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Neuropathology of dementia

Neuropathology of dementia. David Hilton Derriford Hospital. 24 million have dementia, will double every 20 years 60% in developing countries 800,000 in UK have significant cognitive impairment. 250,000 in institutions – total cost in health and social care £23 billion/year (2012)

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Neuropathology of dementia

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  1. Neuropathology of dementia David Hilton Derriford Hospital

  2. 24 million have dementia, will double every 20 years • 60% in developing countries • 800,000 in UK have significant cognitive impairment. 250,000 in institutions– total cost in health and social care £23 billion/year (2012) • Psychological, practical and economic burden on carers • Most important cause of disability over age 60 years

  3. Main clinical patterns • Temporoparietal – memory disturbance, later dysphasia and dyspraxia • Frontotemporal – behavioural changes, later memory disturbance. Parietal function retained • Subcortical – slowing of thought processes

  4. Causes of dementia • Neurodegenerative • Cerebrovascular disease • Prion disease • Hydrocephalus • Toxic, metabolic and nutritional • Mitochondrial • Demyelination • Head injury • Infections • Neoplasia

  5. Neurodegenerative causes • Alzheimer’s disease Aβ and tau • Dementia with Lewy bodies α synuclein • Frontotemporal dementias: Picks disease tau Chromosome 17-linked tau FTLD-MND TDP43 FTLD-NF neurofilament FTLD-FUS FUS FTLD-other unknown • Progressive supranuclear palsy tau • Corticobasal degeneration tau • Multiple system atrophy α synuclein • Neuroferritinopathy ferritin • Huntington’s disease huntingtin • Tangle-only dementia tau • Familial British dementia Abri and tau

  6. Alzheimer’s disease • 70% all cases of dementia • Prevalence of AD 1% at 65, 40% at 90 (doubles every 5 years) • Female predominance • 10% familial • Presents with early memory disturbance, progressing to dyspraxia and dysphasia, eventually immobile and mute

  7. Neuropathology • Cerebral atrophy • Ventricular dilation (hydrocephalus ex vacuo) • Loss of synapses, and later, of neurons • Neurofibrillary tangles (tau) • Dystrophic neurites and neuropil threads (tau) • Granulovacuolar degeneration (tau) • Amyloid plaques (Aβ) • Amyloid angiopathy (Aβ) • Hirano bodies (actin)

  8. Neurofibrillary tangles • predominantly composed of tau • normal tau stabilises microtubules • tau is hyperphosphorylated in NFTs and forms paired helical filaments

  9. Amyloid plaques • Extracellular proteinaceous deposits • Largely composed of Aβ peptides – eitherdiffuse or neuritic (surrounded by dystrophic neurites) Aβ Aβ tau

  10. Staging of AD • CERAD (consortium to establish a registry for AD) – derived from semiquantitative assessment of plaque density and age. • Braak and Braak – extent of distribution of tangles

  11. Amyloid angiopathy(congophilic angiopathy/cerebral amyloid angiopathy) • derived from Aβ • arteries and arterioles of cerebral and cerebellar cortex • present in 90%cases

  12. Neurochemical changes • Marked loss of ACh, related to neuronal loss from nucleus basalis of Meynert • Loss of GABA from cortex secondary to neuronal loss • Serotonin (5HT) input from dorsal raphe nuclei reduced • Noradrenaline input from locus ceruleus reduced

  13. Genes involved in FAD Amyloid precursor protein gene - chromosome 21 (trisomy, mutations, duplications). 15% early onset cases. Presenilin-1 gene - chromosome 14 (mutations). 80% early onset cases. Presenilin-2 gene - chromosome 2 (mutations). 5% early onset cases.

  14. Genes involved in LOAD Apolipoprotein E- chromosome 19,three isoforms (E2,3+4) encoded by alleles 2,3+4. 4 homozygotes have 19x risk of AD compared with 3 homozygotes. Recently 4 large genome-wide association studies have identified a further 9 loci. Immune system function: CLU, CRE, ABCA7, MS4A, CD33, EPHA1 Cholesterol metabolism: APOE, CLU, ABCA7 Synaptic/cell membrane function: PICALM, BIN1, CD33, EPHA1

  15. Amyloid cascade hypothesis FOR: mutations in APP and ‘related’ genes in FADDowns syndromeneurotoxicity of Aβ peptides AGAINST:plaques may be numerous in non-demented elderlypoor correlation between plaques and NFTs poor correlation between plaques and dementiaimmunisation with Aβ not beneficial

  16. Dementia with Lewy bodies(diffuse LBD/cortical LBD/senile dementia of LB type/LB variant of AD) • 10-25% cases in hospital-based series • fluctuating cognition with pronounced variation in attention and alertness • recurrent visual hallucinations (well formed) • parkinsonism • falls, syncope or transient loss of consciousness • neuroleptic sensitivity • delusions • non-visual hallucinations

  17. Pathology • atrophy similar to AD, but less severe • pallor of substantia nigra • Lewy bodies (essential) • Lewy-related neurites • Aβplaques (all types) • neurofibrillary tangles • neuronal loss (esp. s.nigra, locus ceruleus and basal nucleus of Meynert) • synaptic loss • focal spongiform change

  18. Clinicopathological correlations: • Cognitive impairment: subcortical nuclei, cortex, limbic system • Visual hallucinations: subcortical nuclei e.g.amygdala and ventral temporal lobe • Mood disturbance: Raphe nuclei and locus ceruleus • Olfactory deficit: Olfactory bulbs and nuclei • Pain: posterior horns of cord, brain stem, thalamus, limbic system • Hypersomnolence: Pedunculopontine nuclei, locus ceruleus, raphe nuclei, hypothalamus

  19. Frontotemporal dementias • 10-20% all cases (higher in young onset) • 40% familial (mutations in MAPT, CHMP2B and progranulin, valosin containing protein, FUS, chromosome 9-linked due to C9orf72 expansion) • frontal signs, semantic dementia and aphasia • Pathological subtypes: FTLD-tau (Picks disease, Chromosome 17-linked) FTLD-TDP (transactivated response element DNA binding protein 43) FTLD-FUS (fused in sarcoma protein) FTLD-CHMP2B (charged multivesicular body) FTLD-UPS (ubiquitin proteosomal system) FTLD-ni (no inclusions) • Also frontal variant of AD

  20. FTLD clinical presentations • Frontotemporal dementia (tau/ubiquitin) Social behaviour: emotion (blunting, lack of sympathy, fatuous), social conduct (disinhibition, inappropriate behaviour, self neglect, lack of care and responsibility), repetitive behaviour (mannerisms, routines, verbal and motor activities), diet (gluttony, sweet food preference, hyperorality)Executive functioning: planning, organising, attention, abstraction, monitoring and flexibility of behaviour • Progressive non-fluent aphasia (ubiquitin esp intranuclear, left TL worse)Expressive language disorder, cannot construct sentences and find words, good comprehension, may develop right sided rigidity. • Semantic dementia (ubiquitin esp dystrophic neurites, middle and inferior temporal gyri, left usually worse that right)Normal fluency, but lack of word meaning. May affect other modalities e.g. face/object recognition. Physically well, but may develop parkinsonian features. 10% develop MND.

  21. Transmissible spongiform encephalopathies (prion diseases) • Fatal neurological diseases • Transmissible • Affect humans and animals • Similar pathology • No effective treatment

  22. Human prion diseases • IdiopathicSporadic Creutzfeldt-Jakob disease • AcquiredIatrogenic Creutzfeldt-Jakob diseaseKuruVariant Creutzfeldt-Jakob disease • InheritedFamilial Creutzfeldt-Jakob diseaseGerstmann-Straussler-Scheinker syndromeFatal familial insomnia

  23. Sporadic Creutzfeldt-Jakob Disease • Incidence 1:106 • Age 60 - 70 years • Rapidly progressive dementia with myoclonus • EEG - periodic triphasic complexes (70%) • MRI - high signal in basal ganglia (80%) • Elevated CSF 14-3-3 protein (80%) • Death usually within 6 months

  24. Neuropathology • Brain weight often normal • Spongiform change at microscopic level • Neuronal loss • Gliosis • Prion protein accumulation • No inflamation PrP

  25. Iatrogenic CJD • Pituitary hormone recipients (hGH, hGn <1986) • >100 cases • Lifetime risk 3.5% • mean incubation period 12-17y (2-30y+) • Dural grafts (<1992) • Corneal transplants • Neurosurgery

  26. Kuru • Confined to Fore tribe in New Guinea • Described in 1957, but first cases in early 1900’s • Predominantly women and children • Progressive cerebellar disorder (dementia not a feature) • Amyloid plaques in cerebellum • Incubation period may be 40+years

  27. Variant CJD • Disease onset from February 1994 • 176 cases in UK • Age at onset 28 years (12-74) • Age at death 29 years (14-74) • Survival 13 months (6-39) • EEG - normal or slow waves • MRI - high signal in posterior thalamus (80%) • Elevated CSF 14-3-3 protein (50%)

  28. vCJD-clinical presentation • Psychiatric symptoms - depression, anxiety, apathy, withdrawal, psychoses • Sensory disturbance - dysaesthesia, paraesthesia, ‘cold feet’ • Later features - ataxia, upward gaze paresis, myoclonus, dementia, akinetic mutism

  29. vCJD-pathology • ‘Florid’ plaques • Severe spongiform change in caudate and putamen • Extensive PrP deposition in brain • PrP accumulation in lymphoreticular system PrP

  30. Links between BSE and vCJD • Temporal and geographic association • BSE spread to other species • Same ‘strain’ profile of PrP in transmission studies • Same glycosylation pattern (type 4)

  31. Codon 129 polymorphisms in PrP gene

  32. Prion • Protein present in all cells, especially CNS and lymphoreticular cells • Membrane associated glycoprotein • PrPc denatured by heat, protease sensitive • PrPres (PrPSc) resistant and accumulates within cells and the extracellular space

  33. Summary points • Alzheimer’s disease is the leading cause of disability in the elderly and its prevalence is increasing • Many dementias can be regarded as ‘protein-misfolding’ disorders • Genetic polymorphisms have a key role in determining susceptibility and some may be directly inherited • Understanding disease pathogenesis is key to the development of treatment strategies

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