Neuropathology of dementia

David Hilton

Derriford Hospital

• 24 million have dementia, will double every 20 years

• 60% in developing countries• 700,000 in UK have significant cognitive

impairment. 250,000 in institutions– total cost in health and social care £17 billion/year (2007)

• Psychological, practical and economic burden on carers

• Most important cause of disability over age 60 years

Main clinical patterns

• Temporoparietal – memory disturbance, later dysphasia and dyspraxia

• Frontotemporal – behavioural changes, later memory disturbance. Parietal function retained

• Subcortical – slowing of thought processes

• Neurodegenerative • Cerebrovascular disease• Prion disease• Hydrocephalus• Toxic, metabolic and nutritional• Mitochondrial • Demyelination• Head injury• Infections• Neoplasia

Causes of dementia

Neurodegenerative causes• Alzheimer’s disease Aβ and tau• Dementia with Lewy bodies α synuclein• Frontotemporal dementias:

Picks disease tauChromosome 17-linked tau

FTLD-U/MND TDP43 FTLD-NF neurofilamentFTLD-FUS FUSFTLD 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

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

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)

Neurofibrillary tangles

• predominantly composed of tau

• normal tau stabilises microtubules

• tau is hyperphosphorylated in NFTs and forms paired helical filaments

Amyloid plaques

• Extracellular proteinaceous deposits

• Largely composed of Aβ peptides – eitherdiffuse or neuritic (surrounded by dystrophic neurites)

Aβ TauAβ

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

Amyloid angiopathy (congophilic angiopathy/cerebral amyloid angiopathy)

• derived from Aβ

• arteries and arterioles of cerebral and cerebellar cortex

• present in 90% cases

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

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.

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, CRI, ABCA7, MS4A, CD33, EPHA1

Cholesterol metabolism: APOE, CLU, ABCA7

Synaptic/cell membrane function: PICALM, BIN1, CD33, EPHA1

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

• 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)

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

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

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)

• present with frontal signs, semantic dementia and aphasia• FTLD-tau

Picks disease (tau)Chromosome 17-linked (tau)

• FTLD-TDP FTLD-MND/Ubiquitin (TDP43)

• FTLD-UPS (ubiquitin proteosomal system)• FTLD-FUS (fused in sarcoma protein)• Also frontal variant of AD

FTLD 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.

Transmissible spongiform encephalopathies (prion diseases)

• Fatal neurological diseases

• Transmissible

• Affect humans and animals

• Similar pathology

• No effective treatment

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

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

Neuropathology

• Brain weight often normal

• Spongiform change at microscopic level

• Neuronal loss

• Gliosis

• Prion protein accumulation

• No inflamation

PrP

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

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

Variant CJD• Disease onset from February 1994• 175 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%)

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

vCJD-pathology

• ‘Florid’ plaques • Severe spongiform change in caudate and

putamen• Extensive PrP deposition in brain• PrP accumulation in lymphoreticular

system

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)

Codon 129 polymorphisms in PrP gene

MM MV VV

Controls 37% 52% 11%

sCJD 78% 12% 10%

iCJD 60% 11% 29%

vCJD 100%

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

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