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Differentiating the dementias: a

neurological approach
Saiffuddin Sheriff Shaik MRCP, Anoop Ranjan Varma DM, FRCP, MD

With improving lifespan, primary degenerative and vascular dementias are increasingly
being recognised as prominent health problems. The four commonest causes of primary
dementia are Alzheimer’s disease, frontotemporal dementia, vascular dementia and
dementia with Lewy bodies. An accurate diagnosis is critical for the proper management
and treatment of these disorders. Here, Dr Shaik and Dr Varma describe the clinical and
imaging characteristics of each of these types of dementia.

D ementia has been traditionally seen as a gener-

alised impairment of intellect and memory. It is
commonly defined as acquired diffuse intellectual
impairment with no disturbance of consciousness.1
This approach is perpetuated in textbooks: ‘the gen-
eral clinical picture is similar in all [primary dementias]
– a general progressive deterioration of intellect, memory and
personality’;2 ‘the clinical picture is almost identical … both
[Alzheimer’s and Pick’s disease] have progressive demen-
tia … consensus of opinion that differential diagnosis can Figure 1. Alzheimer’s disease. Coronal MRI (left) and SPECT images
be made only at autopsy’. 3 Interestingly, progressive showing mild atrophy and reduced blood flow in the parietal regions
dementia was not qualified any further in terms of
the types of cognitive deficits seen, because the term Dementia, therefore, includes chronic progres-
in itself was seen to be a sufficient description. These sive disorders with distinctive cognitive and behav-
traditional definitions continue to be entrenched ioural changes, neurological symptoms and signs,
even in relatively recent textbooks, for example and changes on imaging (single photon emission
dementia denotes ‘deterioration of all intellectual or cog- tomography [SPECT] and magnetic resonance
nitive functions’.4 imaging [MRI]). A critical neurological and neu-
Careful clinicopathological analyses in the ensu- ropsychological analysis (supported by neuroimag-
ing years have led to the recognition of different clin- ing) aids the delineation of the various forms of
ical patterns in patients with diverse pathologies.5 dementias.
With the elucidation of non-Alzheimer dementias, eg
frontotemporal dementia6-9 and dementia with Lewy Approach to assessing a patient with dementia
bodies,10-12 it has become evident that these disor- Patient history is vital and should be obtained from
ders occur far more commonly than previously the carer as well as the patient. Special attention
thought. It has also become clear that Alzheimer’s should be paid to the mode of onset, progression,
disease cannot be assumed to be the cause of all fluctuations and evolution of the disorder. All cogni-
degenerative dementias. tive (memory, language, calculation, perception, spa-
The last three decades have seen a rising interest tial function and complex executive tasks) and
in the differentiation of various forms of demen- behavioural (character change, apathy, disinhibition,
tia13,14 and current approaches view dementia as a mood, hallucinations, delusions, repetitive-stereotyp-
generic term encompassing the neuropsychological ies, obsessive-compulsive behaviours) functions
syndromes accompanying brain diseases.15 That these should be explored.
syndromes can be clinically differentiated, each char- Almost all dementia patients present with poor
acterised by identifiable clinical deficits determined memory. However, a careful history will distinguish
by the topographical distribution of pathology, is a severe memory impairment (inability to keep track
concept that has enthused many involved in contem- of day and date, mislaying of personal possessions
porary dementia research. and rapid loss of information) from patchy and vari-

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able loss. Mere word-finding difficulty should be dis- example, memor y can be impaired both in
tinguished from primar y language impairment, Alzheimer’s disease and frontotemporal dementia,
which includes word errors, poor spelling, and dif- but for widely different reasons, ie retention disor-
ficulty in reading and writing. Losing track of tasks der (Alzheimer’s disease) and secondary to prob-
or conversations suggests a short memor y span. lems in retrieval and organisation (frontotemporal
Difficulty in laying cutlery, dressing or negotiating dementia).19 Severe amnesia with disorientation in
environment (being lost in unfamiliar or familiar time and place suggests medial temporal pathology;
surroundings, bumping into furniture) denotes primar y language impairment occurs with domi-
visuospatial impairment. Inability to recognise fam- nant perisylvian lesions; acalculia and a short mem-
ily, friends or objects, eg microwave, refrigerator, or y span are associated with parietal deficit;
could be due to a perceptual deficit. Severe amne- visuospatial disorientation is seen in biparietal dis-
sia, especially in Alzheimer’s disease, may sometimes order; perceptual deficit (agnosia) is due to tempo-
lead to misidentification of one’s own image in a ral pathology; and apraxias accompany parietal
mirror. disease. Executive dysfunction and early personality
The history of change in character and personal- change are seen with affliction of the frontal cor-
ity must be carefully analysed. Superficially, any cog- tices. The characteristics of a subcortical deficit are
nitive change is reported to be a change in personality discussed below.
by most carers. However, personality change is signif- The Mini-Mental State Examination (MMSE) is a
icant only when it includes clear departure from pre- heavily left hemisphere (predominantly verbal mem-
vious character accompanied by behavioural change ory and language) based instrument and of less value
and breakdown of social and personal conduct. in detecting frontotemporal dementia. However, it
Behavioural changes (affect and social behaviour, eat- remains a useful bedside instrument in the detection
ing and vegetative behaviours, repetitive behaviours, and quantification of cognitive deficits. The frontal
hallucinations and delusions) can be further explored assessment battery (FAB) is sensitive and specific in
along the principles outlined in the Manchester differentiating frontotemporal dementia from
Behavioural questionnaire.16 Alzheimer’s disease. 20 The Cambridge Cognitive
A thorough neurological examination must addi- Examination (CAMCOG) and Alzheimer’s Disease
tionally incorporate observation of behaviour and eval- Assessment Scale – cognitive subscale (ADAS-cog)
uation of visual attention and orientation, myoclonus, are standardised instruments in the neuro -
sensory attention and tactile localisation, praxis and psychological evaluation of dementias. For detailed
primitive reflexes. Myoclonus is absent in fronto - and accurate characterisation of the dementias, neu-
temporal dementia. Primitive reflexes, eg grasp ropsychological assessment by experienced neuropsy-
reflexes, are observed in frontotemporal dementia chologists (adept at analysing the qualitative reasons
but are uncommon in mild-to-moderate Alzheimer’s for possible failure of various tests) is desirable.
disease. However, such services are few and far between in
The differentiation of dementias in a clinical set- the UK. A practical approach to diagnosing the
ting is strongly dependent on careful neuropsycho- dementias would include neuropsychological analy-
logical analysis. Qualitative evaluation is of sis based on histor y and subsequent intelligent
paramount value and no amount of quantification deployment of bedside tools (such as MMSE, FAB,
(scores) can override the importance of the neu- etc) to detect the broad underlying patterns of
ropsychologist as an observer of behaviour.17,18 For deficits. Additional data from appropriately inter-
preted imaging will help clinicians to arrive at a diag-
Cortical Subcortical Cortico-subcortical nosis with improved accuracy.21
The history, neurological signs and patterns of
• Alzheimer’s • vascular dementia • dementia with Lewy neuropsychological deficits together point to the clin-
disease • progressive bodies ical diagnosis in various dementias. The diagnostic
• frontotemporal supranuclear palsy • Creutzfeldt-Jakob process requires pattern recognition and hence famil-
degeneration • multiple system disease iarity with various usual and unusual presentations of
atrophy • corticobasal
the dementias. Distinct dementia syndromes are
• Huntington’s disease degeneration
• multiple sclerosis
described below. They are usefully classified into cor-
• hydrocephalus tical, subcortical and cortico-subcortical groups (see
Table 1). The four most common types of dementias
Table 1. Classification of the dementias (Alzheimer’s, frontotemporal dementia, vascular

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dementia and dementia with Lewy bodies) will be dis-

cussed in detail.

Cortical dementias
Patients with cortical dementias (such as Alzheimer’s
and frontotemporal dementia) look well and have few
physical signs. The distinction lies in the careful analy-
sis of patients’ behaviours and neuropsychological
deficits.
Figure 2. Frontotemporal dementia. Coronal MRI (left) and SPECT
Alzheimer’s disease images showing severe atrophy and reduced blood flow in the frontal
regions
Alzheimer’s disease predominantly affects the medial
temporal and temporoparietal cortex.22 The earliest
symptom is usually insidious loss of memory. Patients Frontotemporal degeneration
have difficulty remembering day-to-day events and Frontotemporal degeneration is associated with
are frequently unable to keep track of the day and severe atrophy of the frontal lobes and the anterior
date. They may misplace personal possessions. They temporal lobes.15,27 The precise syndrome depends
may also have linguistic problems when the perisyl- on the preferential site of atrophy within the frontal
vian temporoparietal areas are involved. Speech is and temporal lobes, ie predominant bifrontal: fronto-
halting with difficulty in finding the right word. temporal dementia; predominant temporal: semantic
Patients may make word errors and be unable to dementia; predominant left frontotemporal: progres-
comprehend conversations, especially complex ones. sive non-fluent aphasia.
Patients lose literacy skills (reading and writing), and Frontotemporal dementia is the second most com-
may experience difficulty in reckoning change and mon cause of presenile dementia. 7,28 The most
dealing with financial affairs. Visuospatial impair- prominent early features are changes in personality,
ment may result in difficulty in dressing, aligning cut- and social and personal behaviour. There is rapid
lery, negotiating stairs or finding the way; initially in inability to manage one’s own affairs and patients
unfamiliar surroundings and later in the patient’s may lose their jobs due to lack of judgement.
own home. Usually in the later stages, patients may Behavioural changes range from disinhibition/over-
fail to recognise faces, including those of their activity to apathy/inertia. Patients may become dis-
spouse, children and even their own reflection in the inhibited, overactive and restless with a fatuous,
mirror.23-25 unconcerned affect. They may clown, sing and
Despite these severe cognitive deficits, social dance, usually in a stereotypical fashion.
graces and façade are well preserved. The degree Alternatively, patients may become apathetic and
of insight is inversely proportional to the severity of inert, lacking in drive and motivation, showing lit-
amnesia. Patients remain physically well and neuro- tle response to stimuli. As the disease progresses, dis-
logical examination reveals few signs. inhibition may give way to apathy but not vice versa.
Extrapyramidal signs (bradykinesia and rigidity) There is early loss of insight and patients are not dis-
and myoclonus emerge with the evolution of the tressed or concerned by their failures. In all patients
disorder. there is emotional shallowness with loss of sympathy
Neuropsychological investigation reveals dense and empathy.15,29 Stereotyped behaviours including
amnesia with loss of information over time, a short repetitive actions and complex rituals may occur.
memor y span, visuospatial and constructional Patients may cram food or develop a sweet tooth.16
impairment, primar y language deficits including Patients look well physically and neurological
paraphasias, alexia and agraphia in varying combina- examination, including extrapyramidal signs (rigidity,
tions.13,17,26 bradykinesia) and primitive (eg grasp) reflexes,
EEG shows nonspecific slow waves. Structural reveals few signs. Myoclonus does not occur.
imaging shows atrophy with hippocampal empha- Neuropsychological evaluation reveals frontal
sis, whereas functional imaging (PET and SPECT behaviours (rapid, impulsive behaviours with inabil-
scans) shows characteristic parietotemporal cere- ity to check responses, apathy and inflexibility).
bral blood flow abnormalities (see Figure 1). Tests sensitive to frontal lobe function reveal severe
Deficits in the anterior regions are usually a feature difficulties in organisation and strategic skills, and
of later stages. mental set shifting. Responses are concrete and per-

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severative. Formal memory tests may reveal an inef-

ficient memory due to impaired attention. However,
patients are not clinically amnesic and remain ori-
ented in time and place. Speech is usually econom-
ical and concrete. There is an absence of
visuospatial impairment. Constructional abnormal-
ities may occur due to poor strategy and organisa-
tion, but overall spatial configuration is
maintained.15,30
EEG is normal. MRI shows severe frontal and ante-
Figure 3. Semantic dementia. Coronal MRI (left) and SPECT images
rior temporal atrophy and SPECT shows cerebral showing severe atrophy and reduced blood flow in the temporal
blood flow defects in similar areas (see Figure 2). regions
Semantic dementia Patients with semantic dementia
lose the meaning of words and objects.31-33 Speech
is fluent and effortless but empty and full of seman-
tic (verbal) paraphasias and the repertoire becomes
progressively limited. Patients fail to recognise
objects but are able to copy and match objects accu-
rately. Visuospatial skills and day-to-day memory are
well preserved. Behavioural changes involve repeti-
tive stereotypies, obsessional behaviours and food
fads.33 With progression, frontal behaviours (disinhi-
bition, apathy) may emerge. CT/MRI scans reveal Figure 4. Primary nonfluent aphasia. Coronal MRI (left) and axial
severe temporal atrophy that may be asymmetric. SPECT images showing atrophy and reduced blood flow in the left
SPECT reveals reduced cerebral blood flow in tempo- frontoparietotemporal regions
ral and later frontal regions (see Figure 3). EEG is
normal. manipulation, eg mental arithmetic, comprehending
Progressive non-fluent aphasia In patients with pro- complex syntax, reversing digits or sequences, eg
gressive non-fluent aphasia, the prominent defect is months of the year.36
a circumscribed language disorder. With progression
of the disorder, mutism supervenes.15 There is selec- Vascular dementia
tive left frontotemporal atrophy on MRI and reduced Vascular dementia includes multi-infarct dementia,
cerebral blood flow on SPECT in the left hemisphere stroke with dementia and subcortical vascular demen-
(see Figure 4). tia. It is being increasingly recognised that subcortical
Motor neurone disease Some patients may have small vessel disease is a prominent cause of vascular
frontotemporal degeneration associated with motor dementia.37,38 Consequently, the classical stepwise
neurone disease and therefore have a short lifespan.34 course with relatively acute deteriorating events is not
a necessary requisite for a possible vascular cause for
Subcortical dementias the dementing syndrome.
Several disorders affect subcortical structures (white Patients present with physical and mental decline.
matter, basal ganglia, thalamus) with relative sparing They look unwell and old for their age. Neurological
of the cerebral cortex. 35 These include vascular examination reveals focal signs (dysarthria, pyrami-
dementia, Parkinson’s disease, Huntington’s disease dal weakness, rigidity, akinesia, ataxia and gait disor-
and progressive supranuclear palsy. These disorders der). Neuropsychology testing detects a subcortical
are characterised by a plethora of physical signs (in deficit (as described above).36 MRI shows nonspecific
contrast to the cortical dementias) and an absence of atrophy with deep white matter lesions and/or
cortical features (visuospatial deficit, agnosia, aphasia lacunes. SPECT may show patchy uptake or mild
and apraxia). Subcortical dementia is characterised frontal change (see Figure 5).
by bradyphrenia (slowness and rigidity of thinking) Although subcortical dementia may resemble the
with difficulty in planning, organising and sequenc- neuropsychological deficits (frontal) of frontotempo-
ing mental events. These patients are forgetful but ral dementia, the presence of florid neurological signs
their amnesia is not severe. They may be apathetic and the absence of a prominent personality change
and exhibit difficulties in tasks requiring mental and preservation of insight differentiate it.

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Cortico-subcortical dementias
Creutzfeldt-Jakob disease is a rare but classical multi-
focal rapid and aggressive cortico-subcortical disor-
der. However, dementia with Lewy bodies is the
commoner and far more prevalent form of cortico-
subcortical dementia.12

Dementia with Lewy bodies

Dementia with Lewy bodies is characterised by cog- Figure 5. Vascular dementia. Axial MRI showing severe deep white
nitive, behavioural and physical symptoms and signs matter hyperintensities and lacune (left); axial SPECT showing patchy
in varying combinations. This variability in presenta- reduction of blood flow (right)
tion is the subject of much nosological debating.39
The recognition of the clinical syndrome is of practi-
cal relevance with therapeutic significance. Patients
develop poor memory, mental confusion, incoherent
speech and distractibility. They may lose their way.
The behavioural syndrome is prominent and usually
comprises of visual hallucinations and mispercep-
tions. The visual hallucinations are formed and may
comprise of, for example, little animals or people.
Patients may also imagine ‘seeing’ objects, people or
animals in patterns of curtains, carpets or stained glass
windows. They can exhibit dramatic fluctuations
between periods of lucidity and confusional states.
They also show a physical decline with bradykinesia,
rigidity and sometimes tremor. If the behavioural syn-
drome is treated with neuroleptics it may lead to sud-
Figure 6. Dementia with Lewy bodies. Sagittal SPECT showing
den deterioration and even death (neuroleptic
posterior reduction in blood flow
sensitivity).40
Neurological examination reveals extrapyramidal It must be emphasised that investigations aid the
signs (rigidity, akinesia) and myoclonus. Neuro - diagnostic process but are not pathognomonic of a
psychological evaluation reveals a fluctuating mental dementia. It is common to receive reports suggest-
state with interference, intrusions, distractibility, con- ing that a dementia is vascular, based on white mat-
fabulatory responses, misperceptions and visuospa- ter hyperintensities on MRI (interpreted as
tial dysfunction.41 ischaemic). However, such changes occur widely
EEG can be grossly abnormal and reveal periodic across Alzheimer’s disease, vascular dementia, fron-
complexes. 42 MRI shows atrophy and blood flow totemporal dementia and dementia with Lewy bod-
SPECT shows changes similar to Alzheimer’s disease43 ies 44,45 and provide relative (not absolute)
(see Figure 6). differences between these disorders. Conversely, a
normal MRI would be a strong argument against vas-
Diagnosis cular dementia. Characteristic blood flow changes
The process of diagnosis involves the building up of on SPECT and atrophy on MRI increase the likeli-
a clinical picture successively at each step, from the hood of one dementia against another, but are also
history, to the neurological examination and finally not absolutely specific.46,47
to the neuropsychological assessment. Since clinical
psychologists are increasingly carrying out neuropsy- Genetic tests
chological assessments in isolation, it is useful to dis- Alzheimer disease Three decades of genetic research in
cuss the findings in multidisciplinar y meetings. Alzheimer’s disease have broadened our understand-
Alternatively, free interchange of information ing of the pathogenetic mechanisms in dementia.48
between neurologists and neuropsychologists (sim- Three causative genes have been implicated in auto-
ilar to the long-established tradition of close discus- somal dominant Alzheimer’s disease: amyloid protein
sions between neurologists and neuroradiologists) precursor gene (APP), locus on chromosome 21 and
improves diagnostic accuracy. presenilin genes (PS1 and PS2) on chromosomes 14

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Alzheimer’s Frontotemporal Vascular Dementia with

disease dementia dementia Lewy bodies

History memory loss, early personality change mental and physical confusion,
spatial disorientation, stereotyped behaviour decline physical slowness
language failure

Neurology myoclonus early primitive reflexes pyramidal weakness, akinesia, rigidity,

akinesia, rigidity (late) occasional akinesia, rigidity ataxia myoclonus
pseudobulbar palsy

Memory severe amnesia variable loss variable loss variable loss/amnesia

Language aphasia adynamic speech, mutism dysarthria incoherent, rambling

Visuo-spatial spatial disorientation preserved preserved spatial disorientation

function

Perception primary recognition preserved preserved misperceptions

failure

Conduct appropriate concern inappropriate unconcern appropriate concern appropriate concern

Mental high low slow slow

effort

Motor impaired spatial impaired sequencing impaired sequencing impaired sequencing/

skills configuration spatial configuration

CT/MRI hippocampal atrophy severe anterior atrophy prominent white atrophy

matter change/lacune

SPECT posterior anterior patchy posterior

EEG slow normal slow grossly slow

Table 2. Clinical, neuropsychological and imaging characteristics of Alzheimer’s, frontotemporal, vascular and Lewy body dementias

and 1. The APOE4 allele48,49 poses a genetic risk for testing there remained a number of linked families
developing late-onset Alzheimer’s disease. Until in whom no mutations in MAPT could be identified.
recently, clinical gene testing only included APOE This led to the identification of progranulin (PGRN)
genotyping and testing for PS1 mutations; these may gene in 2006.54
be broadened to include PS2 and APP genes in the
future. However, most genetic tests are not clinically Summary
appropriate for the vast majority of patients with Dementias encompass distinct neuropsychological
Alzheimer’s disease.50 syndromes reflecting the topographic selectivity of
Frontotemporal lobar degeneration Around 40 per the underlying pathology. Alzheimer’s disease,
cent of patients report a family history of dementia, frontotemporal dementia, vascular dementia and
and 10-20 per cent have a clear pattern of autoso- dementia with Lewy bodies are the four commonest
mal dominant inheritance. 51 Gene mutations are causes of primary dementing disorders. A careful
found in 30-40 per cent of cases with positive family clinical (history and neurological examination) and
histor y. 52 Mutations in the tau gene, MAPT were neuropsychological analysis delineates these disor-
shown to cause familial frontotemporal dementia ders. Neuroimaging (MRI and SPECT) provides sup-
with parkinsonism linked to chromosome 17q21 portive evidence for the diagnosis, and where
(FTDP-17).53 However, despite advances in genetic strikingly discordant with the clinical diagnosis, this

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Dementia z Review

prompts re-evaluation of the basis for making that Dr Shaik is a Specialist Registrar and Dr Varma is a
clinical diagnosis. Consultant in the Department of Neurology, Greater
Alzheimer’s disease is a posterior cortical disor- Manchester Neurosciences Centre, Salford Royal Hospital,
der characterised by amnesia, aphasia, visuospatial Manchester
disorientation and apraxia. Bilateral parietotemporal
defects on SPECT are strongly supportive of the diag- References
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