Compare and contrast the clinical features and brain areas involved in the four common dementias

The four common dementias are Alzheimer’s disease (AD), vascular dementia (VaD), dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD/FTLD). AD and VaD account for the vast majority and frequently coexist; DLB is the second commonest neurodegenerative dementia (15–20% of autopsy series); FTLD accounts for 3–20% and is the second commonest dementia under age 65.

A useful organising principle is the cortical versus subcortical distinction: cortical dementias show prominent memory impairment with heteromodal cortical symptoms (aphasia, apraxia, agnosia); subcortical dementias show prominent executive dysfunction, milder memory deficit, perseveration, mood change, gait disturbance and extrapyramidal signs.

Brain areas: earliest involvement of the entorhinal cortex and hippocampus (medial temporal lobe), spreading to temporoparietal association cortex and posterior cingulate/precuneus, with relative sparing of primary motor and sensory cortex until late. Severe temporal lobe atrophy and hippocampal or insular hyperintensities are typical on MRI.

Clinical features: insidious onset with amnestic syndrome of the hippocampal type — impaired encoding and storage with poor benefit from cueing — followed by language, visuospatial and executive decline, then apraxia and agnosia. Apathy is the commonest NPS. Motor signs and falls are late.

Imaging signature: HMPAO-SPECT shows temporoparietal hypoperfusion; FDG-PET shows temporoparietal and posterior cingulate hypometabolism; PIB-PET amyloid imaging is highly sensitive and specific, even at preclinical stages.

Brain areas depend on vessel size. Large-vessel disease produces cortical infarcts in strategic locations: frontal lobe (aphasia, apraxia, disinhibition, apathy), hippocampus and basal forebrain (amnesia), gyrus angularis (construction problems), parietal lobe (alexia, agraphia) — giving a cortical type of dementia.

Small-vessel disease produces subcortical infarcts in the thalamus, caudate nucleus and internal capsule, disrupting specific frontal–subcortical circuits or non-specific thalamocortical circuits, producing executive dysfunction, attention deficit, apathy and personality change — a subcortical type of dementia. Subcortical ischaemic vascular disease (SIVD) — the lacunar state and Binswanger’s disease — is the commonest subtype (82.2% small-vessel versus 25.9% large-vessel in one study).

Clinical course: classically abrupt onset with stepwise deterioration and a fluctuating course with plateaus in cortical VaD; but 60% have slow, less abrupt onset and 80% slow progression with or without stepwise decline. SIVD causes slow, subacute-onset dementia with executive dysfunction, impaired attention and slowed processing speed, with comparatively mild memory deficit.

Motor signature: “lower-half parkinsonism” with hesitation, marche à petit pas and diminished step height. Crucially, the triad of dementia, urinary incontinence and gait disturbance is more often produced by small-vessel VaD than by normal-pressure hydrocephalus — a favourite examiner point.

Imaging: basal ganglionic and thalamic hyperintense foci, thromboembolic infarcts, confluent white matter and irregular periventricular hyperintensities (leukoencephalopathy). Leukoencephalopathy involving at least 25% of total white matter is required to diagnose small-vessel cerebrovascular disease. SPECT shows multiple focal deficits.

Brain areas and pathology: α-synuclein-positive Lewy bodies and Lewy neurites, with presynaptic α-synuclein aggregates thought to be the synapto-toxic species. Three distribution patterns: brainstem-predominant (PDD phenotype), cerebral cortex-predominant (DLB phenotype) and transitional. Concomitant AD pathology is present in 90% of Lewy body disease cases, and there is relative preservation of medial temporal lobe structures on MRI.

Core clinical features: fluctuating cognition with pronounced variation in attention and alertness; recurrent vivid visual hallucinations; REM sleep behaviour disorder, which may precede cognitive decline; and spontaneous parkinsonism. The neuropsychological profile is dysexecutive, with prominent visuospatial impairment even early, while amnesia may be mild initially.

Imaging signature: reduced dopamine transporter uptake in basal ganglia on SPECT/PET; abnormal (low) uptake on 123I-MIBG myocardial scintigraphy; reduced occipital activity on perfusion/metabolism scans (contrasting with posterior parietotemporal reduction in AD); and the posterior cingulate island sign on FDG-PET, which is sensitive and specific for DLB. EEG shows prominent posterior slow-wave activity with periodic pre-alpha/theta fluctuations.

Brain areas: relatively circumscribed, often asymmetric frontal and anterior temporal atrophy. bvFTD — frontal and/or anterior temporal cortex with later basal ganglia involvement; semantic dementia — anterior temporal lobe (left or right variant); progressive non-fluent aphasia — left inferior frontal lobe, anterior insula and basal ganglia. SPECT shows diminished anterior perfusion.

Clinical features by variant: bvFTD (≥70%) — early, profound change in personality and social conduct with disinhibition, apathy, social withdrawal, loss of empathy, hyperorality and dietary change, diminished insight, neglect of hygiene, mental rigidity, perseveration and stereotypic behaviour, with relative preservation of memory, spatial skills and praxis. Semantic dementia (~15%) — loss of word and object meaning with fluent, empty speech. PNFA (~10%) — non-fluent effortful speech, agrammatism, phonological paraphasia, anomia, with preserved single-word comprehension early.

Distinguishing epidemiology: onset most commonly between 45 and 65, equal gender distribution, family history in ~40% of first-degree relatives, and faster cognitive and functional decline with shorter survival than AD — about 9 years in FTLD-U and tau-positive groups but under 3 years in FTLD-MND.

The red flags that should arouse suspicion of non-Alzheimer dementia, most salient early in the course: prominent executive dysfunction, marked speech disturbance, marked behavioural change (disinhibition, euphoria, stereotyped behaviour, apathy, self-neglect), frequent falls, vivid visual hallucinations, focal neurological deficit, extrapyramidal signs, vertical gaze limitation, and asymmetric apraxia or dystonia.