Frontotemporal dementia: Neural circuits, genetics and neuropathology
Neuropathology of dementia
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Transcript of Neuropathology of dementia
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Neuropathology of dementia
David Hilton
Derriford Hospital
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• 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
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Main clinical patterns
• Temporoparietal – memory disturbance, later dysphasia and dyspraxia
• Frontotemporal – behavioural changes, later memory disturbance. Parietal function retained
• Subcortical – slowing of thought processes
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• Neurodegenerative • Cerebrovascular disease• Prion disease• Hydrocephalus• Toxic, metabolic and nutritional• Mitochondrial • Demyelination• Head injury• Infections• Neoplasia
Causes of dementia
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Neurodegenerative causes• Alzheimer’s disease Aβ and tau• Dementia with Lewy bodies α synuclein• Frontotemporal dementias:
Picks disease tauChromosome 17-linked tau
FTLD-MND TDP43 FTLD-NF neurofilamentFTLD-FUS FUSFTLD-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
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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
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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)
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Neurofibrillary tangles• predominantly composed of tau• normal tau stabilises microtubules• tau is hyperphosphorylated in NFTs and forms
paired helical filaments
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Amyloid plaques• Extracellular proteinaceous deposits• Largely composed of Aβ peptides – either
diffuse or neuritic (surrounded by dystrophic neurites)
Aβ tauAβ
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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
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Amyloid angiopathy
(congophilic angiopathy/cerebral
amyloid angiopathy)
• derived from Aβ
• arteries and arterioles of cerebral and cerebellar cortex
• present in 90%cases
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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
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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.
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Genes involved in LOADApolipoprotein 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
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Amyloid cascade hypothesisFOR:
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
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• 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
Dementia with Lewy bodies(diffuse LBD/cortical LBD/senile dementia of LB type/LB variant of AD)
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Pathology• atrophy similar to AD, but less severe• pallor of substantia nigra• Lewy bodies (essential)• Lewy-related neurites• Aβ plaques (all types)• neurofibrillary tangles• neuronal loss (esp. s.nigra, locus ceruleus and
basal nucleus of Meynert)• synaptic loss• focal spongiform change
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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
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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
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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.
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Transmissible spongiform encephalopathies (prion diseases)
• Fatal neurological diseases
• Transmissible
• Affect humans and animals
• Similar pathology
• No effective treatment
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Human prion diseases• Idiopathic
Sporadic Creutzfeldt-Jakob disease
• Acquired Iatrogenic Creutzfeldt-Jakob diseaseKuruVariant Creutzfeldt-Jakob disease
• InheritedFamilial Creutzfeldt-Jakob diseaseGerstmann-Straussler-Scheinker syndromeFatal familial insomnia
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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
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Neuropathology
• Brain weight often normal
• Spongiform change at microscopic level
• Neuronal loss• Gliosis• Prion protein
accumulation• No inflamation
PrP
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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
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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
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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%)
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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
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vCJD-pathology
• ‘Florid’ plaques • Severe spongiform
change in caudate and putamen
• Extensive PrP deposition in brain
• PrP accumulation in lymphoreticular system
PrP
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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)
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Codon 129 polymorphisms in PrP gene
MM MV VV
Controls 37% 52% 11%
sCJD 78% 12% 10%
iCJD 60% 11% 29%
vCJD 100%
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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
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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