examination, now in its third iteration (ACE-III),4 is the most detailed cognitive screening test in
wide usage. Similar to the MoCA, the ACE-III covers a range of
cognitive domains including attention/concentration, memory,
verbal uency (executive function), language and visuospatial
ability. It is scored out of 100 points and a cut-off of <88/100
detects dementia with high sensitivity and specicity. Subscores
for each of the main cognitive domains can also be obtained
(attention/concentration 18 points, memory 26 points, verbal
uency 14 points, language 26 points and visuospatial function
16 points).
One advantage of the ACE-III is its ability to distinguish different dementia syndromes by considering the pattern of cognitive decits, rather than just the severity of any impairment. In
particular, the ACE-III reliably distinguishes FTD and
Alzheimers disease, primarily because of the more detailed language and executive assessments. These benets are achieved
with only a modest increase in the administration time
(1220 min)5 compared to other screening tools. The ACE-III is
also useful for tracking the progression of cognitive decits over
time, because it includes a broader range of scores. While

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originally developed as a pen-and-paper test, the ACE is also
available in an electronic version (ACEmobile), which allows
administration and scoring on tablet devices (see http://www.
acemobile.org).
Overall, it is important to remember that broad screening
measures are just that: they may not be sensitive to subtle cognitive decits, especially in very intelligent or highly educated
individuals. This emphasises the need for specic and cognitively demanding tasks in such individuals.

DOMAIN-SPECIFIC NEUROPSYCHOLOGICAL TESTING


A neuropsychological assessment aims to probe each cognitive
domain independently. In practice, however, most cognitive
tasks are not pure measures of a single cognitive domain and
optimal performance usually relies on a combination of cognitive processes. An understanding of the domains tested by each
task is required to interpret the results. Comprehensive neuropsychological testing may take between 2 and 7 h, depending on
the presenting symptoms and severity of decits.

Estimating general premorbid cognitive ability


An estimate of premorbid general cognitive function is an
internal benchmark against which performance on cognitive
testing is interpreted. An individual of high cognitive aptitude
should perform better on neuropsychological tasks than
someone with low cognitive capacity, even in the context of
early dementia. The simplest method to estimate premorbid
ability is to use educational and vocational attainment. Another
common approach is to assess word reading ability, which
reects lifelong learning/knowledge capacity and is relatively
resistant to the effects of cognitive decline and ageing.6 In
English, one such task is the National Adult Reading Task
(NART),7 which is composed of 50 irregular words of decreasing frequency. Knowledge and pronunciation of irregular words
(eg, cello), which cannot be read correctly with the application
of common phonetic rules, can only be acquired through exposure and correlate with general intelligence.

Attention and concentration


Cognition may be considered hierarchical, with aspects of attention and concentration necessary for other cognitive abilities.
Patients must be able to concentrate on the cognitive tasks at
hand during the examination or testing will at best uninterpretable and at worst impossible to perform. As such, concentration
is often investigated rst, either by assessing ability to respond
to simple questions or commands ( provided language is intact),
or by observing distractibility, lethargy and drowsiness during
interactions and testing.
Formal tests of attention are varied but include span tasks.
Digit span forwards, for example, examines the ability to sustain
attention. A series of digits is repeated in order, with the
number of digits increasing as the test proceeds.
English-speaking adults are generally able to repeat 68 digits in
the correct order. Separately, ability to divide attention can be
assessed by so-called Oddball tasks, which require a response
to an infrequent (and irregular) target stimulus presented
among a series of standard stimuli.8 Other simple tasks include
counting from 1 to 20, reciting the days of the week or months
of the year, followed by the same tasks in reverse order.
Working memory is sometimes conceptualised as a separate
domain that is aligned with, but distinct from, executive function. Clinically, however, it is often examined with attention/
concentration abilities with such tasks as digit span backwards.
This task requires a sequence of digits to be repeated in reverse
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order.7 9 10 Most normal people can repeat at least four digits


in reverse, but patients with signicantly impaired working
memory may be unable to repeat more than two digits.

Memory
Given its prominent breakdown in many conditions, memory
has attracted more attention than other cognitive domains.
Memory is conceptualised in different ways such as declarative
or explicit when referring to conscious recollection of facts, or
non-declarative or implicit when referring to memory for
skills and procedures. Declarative memory is further subdivided
into episodic memory (eg, where you went to dinner on your
last birthday) or semantic memory (eg, knowledge of the
Australian states or English counties). Generally, only declarative
memory, particularly episodic memory, is routinely tested, with
verbal and visuospatial (non-verbal) aspects tested separately.
Most memory tests assess various components necessary for
adequate memory performance and can be summarised as
follows: (1) encoding (ie, capacity to take in novel information),
(2) retention (ie, capacity to hold this information over time);
and (3) retrieval (ie, capacity to bring back this information after
a delay). Retrieval can be examined further using free recall (no
external assistance), cued recall (in response to a general or specic cue) or recognition. In general free recall is more difcult
than cued recall, which is in turn more difcult than recognition.
In clinical practice, verbal memory is tested using verbal information that varies in grammatical and semantic structure
(see Lezak et al10 for an exhaustive review). In addition to prose
passages (eg, WMS Logical Memory), common tasks include
pairs, arrays or lists of words with variable semantic relations
(eg, Paired-Associate Learning, The Free and Cued Selective
Reminding Test (FCSRT), Rey Auditory Verbal Learning
Test).7 10 Most of these tasks include immediate and delayed
(ie, after 30 min) recall (free and/or cued) components, as well
as recognition. The FCSRT appears to be particularly sensitive
in differentiating episodic memory decits due to mild cognitive
impairment from those due to early Alzheimers disease,11 12
and in the distinction of Alzheimers disease and FTD.13 The
FCSRT has been incorporated into trials of antiamyloid
therapies.
Visuospatial memory is assessed by recognition of visual stimuli
or by recollection and reproduction of line drawings from
memory. For example, in one of four components of the Doors
and People test7 patients are presented with 12 pictures of different types of doors to memorise. Correct recognition of doors
from an array of four similar doors responses is scored.
Reproduction from memory of a complex line drawing
(gure 1)6 7 10 is another common test of visuospatial memory.
Semantic memory is generally examined using tests of word
knowledge, knowledge of famous faces or less commonly world
events. Aspects of autobiographical and procedural memory are
seldom tested in routine clinical practice.
One criticism of common memory tasks is that they bear little
relevance to functional, day-to-day memory ability. The
Rivermead Behavioural Memory Test was developed as an ecological measure of memory in order to address this confound. It
comprises tasks such as memory for faces and objects, appointments, messages and location of a hidden object.7

Language
Although speech and language pathologists focus exclusively on
language disturbances, neuropsychological assessments also
examine integrity of verbal and written language skills. Aspects
to consider include speech uency, prosody (ie, the intonation

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Cognitive neurology

Figure 1 The Rey Complex Figure. (A) In the rst part of the test, patients are required to copy The Rey Complex Figure. Time taken to produce
the copy is recorded, and accuracy is scored for comparison with controls. In the second part of the test patients are required to reproduce the Rey
Complex Figure form memory. (B) An example of an impaired Rey Complex Figure from a patient with dementia. The patient took 11 min and 23 s
to complete the task.
of verbal output), rate of speech, errors in grammar and motor
speech problems (eg, effortful, distorted speech). This is often
accomplished by engaging the patient in unstructured conversation, or perhaps by asking them to describe a complex visual
scene, such as the Cookie theft7 or Beach scenes from the
Western Aphasia Battery.14
Formal language tests include naming, picture-word matching,
single word repetition and sentence repetition tasks. A common
naming task is the Boston Naming Test, which consists of 60 linedrawn objects of increasing difculty.7 10 Common word-picture
matching tasks include the Pyramid and Palm-trees15 or Camel
and Cactus16 tasks. The Sydney language battery (SYDBAT) is a
recent test that combines a number of these tasks.17 The advantage of the SYDBAT is that it consists of four subtests including
confrontation naming, word comprehension, semantic association and single word repetition using the same stimulus set. The
prole of impairment across SYDBAT subtests is useful in distinguishing subtypes of primary progressive aphasia.17
Other aspects of language, such as production and interpretation of grammar, are less frequently assessed. The test of reception of grammar (TROG) is used to probe grammatical
understanding.7 10 The TROG requires patients to interpret a
number of short sentences, which become increasingly complex
grammatically as the test proceeds. Ability to follow 1-step,
2-step or 3-step commands is another simple way to test grammatical understanding, especially if complex sentence structures
are used (eg, Hand me the pen after touching the paper).

approach to the task are recorded. Obviously, pronounced


motor dysfunction (eg, limb weakness, dystonia, parkinsonism
or apraxia) may confound performance.
Basic visual processing can be assessed using line bisection or
object cancellation tasks.6 7 Another common test, the Visual
Object and Space Perception Battery (VOSP),7 involves the interpretation of information that varies in visual complexity (eg, dot
counting, position discrimination and cube analysis).
Cognitively intact individuals are expected to obtain perfect, or
near-perfect, scores on VOSP subtests (>90% correct). As such,
even a small decline in performance is suggestive of cognitive
impairment.
Higher order visual processing decits are also easily investigated. For example, a verbal description of a complex visual
scene (eg, the Cookie theft) can be used to assess for simultanagnosia (the inability to interpret a complex visual scene).
Similarly, visual agnosiathe impaired ability to recognise
objects despite intact basic visual perceptionmay be suspected
by observing how a patient approaches naming common
objects. For example, the patient may have difculty naming an
object by sight, but produce the correct name when other
sensory modalities (eg, touch) are employed. Prosopagnosia, is a
special case of visual agnosia and refers to the difculty or
inability to recognise faces. This can be assessed using facial recognition tasks which require the matching of a target face with
an array of similar looking faces presented from different
angles.7

Visuospatial and constructional ability

Executive function

Visuospatial function is assessed by measuring ability to interpret various types of visual information. Simple copy or
drawing tasks, such as interlocking pentagons, wire cube, interlocking gure of eights or the reproduction of a clock face
(gure 2), are widely used to assess constructional ability.7
These tasks are easily administered even with very impaired
individuals. The clock face test requires the individual to draw a
clock face from memory, with numbers and hands set at a specic time. Distortions or inability to draw the numbers within
the clock face have been found to be sensitive, but non-specic,
indicators of cognitive decits. Another common, and more difcult task of visuoconstructive ability is the Rey-Osterrieth
Complex Figure task,7 10 where the person is asked to copy a
complex line drawing (gure 1). The accuracy of the copy
(scored out of 36 points), time taken to copy the gure, and

Figure 2 The clock face (AC). Three examples of impaired clock


faces from different individual patients with dementia. Patients are
instructed to draw a clock face, including all the numbers and to set
the time.

Executive function comprises different cognitive skills including


the ability to abstract, shift set, plan, organise and adapt behaviour to current circumstances,6 and is tested using a combination
of approaches. For example, abstraction can be tested by

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concept formation or similarities tasks (eg, what do bicycle
and train have in common?). The type of responses will
inform the examiner as to the capacity of the patient to reason
in abstract terms (eg, They are both modes of transport) or in
concrete terms (eg, They both have wheels).
Set shifting can be tested using the Trail Making Test.7 9 Part
A of the Trail Making Test requires the participant to draw lines
between circles labelled with consecutive numbers (ie, 1, 2,
3, etc). In Part B, the task is made more difcult by alternating
consecutive numbers with consecutive letters (ie, 1, A, 2, B,
3, C, etc). Individuals with executive impairment may take
longer to complete these tasks, or make errors or both.
Fluency tasks, such as letter (eg, F, A, and S), or category
(eg, animals, vegetables) uency, also assess capacity to follow
specic rules and to modify behaviour exibly (ie, set shifting).
Fluency tasks require the generation of as many words as possible in 1 min according to the rule set. Patients with executive
dysfunction produce fewer correct responses on verbal uency
tasks than normal controls, although language prociency and/
or decits need to be considered. Other, non-verbal equivalents
(eg, design uency) also exist, but are not commonly used.
Planning and organisation decits might become apparent by
observing the approach taken to complete a task. For example,
a slow and disorganised approach to a copy task might suggest
executive impairment. Disinhibition, and behaviour modulation
more generally, is infrequently tested in clinical practice. One
option is the Hayling Sentence Completion test, which requires
suppression of a prepotent responses by completion of sentences
with non-sensical endings.7 9
A number of different aspects of executive functioning including temporal judgement, set-shifting, planning and strategy can
be tested formally using such tasks as the Behavioural
Assessment of the Dysexecutive syndrome (BADS).9 More
complex tasks such as the Iowa Gambling Test, or the Wisconsin
Card Sorting test, are used infrequently, either in a research
setting or sometimes clinically, to detect subtle executive
dysfunction.9

Social cognition
Disturbances of social conduct and cognition in dementia, and
their interactions with other cognitive domains, have been
increasingly recognised over the past 20 years. Although still not
widely used in clinical practice, tests of social cognition are
gaining ground in the assessment of dementia syndromes.
Tests of social cognition investigate emotion recognition, disinhibition or theory of mind. Emotion recognition can be tested
using the Ekman 60, where participants are required match
photographs to one of six basic facial emotions (anger, disgust,
fear, sadness, surprise and happiness).18 The Awareness of
Social Inference Test (TASIT) uses videotaped vignettes to assess
evaluation of emotions and social interference.18 Other tasks
have been developed to test recognition of social faux pas19 and
theory of mind. Theory of mind is the ability of an individual to
imagine the inner thoughts of another person, an ability normally acquired throughout childhood and adolescence.20 This
eld is fast evolving, with particular interest in the interactions
between social cognition, neuroeconomics and complex
decision-making in individuals with dementia.

Neuropsychiatric Inventory (NPI) or the Cambridge


Behavioural Inventory (CBI).16 21 The NPI is a structured carer
interview that uses screening questions, as well as detailed subquestions, to probe neuropsychiatric symptoms like delusions,
hallucinations, dysphoria, anxiety, agitation, euphoria, apathy,
irritability, disinhibition, aberrant motor behaviour, night-time
behaviour disturbances and changes in appetite and eating.22
Partly based on the NPI, the CBI examines a wider range of
symptoms21 and may be administered in written form, either
before or during the clinical assessment. Responses to the NPI
and CBI are graded in terms of frequency and severity and can
be converted into scores to indicate the level of behavioural disturbance. In addition, the CBI includes several items designed
to measure functional abilities (eg, use of electrical appliances,
handling money, self-grooming, etc).
A number of tools have been developed to probe different
aspects of behavioural disturbance more specically. For
example, the Geriatric Depression Scale, composed of 30 yes/
no questions, was developed to explore affective symptoms in
older adults, both healthy and demented.23 Other measures
examine apathy,24 stereotyped behaviours25 and changes in
eating and appetite26 through the use of structured questions,
posed to carers or patients themselves. The BADS is a test
battery, which includes six components designed to probe rule
set shifting, problem solving, planning and judgement. It was
developed to assess executive dysfunction in a range of everyday
activities, and thereby provide a measure of functional performance.7 Its usefulness is mitigated by its length of administration
and is therefore rarely administered in its entirety to patients
with dementia.
Several instruments have been developed to specically assess
functional impairment in patients with FTD. For example, the
Frontal Behavioural Inventory (FBI) is a 24-item face-to-face
caregiver interview designed to document the types of behavioural disturbances commonly seen in the behavioural variant of
FTD.27 The Functional Rating Scale (FRS) is another commonly
used assessment that includes a functional assessment. The FRS
examines performance in: behaviour, outings and shopping,
household chores and telephone use, nances, medications,
meal preparation and eating and self-care/mobility.28
Importantly, measures of functional impairment such as the FBI
or FRS may detect behavioural changes in patients with FTD
who perform well on cognitive testing initially.
The progression of functional impairment in dementia can be
measured using tools such as the Clinical Dementia Rating Scale
(CDR), which was specically developed for use in Alzheimers
disease.29 The CDR incorporates patient and informant derived
information to grade performance in: memory, orientation,
judgement and problem solving, community affairs, home and
hobbies and personal care. Each section is rated individually
then combined to produce a global CDR. A CDR score rates
dementia as 0 (no dementia), 0.5 (questionable), 1 (mild), 2
(moderate) and 3 (severe).29 The CDR has been modied for
use in FTD (CDR-FTD) to include behavioural and language
sections.30 By comparing current with previous patient ability,
the CDR may be less inuenced by education, language and
culture than traditional neuropsychological testing.29

Behaviour and functional assessment

DIAGNOSIS OF DEMENTIA AND PATTERNS OF


IMPAIRMENT

Behavioural disturbances and functional capacity are often measured together, through the use of carer-orientated questionnaires. For example, the occurrence and severity of behavioural
disturbances are probed with instruments like the

Reliable in vivo clinical biomarkers of dementia do not currently


exist, despite signicant advances in neuroimaging, pathology
and genetics in recent years. As such, the diagnosis of dementia
is made primarily on clinical grounds. History, examination,

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neuroimaging and performance on neuropsychological assessment all contribute towards a diagnosis. Numerous clinical diagnostic criteria for dementia exist and have been revised over the
years. These include broad indices, such as the DSM-5, as well
as those focusing on specic entities, including Alzheimers
disease,31 FTD,32 primary progressive aphasias.33 The criteria
for the diagnosis of Alzheimers disease, proposed by McKhann
et al,31 emphasise the need for supporting evidence from biomarkers (eg, imaging, blood, cerebrospinal uid), which may
improve diagnostic accuracy in early or even prodromal cases.34
Clinical diagnostic criteria for the main dementia syndromes
are an important reference but, like criteria for other clinical
diagnoses, may be difcult to implement in individual cases. A
discussion on their merits and limitations is, however, beyond
the remit of the present review. Rather, we provide a brief
outline of the various neuropsychological proles observed in
the common dementia syndromes, each of which might be
associated with a different pathological process. This discussion is not intended to be comprehensive, but will provide a
foundation for the general neurologist or psychiatrist and
illustrate the clinical utility of neuropsychological assessment
(table 1).
Patients with the typical, or amnestic, presentation of
Alzheimers disease usually exhibit variable concentration,
marked decits in episodic memory (verbal and visual) and
visuospatial ability, but relatively intact language, behaviour and
social cognition, at least in the initial stages.35 This pattern of
cognitive decits predicts underlying Alzheimers pathology
with >85% accuracy. In a small proportion of cases,
Alzheimers disease may present in an atypical fashion with
predominant decits in language (ie, logopenic progressive
aphasia (LPA)), executive function, motor function (ie, corticobasal syndrome) or vision (ie, posterior cortical atrophy).31 36
The role of specic memory testing in patients with mild cognitive impairment, often considered a prodromal form of
Alzheimers disease remains controversial. Older individuals
often present to clinic with concerns about failing memory and
may even demonstrate subtle memory disturbances on cognitive
screening. Importantly, only a proportion of these individuals
will progress to develop Alzheimers disease or another dementia, and it remains difcult to predict with certainty the
outcome in any individual patient. The pattern of decits on
memory tasks may help, whereby impaired encoding of information together with impaired recall and recognition appears
to associate with the early hippocampal pathology seen in
Alzheimers disease. In contrast, impaired recall but relatively
preserved recognition is suggestive of an alternative diagnosis.11 37 38 Unfortunately, such memory decit proles may not
be as specic as initially thought for the early diagnosis of
Alzheimers disease.39
At a clinical level, vascular dementia can be difcult to distinguish from Alzheimers disease; the two conditions often
coexist pathologically, particularly in very old individuals. A
history of multiple strokes and focal neurological signs on examination is suggestive of vascular dementia, as is marked white
matter signal change on MRI.35 Neuropsychologically, patients
with vascular dementia demonstrate variable memory and
executive impairment, like patients with Alzheimers disease,
although subtle differences may be detectable.35 For example,
patients with vascular dementia may show relatively spared
ability to encode new information but impaired retrieval of
information. In contrast, patients with Alzheimers disease demonstrate impairment in encoding and retrieval of new information. In addition, patients with vascular dementia may

demonstrate impaired cognitive processing speed, thought to


reect the subcortical burden of pathology.6 35
Another important dementia syndrome is dementia with
Lewy bodies (DLB), which exists clinically in a disease continuum with idiopathic Parkinsons disease. DLB is often associated with a mixed pathology, with features of both
Alzheimers and Parkinsons diseases. Clinically, DLB is characterised by impaired and uctuant concentration throughout the
day and visual hallucinations,35 although such uctuation may
be difcult to assess neuropsychologically. Importantly, cognitive
dysfunction in DLB often responds to treatment with anticholinesterase inhibitors.40
Atypical parkinsonian disorders are associated with variable
cognitive decits.35 41 Progressive supranuclear palsy is often
associated with a poverty of verbal output, as well as subtle
executive dysfunction.41 Corticobasal syndrome, on the other
hand, is associated with a wide range of cognitive decits
including memory, language and visuospatial impairments.41
Perhaps the most consistent abnormality identied in corticobasal syndrome is visuospatial impairment, which is often closely
related to limb apraxia.42 In addition, patients with corticobasal
syndrome may develop a non-uent speech disorder, which can
be difcult to distinguish from progressive non-uent aphasia
(PNFA) in the early stages.
FTD is the most common cause of dementia in younger
patients after Alzheimers disease, and presents with a range of
behavioural and cognitive decits.43 Roughly half of patients
with FTD present with the so-called behavioural variant
(bvFTD), which presents with disinhibition, apathy and marked
decits in interpersonal conduct, while cognitive performance
may appear intact initially, although detailed testing usually
demonstrates evidence of executive dysfunction and disinhibition.44 Other decits in language and memory may become
more prominent as the disease progresses.45
When patients present with marked and progressive behavioural disturbance, as well as frontotemporal atrophy on MRI or
hypometabolism on functional imaging, the diagnosis of bvFTD
is relatively straightforward. Patients with atypical Alzheimers
disease (eg, the frontal variant) can present with apathy and
executive decits, despite relatively preserved memory.
Alternatively, some patients with a clinical presentation identical
to bvFTD may have no cortical atrophy on MRI or perform
normally on neuropsychological testing. Whether such patients
have FTD, or a neuropsychiatric mimic of FTD, remains to be
resolved. Finally, a atypical or slowly progressive bvFTD phenotype has been described in carriers of the C9ORF72 repeat
expansion, now recognised as an important cause of familial
and apparently sporadic FTD.46 47
Almost half of patients with FTD present with striking, but
differing, patterns of language impairment.17 35 For example,
the semantic dementia (SD) phenotype is characterised by severe
decits in word and object knowledge, surface dyslexia (ie, difculty reading irregular words) and behavioural disturbances,
with preserved single word and sentence repetition.48 Once
encountered, SD is easily recognised, but may be missed by the
uninitiated. Pathologically, SD is tightly associated with underlying TDP-43 positive intraneuronal inclusions,49 so recognition
of the syndrome is very helpful diagnostically. In contrast, nonuent speech characterised by motor speech errors (called
apraxia of speech) and grammatical errors or agrammatism is
typical of PNFA, which is more commonly associated with
underlying -positive pathology.50
Another non-uent speech syndrome called LPA has been
described.33 LPA is characterised by marked word nding

Burrell JR, Piguet O. J Neurol Neurosurg Psychiatry 2015;86:12161224. doi:10.1136/jnnp-2013-307483

1221

Cognitive domain

Burrell JR, Piguet O. J Neurol Neurosurg Psychiatry 2015;86:12161224. doi:10.1136/jnnp-2013-307483

Attention and
concentration
Memory
Encoding
Retrieval
Recognition
Language
Speech
Motor speech errors
Object naming
Word knowledge
Single word
repetition
Sentence repetition
Word production
Visuospatial
Visuoperception
deficits
Visuoconstruction
deficits
Executive
Social cognition
Behavioural
disturbances
Emotion
Motor symptoms/signs
Performance on MMSE

Alzheimers
disease

Behavioural
variant FTD

Semantic
dementia

Progressive non-fluent
aphasia

Logopenic progressive
aphasia

Vascular
dementia

Dementia with
Lewy bodies

Progressive
supranuclear palsy

Corticobasal
syndrome

++ to +++

+ to ++

+ to ++

+ to ++

+++
+++
+++

Variable
Variable
Variable

Variable
Variable
Variable

+
+++
+

+ to ++
+ to ++
+ to ++

Variable
Variable
Variable

Fluent

Fluent

Fluent

Non-fluent

Non-fluent

Fluent

Fluent

Sparse and adynamic

+
+
+

+++
++ to +++

++ to +++

+ to ++

+ to ++
+ to ++

Sometimes
non-fluent
Variable
Variable
Variable
Variable

++ to +++

Variable

Variable

++ to +++

+++

++

+ to ++

+ to ++

+++

+ to ++

++ to +++

+ to +++

Variable

+ to ++

++ to +++

++

+ to ++

+ to ++

Impaired

++ to +++
Variable
Preserved

+ to +++

Impaired

Impaired

Very impaired

+ to ++
Impaired

++ to +++
Very impaired

++ to +++
Preserved

+
++ to +++
Variable

FTD, frontotemporal dementia; MMSE, Mini-Mental State Examination.

Cognitive neurology

1222

Table 1 Patterns of cognitive impairment across the range of dementia syndromes

Cognitive neurology
Box 2 Key points in the use of clinical neuropsychology
for the assessment of dementia
Neuropsychological testing is helpful for diagnosis and
management of dementia.
Patients need to be able to perform at their best for the
testing to be meaningful; medical illnesses, medications,
anxiety/depression and testing in the patients second
language can all confound the results.
Testing may not be reliable in patients with severe decits
especially language decits.
All main cognitive domains should be considered.
Cognitive screening tasks (eg, Montreal Cognitive
Assessment (MoCA) or ACE-III) are helpful in the diagnosis
of dementia in the clinic.
The pattern of cognitive decits is helpful in establishing a
syndromic diagnosis, which may help dene the molecular
pathology.
The assessment of behaviour and social cognition is an
important part of the neuropsychological assessment.

part by funding to Forefront, a collaborative research group dedicated to the study of


frontotemporal dementia and motor neuron disease, from the National Health and
Medical Research Council of Australia (NHMRC) programme grant (APP1037746)
and the Australian Research Council Centre of Excellence in Cognition and its
Disorders (CE110001021). JRB is supported by an NHMRC Early Career Fellowship
(APP1072451) and OP by an NHMRC Career Development Fellowship
(APP1022684).
Contributors JRB and OP both conceived the idea for this review article and were
involved in drafting and editing the manuscript.
Competing interests None.
Patient consent Obtained.
Provenance and peer review Commissioned; externally peer reviewed.

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1
2

difculties and impaired sentence repetition, despite relatively


preserved single word repetition and only minor phonological
or grammatical errors in spontaneous speech.51 While it resembles PNFA, LPA is almost always associated with underlying
Alzheimers pathology.52
In clinical practice, the distinction of different aphasia syndromes can be difcult, especially in non-uent cases and reliance on clinical neuropsychological features alone can be
misleading. For example, syntactic or grammatical errors or may
occur in PNFA and LPA, as can disturbances of word and sentence repetition. Even for experienced cognitive neurologists, it
may be difcult to condently classify some non-uent cases.
Similarly, impaired naming and word-nding difculties can
occur in LPA and SD, even though the two disorders are quite
distinct clinically and neuroradiologically. Despite the publication of diagnostic criteria based on clinical features,33 more specic markers of underlying pathology are required to better
dene clinicopathological correlations.

FINAL REMARKS
Like many other clinical tools, a detailed neuropsychological
assessment can play a central role in the diagnosis and grading
of cognitive decits in dementia syndromes, provided the benets and limitations are clearly understood by referring clinicians
(box 2). An understanding of cognitive (eg, attention and orientation, memory, language, visuospatial function and executive
function) and behavioural domains is central to the interpretation of neuropsychological reports. It is important to understand how normal performance on cognitive tests is dened,
whether this is relative to an estimate of premorbid function, or
to a set of population norms. Finally, the pattern of decits can
be helpful in dening clinical phenotypes, which can sometimes
accurately predict the underlying molecular pathology. Such
clinicopathological correlation will become invaluable as
disease-modifying treatments for dementia are developed and
implemented.

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