Dementia

1. Dementia Professor Adam Zeman, Cognitive & Behavioural Neurology Group, PMS and School of Psychology, University of Exeter

2. What is dementia? • A disorder of two or more domains of cognition: • memory • language • visuoperceptual ability • Praxis • abstract thinking and judgement • personality • social conduct • Substantially impacting everyday life

3. Delirium vs dementia FEATUREDELIRIUMDEMENTIA Onset abrupt/sub-acuteinsidious Course fluctuatingslow progression Duration hours-weeksmonths-years Alertness abnorm high or lowtypically normal Sleep-wake disruptedtypically normal Attention impairedrelatively normal Orientation impairedintact in early dement. Working mem impairedintact in early dement. Episodic mem impairedimpaired Thought disorganised, delus.impoverished Speech slow/rapid, incoh.word-finding difficulty Perception illusn/halln commonus. intact in early dem. Behaviour withdrawn/agitatedvaries: oft. intact early

4. Cortical vs subcortical dementia FUNCTIONCORTICAL SUBCORTICAL eg AD eg HD Alertness normal‘slowed up’ Attention normal earlyimpaired Executive ftn normal earlyimpaired Episodic mem amnesiaforgetfulness language aphasicreduced output Praxis apraxiarelatively normal Perception + vis/sp impairedimpaired Personality preserved (unlessapathetic, inert frontal type)

5. Causes of ‘dementia’ • InheritedHD, Wilson’s, leucodystrophies • Primary degenAlzheimer’s, Cortical Lewy Body disease , Fronto-temporal dementia • Vascularmulti-infarct, subcortical, strategic infarction • Infective HIV, TSE, HSE, Whipple’s, SSPE • Inflammatory MS, vasculitis, Hashimoto’s • Neoplastic 1o/2o CNS tumours, limbic encephalitis • Traumatic Post head injury • Structural hydrocephalus, chronic subdurals • Metabol/endoc hypothyroidism • Deficiency B12/folate • Sleep-related OSA • Substances/drugs alcohol, anticholinergics, hypnotics etc • Psychiatric depression (pseudo-dementia)

6. Mrs FH, 73 yr old retired teacher • ‘Came because daughter made me, memory not so good’ • 3 year gradual decline in memory • Getting lost on holiday in York • unsure of day, repetitive, paperwork difficult, hot rings left on • No relevant PMH, drugs • Lives alone, daughter in England, attentive neighbours • mother’s memory failed in later life • MMSE 23/30 Name + address 7/7 -> 0/7 • good peformance in other domains • General + neurological exam normal • CT: moderate atrophy, esp R temporal lobe • TFT, B12/folate, VDRL, haem + chem normal

7. Alzheimer’s disease • Episodic memory impairment -> widespread cognitive decline • apathy, disinhibition, agitation; psychosis; mood disturbance • slowly progressive: circa 3 point MMSE decline/year • pyramidal, extrapyramidal signs; primitive reflexes; epilepsy • neuritic plaques: Abeta amyloid derived from APP • neurofibrillary tangles: hyperphosphorylated tau • Cholinergic deficit • <5% autosomal dominant: presenilin 1(14), 2(1), APP (21) • Apolipoprotein E alleles 2, 3 and 4; Down’s syndrome; vascular risk factors • CT, MRI, SPECT, PET, amyloid imaging • central Achase inhibitors; memantine

11. Atypical presentations of AD • <10% AD • Posterior cortical atrophy (PCA) • Almost always due to AD • Slowly progressive aphasia • More varied pathology • Usually non-fluent, occasionally fluent in AD • Slowly progressive apraxia • Dysexecutive or ‘behavioural’ presentation

12. EXECUTIVE FUNCTION ‘Frontal lobe syndrome’ PRAXIS Apraxia PERCEPTUO- SPATIAL FUNCTION Agnosia Spatial disorientation LANGUAGE Aphasia Alexia Agraphia Acalculia MEMORY Amnesia AROUSAL

13. Posterior cortical atrophy - PCA • Circa 5% AD cases have ‘visual presentation’ • Early onset, typically mid 50s-early 60s • Mild female predominance • Most common features are • Alexia and agraphia • Simultanagnosia • Optic ataxia • ‘dorsal stream’ symptoms and signs predominate but both ventral and dorsal streams affected • Relative preservation of memory, insight, language, executive function

15. Posterior cortical atrophy - PCA • Imaging findings • Pathological differential diagnosis: • AD >> CBD, DLB, prion disease, subcortical gliosis • Apo E4 less common in PCA than typical AD • Achase inhibitors may be helpful – no formal evidence

19. Posterior cortical atrophy - PCA • Imaging findings • Pathological differential diagnosis: • AD >> CBD, DLB, prion disease, subcortical gliosis • Apo E4 less common in PCA than typical AD • Achase inhibitors may be helpful – no formal evidence

20. Mr RW, 67 yr old retired bank manager • Forgetful of appointments and recent event • bouts of confusion, lasting a day or two • difficulty dressing, beginning abruptly, 3 months ago • hypertension for ten years, MI 4 years ago, calf pain on walking • Aspirin, atenolol, bendrofluazide, simvastatin • 30 cigarettes/day • Brother: CABG • Glycosuria • Irregular pulse, BP 190/100, carotid bruits, absent foot pulses • MMSE 26/30 • left reflexes > right

21. Vascular dementia • subcortical ischaemic dementia: cognitive slowing, attentional and executive impairment, gait disturbance • multi-infarct dementia: mixed cortical/subcortical features, fluctuating cognition, pseudobulbar palsy/affect, gait/bladder disturbance • strategic infarction eg thalamus, basal forebrain, left angular gyrus • vascular risk factors including thrombophilia, vasculitis, CADASIL • Imaging - MRI • manage vascular risk factors

25. Mr AB, 75 year old retired colonial officer • ‘fatigue and trouble finding words’ • 2 years concern about ‘the organisation’ and ‘the appeared people’ • ‘I haven’t seen my wife recently: could you ring her up?’ • unreliable memory • good and bad days • recently shuffling and slow • unremarkable PMH • No medicn - but neuroleptics -> v slow, sleepy • MMSE 25/30 • stooped, slow to get going, falters in doorway • rigidity of neck and limbs

26. Dementia with Lewy bodies • Cognitive decline + Parkinsonism, visual hallucinations, fluctuations (two features -> probable DLB, one feature possible DLB) • Neuropsychology: impaired psychomotor speed, attention, executive function, visuospatial ability • REM sleep behaviour disorder • more rapidly progressive than pure AD • Lewy body: eosinophilic intraneuronal inclusion bodies, mainly aggregated filaments of alpha-synuclein • DLB and Lewy body variant of AD • Neurochemical pathology • The therapeutic dilemma • Achase inhibitors

29. Atypical dementia • Features atypical of a common cause ! • Age • family history • systemic features (apart from vascular disease) • rapidity • syndromes eg: • cognitive decline, epilepsy, chorea, oral self-mutilation • frontal lobe dementia with bulbar and pseudo-bulbar palsy • apraxia, limb myoclonus, alien limb • falls, axial rigidity, supranuclear gaze palsy, subcortical dementia

30. Ms RN, 52 year old retired cleaner • 8 years’ gradual deterioration of memory and unsteadiness • tendency to fidget • depression • previous investigation 3 years before inconclusive • PMH: nil • FH: father died with ?stroke, ?Parkinson’s disease • Son cares for her at home: lost job because of poor attendance…also fidgety • Thin, muttering, fidgety, unable to keep tongue out • hypereflexia, extensor plantars • MMSE 25/30, very slow responses • 5 animals, 3 ‘p’ words in a minute

32. Mr DF, 65 year old man • businessman • detachment from wife, increasingly self-obsessed • Rude to clients • Unecessary purchases • Shoplifting, stealing from tenants • The shopping trip • On examination: • Made light of his difficulties • MMSE 30/30 • ACE 96/100 • MRI: • right fronto-temporal atrophy

34. Frontotemporal lobar degeneration • 10-15% dementia , 65 years ; some familial • Frontal lobe (behavioural) variant • personality and behavioural change with loss of insight • Temporal lobe variant • L: semantic dementia; • R: recognition + knowledge of people • Progressive non-fluent aphasia • FTD with MND • NB relative preservation of episodic memory • Pathologies: see later! • Imaging: focal atrophy

35. Frontotemporal dementia • FH in 25-50% cases • Autosomal dominant FTD • Microtubule associated protein gene (MAPT) • Progranulin • Valosin-containing protein • Charged multi-vesicular body protein 2B • C9ORF72 • ~50% fam ALS, 7% sporadic ALS, 5% sporadic FTD

36. Recommended nomeclature for FTLD(Neumann et al, 2009)

37. FTD pathologyCambridge brain bank data

39. PSP supranuclear gaze palsy truncal rigidity, instability, akinesia, falls bulbar features subcortical dementia mood, personality, behaviour neurofibrillary tangles (tau) in basal ganglia and brain stem MRI: midbrain atrophy CBD asymmetric limb apraxia alien limb phenomena limb myoclonus Parkinsonism cognitive impairment neurofibrillary tangles (tau) in frontal and parietal cortex and basal ganglia MRI: frontoparietal atrophy PSP + CBD

40. Recommended nomeclature for FTLD(Neumann et al, 2009)

41. FTD pathologyCambridge brain bank data

42. Mr JL, 37 yr old computer programmer • Late 1997/ early 1998 • anxious, low, concerned about ill health, sought HIV test • dysaesthesiae R foot • April 1998 • difficulty at work • unsteady • MMSE 26/30 • subtle pyramidal, extrapyramidal and cerebellar signs • MRI • CSF

43. Prion dementia • spCJD - rapid dementia, ataxia, visual syndromes, multifocal signs, myoclonus: usually 55-70 yrs, median duration circa 4 months • vCJD - psychiatric prodrome, dysaesthesiae, cognitive impairment, multifocal signs, myoclonus: 2nd - 4th decades, med durn 14 m. • iatrogenic and familial CJD; GSS; FFI; kuru • Pathology • The prion gene (chromosome 20) and the prion hypothesis • Investigations: EEG in spCJD; CSF 14-3-3 in spCJD, tau in vCJD; MRI; tonsillar and brain biopsy

48. Ms AH, 24 yr old student • Intermittently unwell for past 4 years • sore throats, swollen glands, leucopaenia + thrombocytopaenia • seen in several clinics • admitted under general physician at St John’s with pneumonia • cognitive slowing • spastic paraparesis

50. HIV-1 associated dementia • 20-30% AIDS patients present with or develop • insidious, subcortical: poor concentration, slowing, forgetfulness, apathy, social withdrawal; pyramidal and cerebellar signs • tends to occur with CD4 count < 200 x 106 • Early entry of HIV-1 to CNS -> persistence in macrophages and microglia -> multinucleated giant cells; white matter affected focally (MGCs) or diffusely; cortical neuronal loss • MRI, CSF • Differential diagnosis: depression, drugs, substance abuse, systemic illness, CNS tumours, opportunistic infection (toxoplasmosis, TB, cryptococcus, CMV, syphilis, PML).