Table 4

Some important ‘zebras’ in dementia diagnosis

Leading clueSyndromic features (especially early)Candidate diagnosesKey investigations
 Socioemotional decline leadingReduced empathy, disinhibition, apathy, obsessionality, stereotypies, altered eating behaviour, executive deficits; atypical parkinsonism (progressive supranuclear palsy/corticobasal syndrome) frequent laterBehavioural variant frontotemporal dementia C9orf72, GRN, MAPT, others less commonlyMRI (figure 2), but atrophy highly variable and may be subtle, may have associated midbrain atrophy (progressive supranuclear palsy), genetics
 Language decline leadingEffortful, misarticulated, apraxic speech, binary reversals, grammatical errors, orofacial apraxia; atypical parkinsonism (progressive supranuclear palsy/corticobasal syndrome) frequent laterNon-fluent primary progressive aphasia GRN, C9orf72, others (uncommon)MRI (figure 2), but atrophy variable; genetics if young/suspicious family history
Loss of vocabulary, severe anomia with impaired single word comprehension despite fluent well-structured speech, often frontotemporal dementia-like behavioursSemantic primary progressive aphasia MAPT, others (rarely)MRI (figure 2) characteristic
Anomia/word-finding pauses, phonemic errors, phrase repetition/verbal working memory deficitsLogopenic aphasia (usually Alzheimer pathology) GRN (rarely)MRI asymmetric (predominantly left-sided) temporoparietal atrophy, CSF Alzheimer markers
 Visuospatial decline leadingDifficulty reading unusual fonts/night driving/using gadgets, mispositioning items; later apperceptive agnosia/disorientation, dyscalculia, anomiaPosterior cortical atrophy (usually Alzheimer pathology; some dementia with Lewy bodies, others)MRI (figure 2), CSF Alzheimer markers
 ‘Frontal’—ataxiaAlso urinary urgency/incontinenceNormal-pressure hydrocephalus†MRI ventriculomegaly and associated features
May have history of prior neurological episodesMultiple sclerosis (especially primary/secondary progressive)MRI (brain/cord) demyelination features, CSF unmatched oligoclonal bands
History of cranial irradiation (often delayed), also pyramidal/other neurological signsPost-irradiation vasculopathyMRI extensive white matter damage
Rapid‡Early widespread cognitive impairment (often prominent visual dysfunction), myoclonus/other neurological signsCreutzfeldt-Jakob disease (classically), Alzheimer’s disease, dementia with Lewy bodies (uncommonly)Prion (Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker, familial fatal insomnia, others)§MRI cortical/basal ganglia signal change, EEG (periodic complexes—Creutzfeldt-Jakob disease), CSF (RT-QuIC, Alzheimer markers), DAT (?dementia with Lewy bodies), genetics
Frontotemporal dementia plus deltoid/triceps fasciculations, pyramidal signsFrontotemporal dementia–motor neurone disease C9orf72 MRI, EMG (often normal), genetics
Behavioural variant frontotemporal dementia-like plus corticobasal syndrome, atypical parkinsonism, young, markedly obsessive/stereotypical behaviourFrontotemporal dementia (FUS-opathy)¶MRI marked caudate atrophy
Headache, fluctuation, seizures, systemic featuresVasculitis (CNS/systemic)†MRI, CT angiogram, CSF pleocytosis, autoantibodies/inflammatory markers; consider brain biopsy
Seizures, jerks, dyskinesias, fluctuation, neuropsychiatric/autonomic/systemic featuresLimbic encephalitis†MRI high signal in hippocampi/mesial temporal lobe, autoantibodies, whole body-PET/neoplasia screens
Executive/behavioural decline with gait disturbance/variable other neurological featuresTumour (eg, lymphoma), subdural haematoma, other space-occupying lesions†MRI mass/gadolinium enhancement, may have non-CNS primary, may need brain biopsy
Immunosuppressed, compatible history of infectionHuman immunodeficiency virus, human herpes viruses, progressive multifocal leukoencephalopathy, tuberculosis, syphilis, Whipple’s disease, fungal†; subacute sclerosing panencephalitisMRI abnormal signal/gadolinium enhancement, blood/CSF serology
Toxic exposure/dietary deficiency statesAlcohol usually nutritional, especially thiamine (Wernicke-Korskakoff syndrome); heroin/other drug abuse, lithium toxicity/ iatrogenic, metals†MRI various patterns with white/grey matter involvement, abnormal signal; drug, metabolic, metal screens
Young adult,**
AtaxiaParaneoplastic†, superficial siderosisSpinocerebellar ataxias, Niemann-Pick C, fragile X, mitochondrial, dentatorubral pallidoluysian atrophy, Kufs’ disease, prionThis group in general requires specialist consultation—principles are (1) definition of phenotype with brain MRI, plus CSF/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–rigidHuntington’s disease, Wilson’s disease,† neurodegeneration with brain iron accumulation (various)
AutonomicSarcoidosis†Porphyria, adrenoleukodystrophy, hereditary sensory and autonomic neuropathy 1E, familial fatal insomnia
Buccolingual mutilationNeuroacanthocytosis, Lesch-Nyhan
Chorea/dystoniaAntiphospholipid, 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,† siderosis, sarcoidosis†Mitochondrial, hereditary sensory and autonomic neuropathy 1E
Eye abnormalitiesBehçet’s disease, sarcoidosis, Susac’s syndrome†Kayser-Fleischer rings: Wilson’s disease†
Cataract: cerebrotendinous xanthomatosis†, myotonic dystrophy, mitochondrial
Retinopathy: mitochondrial
Gaze palsyChronic meningitides (inflammatory/neoplastic)†Gaze apraxia: Huntington’s disease
Supranuclear gaze palsy: (vertical) Niemann–Pick C, (horizontal) spinocerebellar ataxia type 2, Gaucher’s†
External ophthalmoplegia: mitochondrial
Peripheral neuropathySarcoidosis†Mitochondrial, neuroacanthocytosis, Fabry’s,† spinocerebellar ataxias, metachromatic leukodystrophy, adrenoleukodystrophy, hereditary sensory and autonomic neuropathy 1E, cerebrotendinous xanthomatosis,† porphyria†
Pyramidal signsSpinocerebellar 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
StrokesAntiphospholipid syndrome†CADASIL, cerebral amyloid angiopathies (familial), Fabry’s†
SystemicHepatic/gastrointestinalHepatic encephalopathy†Wilson’s disease,† Gaucher’s,† mitochondrial, porphyria†
Musculoskeletal abnormalitiesRheumatological†Paget’s disease, inclusion body myopathy: VCP
Tendon xanthomas: cerebrotendinous xanthomatosis†
Bone cysts: polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy
Renal impairmentUraemic encephalopathy†Fabry’s,† mitochondrial
Skin abnormalitiesBehçet’s disease, rheumatological†Fabry’s†
SplenomegalyNiemann-Pick C, Gaucher’s†
  • This list is not exhaustive.

  • *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).

  • †Potentially treatable process.

  • ‡Slower onset may also occur in some cases

  • §Although genetic prion diseases tend to be rapid, some present indolently.

  • ¶Can be suspected but not presently confirmed during life.

  • **Leading features, not covered above —these tend to be the most striking features but various combinations occur.

  • 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; 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.