How to do it

Suspecting dementia: canaries,

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chameleons and zebras
Jeremy C S Johnson ‍ ‍ ,1 Laura McWhirter,2 Chris J D Hardy,1
Sebastian J Crutch,1 Charles R Marshall,3,4 Catherine J Mummery,1
Jonathan D Rohrer,1 Martin N Rossor,1 Jonathan M Schott,1
Rimona S Weil ‍ ‍ ,1 Nick C Fox,1 Jason D Warren1

1
Dementia Research Centre, Abstract dementia in the first place and deciding why
UCL, London, UK
2 The early and accurate diagnosis of dementia this is not ‘just’ Alzheimer’s disease.
Centre for Clinical Brain
Sciences, University of is more important than ever before but Dementia is a syndrome that can be defined
Edinburgh, Edinburgh, UK remains challenging. Dementia is increasingly very generally as a progressive decline in
3
Preventive Neurology Unit, the business of neurologists and, with ageing cognitive function and/or behaviour that
Wolfson Institute of Preventive
Medicine, London, UK
populations worldwide, will become even impacts daily life functioning. As such, it
4
Department of Neurology, more so in future. Here we outline a practical, has a multiplicity of causes. Most of these
Royal London Hospital, London, symptom-­led, bedside approach to suspecting are neurodegenerative pathologies that are
UK dementia and its likely diagnosis, inspired by not presently reversible; however, the rare
Correspondence to clinical experience and based on recognition of exceptions are not to be missed. A key theme
Prof Jason D Warren, Dementia characteristic syndromic patterns. We show how in dementia (especially in neurodegenerative
Research Centre, University clinical intuition reflects underlying signature disease) is that the causative pathologies
College London, London WC1N
3BG, UK; j​ ason.​warren@​ucl.​
profiles of brain involvement by the diseases initially target certain brain functions rela-
ac.​uk that cause dementia and suggest next steps tively selectively, due to a predilection of
that can be taken to define the diagnosis. We pathogenic proteins to involve particular
Accepted 20 April 2021
Published Online First
propose ‘canaries’ that provide an early warning brain networks.3 Over time, these signature
1 July 2021 signal of emerging dementia and highlight the patterns become obscured as the spread of
‘chameleons’ that disguise or mimic this, as well pathological change leads to convergent,
as the ‘zebras’ that herald a rare (and sometimes widespread damage and impairment. The
curable) diagnostic opportunity. window of greatest opportunity for accurate
diagnosis (and anticipated interventions)
​pn.​bmj.​com is therefore early-­ stage disease. Appreci-
ating how profiles of brain damage relate to
Introduction cognitive deficits is key to deciding which
As the number of people worldwide with diseases are likely in patients presenting with
dementia approaches 50 million, the need suspected dementia.
for early and accurate diagnosis is more Here we outline a symptom-­led, bedside
urgent than ever.1 Timely diagnosis avoids approach to suspecting dementia that we
the limbo of diagnostic uncertainty and futile have found useful in busy neurological clinics.
cycles of investigation, equips patients and First, we consider clues that help one decide
families to engage appropriate support and whether or not cognitive decline is present
to plan for the future, and directs rational and, if so, the likely cause. We show how
and appropriate management.2 It will also these clues predictably reflect underlying
be essential for the effective deployment of signature patterns of brain involvement by
disease-­modifying therapies that are on the causative pathologies and suggest next steps
horizon. However, the early diagnosis of that can be taken to define the diagnosis. As
dementia is challenging and remains pecu- with many other disorders, the neurologist’s
© Author(s) (or their liarly reliant on clinical judgement (box 1); essential task is to identify ‘canaries’ that
employer(s)) 2021. No the target diseases are complex and affect provide an early warning signal of emerging
commercial re-­use. See rights disease, avoid being misled by ‘chameleons’
and permissions. Published
aspects of higher brain function that are
by BMJ. generally not assessed in routine neurolog- that disguise or mimic this and remain alert
ical practice. Treatises on dementia conven- to the occasional ‘zebra’ that heralds a rare
To cite: Johnson JCS,
McWhirter L, Hardy CJD, et al. tionally list the clinical features of particular (and sometimes curable) diagnosis.
Pract Neurol 2021;21:300– diseases—in the trenches, however, the We suggest some general principles and
312. biggest challenge is often suspecting tools for cognitive assessment in box 1 and

Johnson JCS, et al. Pract Neurol 2021;21:300–312. doi:10.1136/practneurol-2021-003019 1 of 14

How to do it

figure 1 and outline a bedside framework for cognitive

Box 1 Some principles of bedside cognitive
history taking and examination in table 1. Diagnostic
assessment

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canaries based on characteristic patterns of cerebral
History taking involvement are listed in table 1; potential pitfalls are listed
►► History is the most important aspect of successful in table 2, chameleons in table 3 and zebras in table 4.
dementia diagnosis.
►► Obtaining a history from reliable informants who
Does this patient have dementia?
know the patient well is integral and interviewing Distinguishing early dementia from the ‘worried well’ or a
them separately may encourage sharing of sensitive or ‘functional’ cognitive disorder is an increasingly frequent
embarrassing clues to the diagnosis. challenge faced by neurologists as public awareness and
►► A minute or two spent putting the patient and family
anxiety about dementia continue to increase.4 A func-
at ease is well invested. tional cognitive disorder should be considered if there are
►► How organised and detailed patients seem when
positive features of internal inconsistency, that is, ability
describing their symptoms is informative, particularly if to perform a task well at certain times, but with signif-
at odds with performance on formal cognitive tests. icant difficulty when it becomes the focus of attention.
►► Interpretation of cognitive or behavioural changes
The person who gives a detailed (or even overinclusive)
depends on an appreciation of the patient’s account of their memory lapses, attributes their difficul-
sociocultural background, education, occupation, ties eloquently to specific past events and who is substan-
premorbid language skills, any pre-­existing specific tially more concerned about their cognitive function than
developmental or other deficits, and medical and their partner, children or colleagues—often attending
psychiatric history (including medications). clinic unaccompanied—is more likely to be anxious or
►► Cognitive concerns will most frequently be framed
to have a functional cognitive disorder than dementia.
as a non-­specific ‘memory’ problem: this is the most People with obsessional personalities are more prone
ubiquitous of several potential ‘pitfall’ symptoms that to overinterpret the imperfections of normal memory.
must be deconstructed (see table 2). There is often a flavour of wavering concentration,
►► Domains of cognitive function and behaviour that may
such as being unable to remember why one has entered
not be volunteered should also be explored (as these a room, misplacing household items in odd locations
help define the cognitive profile), framing these as (eg, keys in the fridge) or ‘going blank’ during a conver-
questions about functioning in daily life. sation only to have the required information re-­emerge
►► Particularly in younger people, a detailed family history
soon afterward. Cognitive testing frequently generates
is essential (including parents’ diagnoses and age at considerable anxiety, inducing ‘thought-­ blocking’ and
death if relevant, and the ages of any siblings). performance may vary widely between assessments, often
Examination leading to marked inconsistencies (disastrous test scores
►► It is first essential to establish that the patient is alert
despite evident competence in daily life). This contrasts
and cooperative and that their peripheral vision and with the ‘face-­saving’, humour and minimisation often
hearing are adequate (or corrected as appropriate). seen in Alzheimer’s disease, or indifference in diseases
►► Observing the patient’s conduct and interaction with
where insight is impaired. However, particularly in older
the examiner and others is often telling (it may point patients, functional cognitive impairment may signal an
to frontal lobe dysfunction more clearly than any test; emerging neurodegenerative process which declares itself
see table 2). subsequently.
►► To corroborate the history and to build a diagnostic
Depression or other primary psychiatric diagnoses must
profile of cognitive deficits, it is helpful to have a not be overlooked—these are potentially treatable and
scheme for testing cognition (a ‘walk around the undetected carry significant risk of harm. There is often a
brain’, table 1), armed with some tools to elicit history of previous psychiatric episodes, though this may
cognitive deficits (figure 1): the cognitive profile not be volunteered. Core depressive symptoms are low
in turn predicts the underlying pattern of brain mood or anhedonia, variably accompanied by fatigue,
involvement (figure 2). psychomotor retardation, impaired concentration, a sense
►► Quantitative cognitive assessments such as the Mini-­
of personal worthlessness, significant change in appetite
Mental State Examination, the Montreal Cognitive or recurrent morbid thoughts.5 Depressed patients are
Assessment and Addenbrooke’s Cognitive Examination often downcast and disengaged, giving frequent ‘don’t
are widely available; however, each has its limitations1 know’ responses. Active psychosis also leads to poor
33
and none in itself should be used to diagnose or engagement, and there may be evidence of delusional
exclude dementia. thinking or verbal hallucinations. It is important to keep
►► The general neurological and systemic examinations
in mind that anxiety, mood changes and psychosis occur
are essential, particularly for substantiating diagnoses not uncommonly in ‘organic’ dementias and may be early
other than Alzheimer’s disease (see tables 3 and 4). features6 7; moreover, organic deficits may be elaborated
by patients with abnormal illness behaviour, and certain
syndromes (such as parietal presentations of Alzheimer’s

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 How to do it

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Figure 1 Examples of aids for testing cognition at the bedside. These are some examples of materials that we use to sample
a range of cognitive domains (see also table 1 and figure 2) when examining a patient with suspected dementia (shown with
permission of Professor E K Warrington). (A) A pictorial scene for description, to assess connected language (fluency, word
finding and expressive grammar) and ability to parse a complex environment (visuospatial processing). (B) An array of pictures of
familiar items for assessing word retrieval (naming), single-­word comprehension (pointing to an item named by the examiner) and
subsequent item recall (anterograde episodic memory). (C) A passage for reading aloud to elicit difficulties sounding non-­words
(personal names, eg, ‘Scorba’; phonological dyslexia) or irregular words (eg, ‘yacht’, regularised as ‘yached’; surface dyslexia) or
with tracking lines of text (visuospatial processing). (D) Fragmented letters to assess visual apperceptive function. (E) A Stroop task,
requiring the patient to state the (conflicting) colour of the ink in which each colour name is printed (in fluent readers of English, a
test of response inhibition—one aspect of executive function).

disease and behavioural variant frontotemporal dementia) topographical material (such as reconstructing the journey
are notoriously prone to psychiatric mislabelling even by to the hospital) may be notably affected.
experienced clinicians. Beyond memory, parietal cortical functions including
word retrieval, praxis, calculation and visuospatial func-
Some important canaries tion are affected relatively early in Alzheimer’s disease.
Alzheimer’s disease There may be difficulties with word finding, handling
Older patients with episodic and topographical memory household appliances, managing money or visuospatially
impairment that declines over time will most commonly demanding activities such as driving or do-­ it-­
yourself.
have emerging Alzheimer’s disease. Details of important Coming to grips with new technology taxes learning,
events and conversations are not retained, questions executive and parietal functions and is often particularly
become repetitive and there is often a loss of facility with challenging.
route-­finding and a history of becoming lost. There may
be a signal ‘catastrophic’ episode (often, disorientation in Dementia with Lewy bodies
unfamiliar surroundings, e.g. while on holiday) preceding Dementia commonly develops in Parkinson’s disease
more pervasive deterioration. Difficulty following conver- (particularly in older patients) and is a core feature of
sations in background noise and dislike of noisy environ- Lewy body pathology.10 Clues include an early predisposi-
ments (due to impaired auditory scene processing) tend to tion to severe, prolonged delirium (for example, attending
develop early.8 Loss of pleasure in reading (probably multi- a minor infection or surgical procedure) and sometimes
factorial in nature) is also frequently reported. Retained acting out of dream content (REM sleep behaviour
(partial) awareness of limitations as well as endogenous disorder, due to loss of normal skeletal muscle atonia).
emotional changes wrought by the disease often lead to Later, misperceptions and hallucinations (usually predom-
loss of confidence or initiative, embarrassment, anxiety inantly visual) develop, though these may not be volun-
and withdrawal from social activities, manifesting in the teered. Initially, they may be brief transients glimpsed
clinic as a tendency to ‘trail’ the accompanying person in the periphery but evolve into vivid, animate entities
into the room and to turn to them (‘head-­turning sign’) (commonly faces, people or animals) that emerge out of
when asked a question.6 9 On bedside testing, the extent background features (such as foliage or a pile of clothes)
to which cognitive impairment has been masked by a in stereotyped fashion, particularly under low-­light condi-
well-­preserved social façade may be surprising: knowl- tions. In contrast to psychotic or dopamine-­driven halluci-
edge of current affairs tends to be vague, recall of previ- nations, these are typically non-­threatening though insight
ously presented items does not benefit from cueing and into their nature may be impaired. An ‘extracampine’

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Table 1 Bedside assessment of the patient with suspected dementia: a ‘walk around the cognitive brain’

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Leading or early
Cognitive domain symptoms Associated symptoms Examination findings Brain region(s) First thoughts
Behaviour (social and Loss of empathy/ Disinhibition, loss of initiative, Impulsive, inert, disinhibited Frontal lobe (especially Behavioural variant
emotional) emotional awareness obsessionality/rituals (eg, clock interaction, ‘1000-­yard stare’ right), right temporal lobe, frontotemporal
(eg, family events such watching), gluttony/sweet other dementia
as funerals, illnesses and tooth/food faddism, altered
warmth toward children/ interests/humour, loss of insight/
pets) and self-­centredness anosognosia
Irritability, more anxious Quieter in social situations Diffident/head turning Alzheimer’s disease*
and ‘clingy’
Language output Stumbling over words, Mixing up ‘yes’/no’, Effortful speech, reduced Left inferior frontal gyrus/ Non-­fluent primary
(speech sounds, especially public speaking mispronunciations, monotonous/ articulatory agility (repeating peri-S­ ylvian† progressive aphasia
sentences and prosody) odd accent, syllable strings, eg, ‘puh-­kuh-­
grammatical/spelling slips tuh’), impaired repeating single
words and following complex
commands
Word-­finding difficulty, Reduced speech quantity, pauses Reduced picture naming Left temporoparietal Logopenic aphasia
losing thread of sentences junction
Knowledge of words Forgetting names, Asking meaning of words, Reduced knowledge of specialist Left anteroinferior Semantic primary
(vocabulary), objects circumlocutions, vague keeping personal ‘dictionaries’ vocabulary,‡ reduced naming temporal lobe progressive aphasia
and concepts expressing thoughts and and decline in spelling/ of objects/ability to identify
‘going deaf’ understanding written words pictures/define words named
by examiner, surface dyslexia
(irregular words, eg, ‘yacht’)
Difficulty choosing groceries/ Unable to describe/demonstrate
tools, etc§ use of an object§ (visual
agnosia)
Reading, spelling and Loss of pleasure reading Losing place reading text, Difficulty reading blocked text Left parietal lobe Posterior cortical
calculation Less numerical facility (eg, difficulty resolving closely spaced and acalculia on simple mental atrophy, logopenic
change) text and decline in spelling ability arithmetic aphasia and Alzheimer’s
disease
Working memory Poor ‘concentration’ Difficulty holding information for Reduced forward (passive) digit Left temporoparietal Logopenic aphasia and
(verbal) example, a new phone number span, reduced reverse (active) junction/frontal lobe Alzheimer’s disease
in mind digit span and reduced repetition
Losing thread of conversation of phrases more than words
Action (learnt/ Difficulty learning new Difficulty using household Ideomotor limb apraxia: impaired Left parietal lobe Posterior cortical
voluntary: praxis) devices, loss of facility gadgets copying meaningless/sequential atrophy and
with do-­it-­yourself, etc gestures (Luria), ideational limb corticobasal syndrome
apraxia: impaired pantomime of
learnt actions (eg, tool, waving)
Difficulty positioning self in space Bottom apraxia (difficulty sitting
on chair)
Loss of facility whistling/ Difficulty swallowing Orofacial apraxia: volitional Left frontal lobe† Non-fl­ uent primary
singing cough/yawn/blow kiss, etc progressive aphasia
Object analysis (visual) Difficulty reading large/ Difficulty interpreting complex Difficulty perceiving fragmented Right parietal lobe Posterior cortical
unusual (eg, pixelated/ scenes with patterns, overlaid letters/pictures, distorted views atrophy and dementia
CAPTCHA) font; objects, identifying slopes/ with Lewy bodies
not confident on steps, etc;
escalators; difficulty recognising or
often multiple optician misrecognising objects in
visits suboptimal viewing conditions
Spatial awareness Bumps/scrapes in car, Unable to find items in an array, Difficulty drawing clockface/ Right parietal lobe Posterior cortical
(visual) difficulty parking and placing items too close to table copying design/counting dots, atrophy and Alzheimer’s
difficulty filling forms, etc edge finding examiner’s outstretched disease
hand (visual disorientation)
Perception Difficulty driving if night-­ Abnormally prolonged after-­ Impaired colour/shape Sensory cortices/ Posterior cortical
(early sensory–visual, time/raining images (colour ‘washes’, often discrimination (e.g., oblong vs thalamus¶ atrophy, ‘visual’
auditory, somatic and red/green), visual ‘tilt’ and other square) Creutzfeldt-­Jakob
interoceptive) distortions disease
‘Double vision’, brief Illusions/hallucinations Check visual acuity Dementia with Lewy
misperceptions bodies
Dislikes noisy Difficulty conversing in noise Check peripheral hearing Alzheimer’s disease and
environments variants
Tinnitus/hyperacusis Altered pain/temperature Check basic sensory function Semantic primary
awareness progressive aphasia
and behavioural
variant frontotemporal
dementia
Continued

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Table 1 Continued

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Leading or early
Cognitive domain symptoms Associated symptoms Examination findings Brain region(s) First thoughts
Face recognition Loss of facility recognising ‘Blanking’ familiar people and Impaired famous face Right anteroinferior Semantic primary
faces misidentification of ‘impostors’ recognition** temporal lobe and progressive aphasia
connections and right temporal lobe
atrophy††
Impaired perception of faces Right temporal lobe/ Alzheimer’s disease and
(age/gender) parietal lobe dementia with Lewy
bodies
Executive function Disorganised, distractible, Difficulty with inference/ Reduced/bizarre verbal fluency Bilateral frontal lobe and May be behavioural
poor planning/decision abstraction, choosing (category/letter–number of connections variant frontotemporal
making/multitasking/ alternatives, envisaging/learning animals/‘S’ words in 1 min),‡‡ dementia but depends
prioritising, apathetic from consequences and dealing Stroop task errors, concrete on associated problems
with novelty proverb interpretation, inaccurate
cognitive estimates (eg, ‘How
many lions in Belgium?’)§§¶¶
Memory (episodic and More repetitive and less Vague knowledge of current Orientation to date/time/place, Hippocampi and Alzheimer’s disease (but
topographical) facility with route finding affairs and getting lost details of hospital journey/stay connections beware)
and incidental recall of pictures
from naming test
Forgetful, absent-­minded Poor concentration, disorganised Improves on cueing/foils; ‘Did Vascular/other
you see a…?’)
This table presents early symptoms (‘canaries’; see also table 2) that signal difficulty in each major cognitive domain, together with associated symptoms that may be elicited on history. For
each domain, we suggest bedside tests (see also box 1) and features that may be used to corroborate the historical impression and indicate major neuroanatomical associations (see also
figure 2) and leading diagnostic considerations.
*Refers to the clinical syndrome of typical (memory-­led) Alzheimer’s disease.
†Prosody/ singing may be additionally linked to right peri-­Sylvian cortical regions
‡Initial loss of knowledge of lower-­frequency words reflecting patient’s interests/occupation.
§May indicate visual agnosia (the patient with apraxia recognises how an object is used).
¶Usually conjoint ‘top-­down’ abnormalities in attentional/executive/semantic functions.
**Ask for other biographical details if patient cannot name.
††Refers to the syndrome associated with right temporal lobe atrophy, within the behavioural variant frontotemporal dementia spectrum.
‡‡In non-­aphasic patients.
§§Dependent on education and culture.
¶¶The manner in which the patient approaches executive tests is also informative, for example, are they impulsive? do they produce odd items on fluency tasks? do they produce overprecise,
incorrect estimates that they cannot revise? etc.

sense of a presence beyond the field of vision is common. often significant slowing of mentation. Brisk tendon and
Marked fluctuations in alertness, attention and cognitive pout reflexes (despite flexor plantar responses) where
competence even within the course of a day (particularly present are characteristic and in more advanced cases gait
deterioration later in the day) are also characteristic.11 may be wide-­based and shuffling. Dysphagia may develop
Complaints of ‘double vision’ and problems reading later in the disease. Though this is one of the few diag-
(without identifiable ocular pathology) are common, and noses in neurology where a compatible scan is sine qua
difficulty using gadgets such as a smartphone exposes non, over-­ diagnosis of incidental vascular changes is a
executive and parietal dysfunction. Features of associated significant pitfall, compounded by the frequent coexis-
Parkinsonism (such as hypomimia or gait changes) may tence of cerebrovascular with primary neurodegenerative
be subtle initially but it is worth asking about autonomic pathologies.
symptoms (particularly urinary urgency, nocturia or unex-
plained collapses).12 13
Some chameleons and zebras
Vascular cognitive impairment Alzheimer’s disease variants
The most common cognitive syndrome of cerebrovas- Atypical presentations of Alzheimer’s disease dominated
cular disease is not the stepwise decline in function of by non-­amnestic deficits are not uncommon, particularly
classical teaching, but an insidious deterioration char- in younger people16 17; conversely, Alzheimer’s disease is
acterised by disorganisation, loss of verve and initiative, simulated by a variety of other disease processes.18 Table 3
irritability, mental rigidity, emotional lability and other summarises some of these chameleons; it is particularly
mood changes, and sometimes inappropriate or disinhib- important to consider potentially reversible mimics,
ited social behaviour. Vascular risk factors are common, such as transient epileptic amnesia or obstructive sleep
but their absence does not exclude the diagnosis. Exam- apnoea.18–24 There are three major Alzheimer variant
ination typically reveals cognitive and affective blunting, syndromes, likely reflecting differential involvement of
executive dysfunction, impaired attention and recall the same core temporo–parieto–frontal brain network
(which in contrast to Alzheimer’s disease, does generally targeted by Alzheimer pathology (see tables 1 and 2, and
benefit from cueing) with variable additional, more focal figure 2).16–18 These variants lie on a clinical continuum
deficits;14 15 however these may be over-­estimated due to and overlap is frequent.

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Table 2 Some noteworthy potential ‘pitfall’ symptoms and signs requiring further clarification or interpretation in suspected dementia

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Feature Clarification/interpretation Major causes
Ambiguous symptoms
 ‘Poor memory’ Often used as a shorthand for ‘cognitive problem’; does it mean episodic Any (may have poor episodic memory
memory (events, routes, conversations, etc), semantic memory (words in dementia with Lewy bodies,
and concepts) or another domain of cognition? If the issue is with frontotemporal dementia, etc, as well as
memory, is it with encoding information (attention), retaining new Alzheimer’s disease*)
information (anterograde memory) or retrieving old information?
 ‘Getting lost’ Is this truly difficulty completing a route without assistance Alzheimer’s disease (topography) and
(topographical disorientation) or wandering (but ultimately getting behavioural variant frontotemporal
there)? A useful question can be ‘how would you make your way home dementia (wandering)
from here if you had to do it alone’?
 ‘Word-­finding difficulty’ Often used as a shorthand for ‘language problem’; is it difficulty Alzheimer’s disease/others (retrieval),
retrieving the name (very common), loss of vocabulary or difficulty semantic primary progressive aphasia
pronouncing the word (uncommon)? (vocabulary) and non-­fluent primary
progressive aphasia (articulation)
 ‘Lost interest in reading’ Is this a general loss of concentration or initiative, anhedonia, difficulty Alzheimer’s disease (multifactorial) and
following the plot or a more specific problem tracking lines of text? posterior cortical atrophy (text tracking)
 ‘Doesn’t recognise people’ Is this inability to recall their name (personal anomia, common) Alzheimer’s/others (names), semantic
or to recognise faces or voices, ‘blanking’ familiar people? (true primary progressive aphasia/right
prosopagnosia or phonagnosia, uncommon) temporal lobe atrophy† (familiarity)
 ‘More anxious/irritable’ Might be psychiatric (eg, atypical depression) but also an early feature Alzheimer’s disease, dementia with
of many ‘organic’ dementias Lewy bodies, vascular and some
frontotemporal dementias (eg, C9orf72
mutations)
 ‘Black sheep of family’ Youthful delinquency that contrasts with law-­abiding siblings Latent learning disability, very rarely
genetic prion disease
Counterintuitive symptoms
 ‘Asks meaning of words’ Loss of ability to understand words in a familiar language Semantic primary progressive aphasia
 ‘Reads fine print but not Visual apperceptive agnosia exposed by non-­canonical (eg, very large or Posterior cortical atrophy
the headlines’ pixelated) text
 ‘Can play tennis (etc) but Static visual localisation more impaired than motion vision (or Posterior cortical atrophy
can’t find ball on ground’ occasionally the reverse), reflecting separable neuroanatomical
substrates
 ‘Says spouse is impostor’ Misidentification delusion (Capgras, etc), can also be for location (eg,Alzheimer’s disease, dementia with Lewy
asks to go ‘home’ in own house) bodies
 ‘Much nastier/nicer now’ Altered interpersonal awareness and conduct Behavioural variant frontotemporal
dementia (nasty) and Alzheimer’s disease
(nice)
 ‘Become very musical/ Enhanced (sometimes loss of) interest/ability in abstract pursuits, Behavioural variant frontotemporal
religious/punctual/good at usually with loss of interest/affection for other people, on a spectrum of dementia and semantic primary
Sudoku’ alterations ranging from basic rewards (sweet food and sleep), through progressive aphasia
sense of humour and timekeeping, to puzzles/complex stimuli
Potentially misleading symptoms  
 ‘It all started after that… Usually, this is attribution bias; occasionally we have seen cases where Any
(accident/operation, etc)’ severe psychological trauma did seem to provoke catastrophic cognitive
decline in a previously asymptomatic person
 ‘Distant memories are fine’ Usually they are not, but highly overlearnt or emotional memories tend Alzheimer’s disease
to become the focus of cherished anecdote
 ‘Poor short-­term memory’ To a neuropsychologist, this refers to the immediate span of working Any
memory (up to ~30 s) but used colloquially to refer to recent episodic
memory of variable span
 ‘Thinks people are stealing Usually not a harbinger of psychosis but a specific delusion of theft (or Alzheimer’s disease, dementia with Lewy
from them’ infidelity) bodies
 ‘Going deaf’ Peripheral hearing should always be checked but in context may signify Semantic primary progressive aphasia
difficulty understanding word meaning
 ‘Always been spiritual’ Apparent receptivity to ‘ghosts’/presences may signify visual/ Dementia with Lewy bodies
extracampine hallucinations
 ‘Unexplained aches/pains’ Hypochondriasis can occasionally reflect abnormal processing of Right temporal lobe atrophy and
interoceptive signals such as pain semantic primary progressive aphasia
Continued

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Table 2 Continued

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Feature Clarification/interpretation Major causes
Signs not to miss/misinterpret  
 Bottom apraxia Difficulty orienting/positioning self in space as when sitting down in a Posterior cortical atrophy and
chair corticobasal syndrome
 Closing in Patients overlay their hand or drawing on examiner’s target—feature of Alzheimer’s disease and posterior cortical
organic apraxia atrophy
 ‘(Vicar of) Dibley’ sign Binary reversals during conversation—says ‘yes’ but means ‘no’, etc Non-­fluent primary progressive aphasia
 Dysprosodia (isolated) Most cases of ‘foreign accent syndrome’ (recognisable as such, Non-­fluent primary progressive aphasia
sometimes simulated with pantomime exuberance) will be functional,
but occasionally patients present with altered prosody and linguistic
deficits only supervene (much) later
 Executive dysfunction As used, for example, in neuropsychological reports, it is not Any
synonymous with ‘frontal lobe problem’ but reflects processing across
distributed brain networks; moreover, patients with significant frontal
lobe dysfunction (as reflected in abnormal behaviour) may perform well
on executive tests
 Head-­turning To accompanying person, during history taking—lack of confidence/ Alzheimer’s disease
retained awareness of problem/poor memory
 Perioral dyskinesias Subtle trembling movements of lips/lower face Alzheimer’s disease (younger onset)
 Pigeon sign Turns head this way and that, trying to make sense of a picture or visual Posterior cortical atrophy
array
 Repetitiveness conversing Signifies an organic problem with anterograde episodic memory/ Alzheimer’s disease
accelerated forgetting
 Semantic paraphasias Substitution of related words on a naming task usually will not reflect Alzheimer’s disease, others
a primary semantic problem but more likely anomia (impaired word
retrieval) with attempted compensation
 Surface dyslexia Sounds irregularly pronounced words as they are printed, due to loss of Semantic primary progressive aphasia
vocabulary-­based reading
 ‘Thousand yard stare’ Sense of unease/threat conveyed by patient who lacks normal social Right temporal lobe atrophy
facial microreactivity
 Tie sign Patient touches examiner’s tie/face when trying to locate their Posterior cortical atrophy
outstretched hand, due to visuospatial disorientation
 ‘Variable deficit’ Apraxia is intrinsically variable; organic cognitive impairment of any Dementia with Lewy bodies (sleep
cause can be impacted by stress or fatigue, and certain entities are benefit), transient epileptic amnesia
characterised by marked fluctuation‡ (sometimes sleep benefit/ (sleep deterioration), inflammatory,
deterioration), due to seizures, channel dysfunction or impaired immune
dopaminergic/cholinergic switching between brain states
*Refers to the clinical syndrome of typical (memory-­led) Alzheimer’s disease.
†Refers to the syndrome associated with right temporal lobe atrophy, within the behavioural variant frontotemporal dementia spectrum.
‡Not the same as inconsistency—organic cognitive fluctuations are internally consistent.

Posterior cortical atrophy, the ‘visual variant’ of Alzhei- repetition of single words (due to reduced verbal working
mer’s disease, usually presents with impairments of visuo- memory).26
spatial awareness, reading and praxis.17 Beware the patient The ‘frontal’ (behavioural/dysexecutive) variant of
who has made numerous futile visits to the optician or Alzheimer’s disease remains the least well defined.27 Clin-
who describes more difficulty reading pixelated signs than ically, it can closely resemble the behavioural variant of
newsprint (signifying visual apperceptive agnosia): this frontotemporal dementia, but prominent accompanying
is the cardinal degenerative disorder of the visual brain, memory impairment and confabulation may be bedside
disrupting the interpretation of visual scenes despite clues to the diagnosis.
normal sensory acuity. There is usually a full hand of
accompanying parietal lobe deficits, but episodic memory Frontotemporal dementia syndromes
early on is often well preserved. Among the ‘zebras’ of dementia diagnosis, the fronto-
Logopenic aphasia is the language-­led variant of Alzhei- temporal dementias are particularly important because
mer’s disease within the primary progressive aphasia they are collectively a major cause of dementia in
spectrum.25 It is characterised by prominent word-­finding middle life and wreak havoc on social and occupa-
difficulty, conversational pauses (sentences tend to trail tional functioning. This is a diverse group of diseases
off) with speech sound (phonological) errors and, on with complex neurobiology28; however, three major
examination, impaired repetition of phrases despite intact clinical presentations are recognised.

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How to do it

Table 3 Some important ‘chameleons’ of dementia diagnosis

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Disease Chameleons Some useful features to identify the chameleon
Alzheimer’s disease Mimics*
Transient epileptic amnesia† Clinical seizures (not invariable), prominent fluctuation, ‘vacational' amnesia‡; abnormal (extended)
EEG, may have other features of limbic encephalitis, auto-­antibodies / cancer
Obstructive sleep apnoea† Daytime somnolence, non-­refreshing sleep, heavy snoring (from partner); abnormal sleep study
Normal-­pressure hydrocephalus† May have gait apraxia, urinary dysfunction; MRI hydrocephalus and associated features
Vascular MRI: strategic (eg, thalamic) infarct, other vascular patterns (including deep micro-­haemorrhages)
Traumatic brain injury/chronic traumatic History of significant (especially recurrent) head trauma
encephalopathy
Dementia with Lewy bodies frontotemporal Vary according to underlying pathology; may have genetic mutation (frontotemporal dementia,
dementia and other neurodegenerative familial prion), some entities (eg, argyrophilic grain disease, limbic-­predominant age-­related TDP-43
disorders encephalopathy) currently only diagnosed post mortem
Variants
Posterior cortical atrophy Positive Alzheimer markers in CSF (raised total / phospho-­tau, reduced beta-­amyloid42 and beta-­
Logopenic aphasia amyloid42/40 ratio), cortical micro-­haemorrhages associated with amyloid angiopathy
Behavioural variant frontotemporal-­like
Corticobasal syndrome
Young onset (sporadic)
Rapid (may have beta-­amyloid angiitis) Positive Alzheimer CSF and MRI markers, cortical microhaemorrhages/siderosis on MRI
Familial Young, autosomal dominant family history (may be censored); may have spastic paraparesis/other
neurological signs (especially PS1 mutations), prominent neuropsychiatric features, white matter
change on MRI; PS1, PS2 or APP mutation (in addition to Alzheimer CSF markers)
Dementia with Lewy Mimics
bodies Progressive supranuclear palsy and Supranuclear gaze palsy, prominent asymmetric apraxia/axial rigidity; poor levodopa response
corticobasal syndrome
Variants
Alzheimer-­like Florid delirium, prominent fluctuations, early visual hallucinations, REM sleep behaviour disorder,
Behavioural variant frontotemporal-­like emerging parkinsonism
Rapid
Vascular cognitive Mimics
impairment Infectious/inflammatory/autoimmune† Suggestive history, autoantibodies, blood/CSF serology (eg, human immunodeficiency virus and
syphilis)
Genetic arteriopathies Young, lack of vascular risk factors, suggestive family history; migraine, psychiatric features, MRI
involvement of anterior temporal lobe, NOTCH3 mutations with CADASIL
Primary leukodystrophies Young, lack of vascular risk factors, suggestive MRI (confluent, symmetric white matter change),
positive diagnostic tests
Variants
Behavioural variant frontotemporal-­like MRI: significant vascular change, lack of suggestive atrophy profile
Prominent amnestic/focal ‘cortical’ deficits MRI: strategic infarct (especially thalamus, parietal)
Frontotemporal Mimics
dementia§ ‘Frontotemporal dementia phenocopy’ Normal brain MRI/ fluorodeoxyglucose-­PET; some frontotemporal dementia cases (especially C9orf72
(especially older men) mutations) may be very slowly progressive—phenocopy cases often show better preserved insight
than is usual with frontotemporal dementia
Frontal variant of Alzheimer’s disease Prominent associated episodic memory deficit, relatively prominent posterior atrophy on MRI,
Alzheimer biomarkers (CSF, amyloid PET)
Vascular MRI: vascular features
Dementia with Lewy bodies Visual hallucinations, REM sleep behaviour disorder
Variants
Amnestic/Alzheimer-­like Negative Alzheimer biomarkers
Corticobasal syndrome May have GRN mutation
Motor neurone disease May have C9orf72 mutations
Very young onset/rapid MRI: disproportionate caudate atrophy (FUS-­opathy)
Here, chameleons are either ‘mimics’—a different disease that presents similarly to the typical syndrome, listed in the left-­most column—or ‘variants’—an alternative, atypical presentation
of the same disease process that causes the typical syndrome.
*Negative Alzheimer markers may be helpful but Alzheimer pathology frequently coexists with other entities (seizures, obstructive sleep apnoea more common in Alzheimer’s disease).
†Potentially reversible process.
‡No recollection at all of salient events such as vacations (typically in Alzheimer’s disease, there is some recollection of the episode, although degraded).
§Presentation with behavioural variant here taken to be typical (clinical mimics of primary progressive aphasia syndromes are very uncommon).
APP, amyloid precursor protein; CADASIL, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; C9orf72, mutation of chromosome 9 open reading
frame 72; CSF, cerebrospinal fluid; EEG, electroencephalogram; FUS, fused-­in-­sarcoma protein; GRN, progranulin gene; NOTCH3, neurogenic locus notch homolog protein 3 mutations; PET,
positron emission tomography; PS1, presenilin 1 gene mutation; PS2, presenilin 2 gene mutation.

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 Table 4 Some important ‘zebras’ in dementia diagnosis
Candidate diagnoses
Leading clue Syndromic features (especially early) Sporadic Genetic* Key investigations

Unusual
 Socioemotional Reduced empathy, disinhibition, apathy, obsessionality, Behavioural variant frontotemporal dementia C9orf72, GRN, MAPT, others less commonly MRI (figure 2), but atrophy highly variable and may be subtle, may
decline leading stereotypies, altered eating behaviour, executive deficits; atypical have associated midbrain atrophy (progressive supranuclear palsy),
parkinsonism (progressive supranuclear palsy/corticobasal genetics
syndrome) frequent later
 Language decline Effortful, misarticulated, apraxic speech, binary reversals, Non-­fluent primary progressive aphasia GRN, C9orf72, others (uncommon) MRI (figure 2), but atrophy variable; genetics if young/suspicious
leading grammatical errors, orofacial apraxia; atypical parkinsonism family history
(progressive supranuclear palsy/corticobasal syndrome) frequent
later
Loss of vocabulary, severe anomia with impaired single word Semantic primary progressive aphasia MAPT, others (rarely) MRI (figure 2) characteristic
comprehension despite fluent well-­structured speech, often
frontotemporal dementia-­like behaviours
Anomia/word-­finding pauses, phonemic errors, phrase repetition/ Logopenic aphasia (usually Alzheimer GRN (rarely) MRI asymmetric (predominantly left-­sided) temporoparietal atrophy,
verbal working memory deficits pathology) CSF Alzheimer markers
 Visuospatial decline Difficulty reading unusual fonts/night driving/using gadgets, Posterior cortical atrophy (usually Alzheimer MRI (figure 2), CSF Alzheimer markers
leading mispositioning items; later apperceptive agnosia/disorientation, pathology; some dementia with Lewy bodies,
dyscalculia, anomia others)
 ‘Frontal’—ataxia Also urinary urgency/incontinence Normal-­pressure hydrocephalus† MRI ventriculomegaly and associated features
May have history of prior neurological episodes Multiple sclerosis (especially primary/ MRI (brain/cord) demyelination features, CSF unmatched oligoclonal

Johnson JCS, et al. Pract Neurol 2021;21:300–312. doi:10.1136/practneurol-2021-003019

secondary progressive) bands
History of cranial irradiation (often delayed), also pyramidal/other Post-­irradiation vasculopathy MRI extensive white matter damage
neurological signs
Rapid‡ Early widespread cognitive impairment (often prominent visual Creutzfeldt-­Jakob disease (classically), Prion (Creutzfeldt-­Jakob disease, Gerstmann-­Sträussler-­ MRI cortical/basal ganglia signal change, EEG (periodic complexes—
dysfunction), myoclonus/other neurological signs Alzheimer’s disease, dementia with Lewy Scheinker, familial fatal insomnia, others)§ Creutzfeldt-­Jakob disease), CSF (RT-­QuIC, Alzheimer markers), DAT
bodies (uncommonly) (?dementia with Lewy bodies), genetics
Frontotemporal dementia plus deltoid/triceps fasciculations, Frontotemporal dementia–motor neurone C9orf72 MRI, EMG (often normal), genetics
pyramidal signs disease
Behavioural variant frontotemporal dementia-­like plus corticobasal Frontotemporal dementia (FUS-­opathy)¶ MRI marked caudate atrophy
syndrome, atypical parkinsonism, young, markedly obsessive/
stereotypical behaviour
Headache, fluctuation, seizures, systemic features Vasculitis (CNS/systemic)† MRI, CT angiogram, CSF pleocytosis, autoantibodies/inflammatory
markers; consider brain biopsy
Seizures, jerks, dyskinesias, fluctuation, neuropsychiatric/autonomic/ Limbic encephalitis† MRI high signal in hippocampi/mesial temporal lobe, autoantibodies,
systemic features whole body-­PET/neoplasia screens
Executive/behavioural decline with gait disturbance/variable other Tumour (eg, lymphoma), subdural MRI mass/gadolinium enhancement, may have non-­CNS primary,
neurological features haematoma, other space-­occupying lesions† may need brain biopsy
Immunosuppressed, compatible history of infection Human immunodeficiency virus, human MRI abnormal signal/gadolinium enhancement, blood/CSF serology
herpes viruses, progressive multifocal
leukoencephalopathy, tuberculosis, syphilis,
Whipple’s disease, fungal†; subacute
sclerosing panencephalitis

Continued
How to do it

9 of 14
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 Table 4 Continued
Candidate diagnoses

10 of 14
Leading clue Syndromic features (especially early) Sporadic Genetic* Key investigations

Toxic exposure/dietary deficiency states Alcohol usually nutritional, especially MRI various patterns with white/grey matter involvement, abnormal
thiamine (Wernicke-­Korskakoff syndrome); signal; drug, metabolic, metal screens
How to do it

heroin/other drug abuse, lithium toxicity/

iatrogenic, metals†
Young adult,** Ataxia Paraneoplastic†, superficial siderosis Spinocerebellar ataxias, Niemann-­Pick C, fragile X, This group in general requires specialist consultation—principles
neurological mitochondrial, dentatorubral pallidoluysian atrophy, Kufs’ are (1) definition of phenotype with brain MRI, plus CSF/
disease, prion electrophysiology, depending on presentation; (2) blood screens
(metabolic/inflammatory) and/or genetics directed to cause; (3)
tissue biopsy if required for diagnosis (especially muscle/axillary skin
for storage diseases, etc)
Akinetic–rigid Huntington’s disease, Wilson’s disease,† neurodegeneration
with brain iron accumulation (various)
Autonomic Sarcoidosis† Porphyria, adrenoleukodystrophy, hereditary sensory and
autonomic neuropathy 1E, familial fatal insomnia
Buccolingual mutilation Neuroacanthocytosis, Lesch-­Nyhan
Chorea/dystonia Antiphospholipid, rheumatological† Huntington’s disease, Wilson’s disease,†
neuroacanthocytosis, neuronal brain iron accumulation
disorders, dentatorubral pallidoluysian atrophy, Kufs’
disease (especially facial)
Deafness (peripheral) Susac’s syndrome,† Behçet’s disease,† Mitochondrial, hereditary sensory and autonomic
siderosis, sarcoidosis† neuropathy 1E
Eye abnormalities Behçet’s disease, sarcoidosis, Susac’s Kayser-­Fleischer rings: Wilson’s disease†
syndrome† Cataract: cerebrotendinous xanthomatosis†, myotonic
dystrophy, mitochondrial
Retinopathy: mitochondrial
Gaze palsy Chronic meningitides (inflammatory/ Gaze apraxia: Huntington’s disease
neoplastic)† Supranuclear gaze palsy: (vertical) Niemann–Pick C,
(horizontal) spinocerebellar ataxia type 2, Gaucher’s†
External ophthalmoplegia: mitochondrial
Peripheral neuropathy Sarcoidosis† Mitochondrial, neuroacanthocytosis, Fabry’s,†
spinocerebellar ataxias, metachromatic leukodystrophy,
adrenoleukodystrophy, hereditary sensory and autonomic
neuropathy 1E, cerebrotendinous xanthomatosis,†
porphyria†
Pyramidal signs Spinocerebellar ataxias, familial AD (especially PS1),
adrenoleukodystrophy, Krabbe’s
Seizures (especially myoclonic) Poor control, anticonvulsants† Mitochondrial, dentatorubral– pallidoluysian atrophy, Lafora
body disease, Kufs’ disease, other progressive myoclonic
epilepsies
Strokes Antiphospholipid syndrome† CADASIL, cerebral amyloid angiopathies (familial), Fabry’s†
Systemic Hepatic/gastrointestinal Hepatic encephalopathy† Wilson’s disease,† Gaucher’s,† mitochondrial, porphyria†
Musculoskeletal abnormalities Rheumatological† Paget’s disease, inclusion body myopathy: VCP
Tendon xanthomas: cerebrotendinous xanthomatosis†
Bone cysts: polycystic lipomembranous osteodysplasia with
sclerosing leukoencephalopathy

Johnson JCS, et al. Pract Neurol 2021;21:300–312. doi:10.1136/practneurol-2021-003019

Continued

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 How to do it

The behavioural variant of frontotemporal dementia

CADASIL, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; CNS, central nervous system; C9orf72, mutation of chromosome 9 open reading frame 72; CSF, cerebrospinal fluid; DAT, dopamine transporter scan; EEG, electroencephalogram; EMG, electromyogram;
presents with abnormalities of social and emotional aware-

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ness and reactivity.28 29 The patient generally lacks insight,

FUS, fused-­in-­sarcoma protein; GRN, progranulin gene mutations; MAPT, microtubule associated protein tau mutations; PET, positron emission tomography; PS1, presenilin 1; RT-­QuIC, real-­time quaking-­induced conversion prion protein detection; VCP, valosin-­containing protein gene mutation.
but the family complains bitterly that they have ‘changed’,
typically with loss of warmth and social skills (there may
have been embarrassing faux pas), and frequently prom-
inent apathy, rituals and/or impulsivity that may have
resulted in loss of a job or ill-­advised decisions. Gluttony
and development of a pathological sweet tooth are char-
acteristic, exemplifying a much broader repertoire of odd,
inflexible and maladaptive behaviours with valuation of
Key investigations

abstract or impersonal interests over other people. These

features may be particularly striking in patients with selec-
tive right temporal lobe atrophy,30 who also frequently
exhibit prosopagnosia. Behavioural variant frontotem-
poral dementia is challenging to diagnose, particularly
early on, as there are few reliable biomarkers. Patients
may do well on formal cognitive (including executive)
tests. There are several highly pertinent clinical issues
surrounding the diagnosis: it is genetically mediated in up
to perhaps a third of cases (genetic testing for the three
major causative, autosomal dominant mutations should be
*Family history suggesting autosomal dominant or maternal inheritance in successive generations is particularly helpful but may be censored or absent (these patients also tend to be younger).
Niemann-­Pick C, Gaucher’s†

considered in all younger patients) and vigilant neurolog-

Fabry’s,† mitochondrial

ical follow-­up is indicated, both to detect the emergence

of major associations (atypical parkinsonism or motor
neurone disease) and to identify patients who fail to
Genetic*

manifest abnormalities on brain MRI or metabolic (fluo-

Fabry’s†

rodeoxyglucose - positron emission tomography (FDG-­

PET) or single-­photon emission computed tomography
(SPECT)) imaging. The nosological status of these latter
‘phenocopy’ cases is still unclear.
Behçet’s disease, rheumatological†

Among language-­ led dementia syndromes (the

primary progressive aphasias), the non-­fluent/agram-
Uraemic encephalopathy†

matic variant is the most immediately clinically striking.

Candidate diagnoses

These patients characteristically have effortful, unme-

lodious, misarticulated ‘apraxic’ speech and their
**Leading features, not covered above —these tend to be the most striking features but various combinations occur.
Sporadic

utterances may be terse and agrammatic (‘telegraphic’).

Early on, there may be particular difficulty with public
speaking, reversing of ‘yes’ and ‘no’ or re-­emergence of
a childhood stutter. Initially, naming and comprehen-
sion are largely intact and written expression is usually
more fluent than speech.25 26 As the syndrome evolves,
impairments of orofacial praxis (affecting volitional
movements such as whistling) and dysphagia often
§Although genetic prion diseases tend to be rapid, some present indolently.

supervene, frequently with emergence of an extrapy-

Syndromic features (especially early)

ramidal syndrome in the corticobasal—progressive

supranuclear palsy spectrum.
¶Can be suspected but not presently confirmed during life.

In contrast, the semantic variant of primary progres-

sive aphasia presents with increasingly circumlocutory
Skin abnormalities
Renal impairment

and vacant speech that is well constructed and fluent

‡Slower onset may also occur in some cases
Splenomegaly

(even garrulous). These patients characteristically have

asked family members the meanings of words (‘What’s
Continued

†Potentially treatable process.

a tornado?’) and often compile personal ‘dictionaries’.

This list is not exhaustive.

They have early, profound anomia, underpinned by

impaired single-­word comprehension and vocabulary
Leading clue

loss affecting all language channels, often extending

Table 4

to a tendency to sound irregular words (such as ‘sew’)

as they are printed (‘surface dyslexia’25 26). The true

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 How to do it

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Figure 2 Cognitive and neuroanatomical profiles of some major dementia syndromes. The cartoon brain (right) shows cognitive
functions predominantly mediated by different cerebral regions in each cerebral hemisphere. The T1-­weighted coronal MRI sections
(left) show characteristic patterns of regional brain atrophy in representative neurodegenerative disorders (typical Alzheimer’s
disease—disproportionate, bilateral hippocampal atrophy; behavioural variant frontotemporal dementia—predominant bilateral but
asymmetric, frontal and anterior temporal lobe atrophy; non-fluent/agrammatic variant primary progressive aphasia—predominantly left-­
sided, anterior peri-­Sylvian cortical atrophy; posterior cortical atrophy—predominant biparietal atrophy; semantic variant primary progressive
aphasia—selective, predominantly left-­sided anteromesial and inferior temporal lobe atrophy; right temporal lobe atrophy—selective,
predominantly right-­sided anterior temporal lobe atrophy). In each case, the dementia syndrome reflects a profile of brain network
breakdown (see also table 1); this correspondence is indicated by the coloured histograms alongside each scan, which code the
cognitive domains pre-­eminently affected in each syndrome. The histogram colours follow the same convention as the brain cartoon;
the heights of the histogram bars are arbitrary but indicate the relative clinical prominence of deficits across cognitive domains that
are typically seen in a particular syndrome. The left hemisphere is projected on the right (following standard clinical convention)
throughout.

nature of this syndrome is captured in its older desig- usually predominantly left-­ sided anterior temporal
nation, ‘semantic dementia’: this is the paradigmatic lobe atrophy on brain MRI at presentation (figure 2);
disorder of the semantic memory system that mediates if this is absent, we hesitate to invoke the diagnosis.
knowledge about words, objects and concepts. As it
evolves, non-­verbal semantic knowledge about visual Other ‘zebras’
and other sensory objects and about the emotional and These are many and diverse (table 4): clues to their pres-
social signals of other people also disintegrates. Patients ence include younger age of onset, a family history of
generally develop a behavioural syndrome similar younger onset dementia (often labelled as Alzheimer’s
to behavioural variant frontotemporal dementia. In disease or psychiatric illness), prominent extracogni-
our experience, there is invariably focal, asymmetric, tive neurological or systemic features or a rapid course.
The last group includes catastrophic illnesses such as
prion disease but also several reversible processes that
Key points demand careful exclusion (table 4). Diagnosis of the
many rare diseases that cause dementia in younger
►► Dementia is a syndrome of progressive decline in adults due to metabolic, inflammatory, storage and
cognitive function and/or behaviour that impacts other inherited disorders generally depends on clin-
upon daily life functioning and has multiple potential ical features or markers beyond cognition31 32: these
causes. disorders tend to produce a fairly nondescript ‘fronto-
►► Timely diagnosis is desirable and achievable with a subcortical’ cognitive syndrome led by executive and
systematic approach to cognitive assessment. neuropsychiatric dysfunction.
►► The major dementias target particular brain networks
and accordingly have distinct phenotypes.
Next steps after suspecting dementia
►► The diagnosis rests primarily on clinical assessment,
If available, more detailed cognitive testing with a
with neuropsychological, neuroimaging and biomarker
neuropsychologist is often a valuable extension to
support where appropriate.
the bedside assessment to: quantify suspected deficits

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 How to do it

in relation to age-­appropriate norms and premorbid

Further reading
attainment; detect deficits in domains (such as exec-

Pract Neurol: first published as 10.1136/practneurol-2021-003019 on 2 July 2021. Downloaded from http://pn.bmj.com/ on July 24, 2021 by guest. Protected by copyright.
utive function) that are challenging to assess at the ►► McWhirter L, Ritchie C, Stone J, et al. Functional
bedside; and compare performance over serial assess- cognitive disorders: a systematic review. Lancet
ments, which may be diagnostic in cases of clinical Psychiatry 2020;7:191–207.Oxford Textbook of
doubt. Cognitive Neurology and Dementia. Husain M, Schott
Any patient with suspected dementia should have JM, editors. Oxford University Press; 2016.
brain imaging (ideally MRI)—occasionally this will ►► Crutch SJ, Lehmann M, Schott JM, et al. Posterior
show a surgically remediable process but more gener- cortical atrophy. Lancet Neurol 2012;11:170–8.
ally it defines the profile of atrophy in neurodegener- ►► Sivasathiaseelan H, Marshall CR, Agustus JL, et al.
ative diseases (figure 2) and detects signal alterations Frontotemporal dementia: a clinical review. Semin
such as those associated with cerebrovascular disease, Neurol 2019;39:251–63.
leukodystrophies and prion disease. Serial imaging of
change over a year or more can be informative if the
first scan is normal. Conversely, frontal or parietal
‘atrophy’ is quite commonly overinterpreted on MRI. tools, clinical judgement is likely to remain essential
Brain FDG-­ PET or SPECT is sometimes useful to and indeed, to assume even greater importance as
demonstrate regional cerebral hypometabolism where effective treatments become available.
Alzheimer’s disease or a frontotemporal dementia is
suspected but MRI is inconclusive. Twitter Chris J D Hardy @cjdhardy, Charles R Marshall @
Although basic haematological and metabolic charl_marshall, Jonathan D Rohrer @ftdtalk, Jonathan M
Schott @jmschott and Rimona S Weil @rimonaweil
screens are worthwhile to detect potentially reversible
factors that may contribute to cognitive decline, these Acknowledgements The Dementia Research Centre is
are rarely the primary culprit. Diagnostic markers supported by Alzheimer's Research UK, Brain Research UK,
and the Wolfson Foundation. This work was supported by the
of dementia are currently largely derived from CSF
Alzheimer’s Society, Alzheimer’s Research UK and the National
analysis, which should be considered in anyone with Institute for Health Research University College London
younger onset dementia (arbitrarily, before the age of Hospitals Biomedical Research Centre.
65 years) or rapid evolution, when it is likely to have Contributors JCSJ and JDW conceived of and drafted the main
the most useful predictive value (see tables 3 and 4)— manuscript. All authors contributed significantly to the content
relevant CSF constituents include cells and oligoclonal of the manuscript and reviewed the drafts and provided
bands (pointers to brain inflammation), neurofilament feedback.
light chain (a non-­specific indicator of the presence Funding JCSJ is supported by an Association of British
Neurologists Clinical Research Training Fellowship, funded
and severity of neuronal damage) and more specific
by Guarantors of Brain. CJDH is supported by a RNID-­
protein profiles of Alzheimer pathology (raised total Dunhill Medical Trust Pauline Ashley Fellowship (PA23). SJC
and phospho-­ tau, elevated tau:beta-­ amyloid42 or receives support from the ESRC/NIHR Dementia Research
beta-­amyloid40:amyloid42 ratio). Initiative (ES/S010467/1). CRM is supported by a grant from
Diagnostic testing for causative genetic mutations Bart’s Charity. RSW is supported by a Wellcome Clinical
Research Career Development Fellowship (201567/Z/16/Z).
should be considered in younger patients where there LMcW receives philanthropic funding from Baillie Gifford.
is a compatible phenotype and in particular a suggestive JDW receives grant support from Alzheimer’s Research
(autosomal dominant) family history, but only after appro- UK, the Alzheimer’s Society and the National Brain Appeal
priately informed counselling in the clinic, particularly (Frontotemporal Dementia Research Studentship in Memory of
David Blechner).
with respect to the implications for other family members.
Competing interests None declared.
Other more specialised investigations may be appropriate
in certain clinical contexts (see table 4). Patient consent for publication Not required.
Local services should be engaged for support early and Provenance and peer review Commissioned. Externally peer
reviewed by Anthony Bayer, Cardiff, UK.
people with atypical forms of Alzheimer's disease or non-­
Alzheimer dementias can be directed to Rare Dementia ORCID iDs
Support (https://www.​raredementiasupport.​org/). Jeremy C S Johnson http://​orcid.​org/​0000-​0002-​4265-​7997
Rimona S Weil http://​orcid.​org/​0000-​0002-​5092-​6325
Conclusions
Early and accurate diagnosis of dementia is desirable
and achievable, but it must first be suspected. As always References
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lenge is to determine whether dementia is likely and Dementia prevention, intervention, and care. Lancet
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