Dementia Flashcards
What abnormal proteins are associated with Parkinson’s disase and Alzheimer’s dementia?
Parkinson’s disease - alpha synuclein
Alzheimer’s disease - APP and Abeta amyloid
Most common neurodegenerative condition?
AD - >90% of overall; 1:300
PD - 1:5000
DLB - 6:100000
FTD - 3:100000
HD - 6:1000000
Incidence of Alzheimer’s?
1% at age 60, doubles every 5 years thereafter (at 85 years 32%)
Higher in hispanics, african american
Lower in asians
Natural history of Alzheimer’s disease?
Normal –> Preclinical (25 years) –> Prodromal “MCI” (5-8 years) –> Dementia (~9-10 years)
Episodic memory –> Semantic memory –> Attention, Executive (frontal, Visuospatial
Spread (particularly tau protein - neurofibriliary tangles):
Medial temporal –> temporal neocortex –> other multimodal association cortex
Other symptoms associated with amnestic AD?
Weight loss (40%), insomnia, circadian rhythm changes
Acute onset or very rapid progression of cognition - what would be likely diagnosis?
Prion disease, autoimmune, infectious, cancer, toxic-metabolic, and vascular causes, leukoencephalopathies.
Atypical presentations of Alzheimer’s disease?
- Logopaenic primary progressive aphasia
- Hesitant, word-finding pauses, empty, paraphasia, impaired phase repetition
- Posterior cortical atrophy
- Biparietal: dorsal “where” pathway (location) –> apraxia, Gerstmann’s syndrome
- Occipto-temporal: ventral “what” pathway (object, face, word), agnosia, alexia
- Frontal variant AD
- Executive > behavioural deficits
- Visual variant (occipital lobe)
- Cortical blindness
- Acalculia variant (inferior parietal lobe)
- Relatively pure numerical and symbol difficulties
- Congophilic angiopathy
- Micro or lobar haemorrhages, superficial siderosis, amyloid angiitis (inflammatory changes)
- Associated with transient neurological deficits
- Occurs alone or in most patients with AD 90%
Pathology of AD?
Microscopic:
Misfolded protein accumulation is the likely basis of AD
- Beta amyloid oligomers
- Disrupt synapses as earliest toxic change
- Although Abeta40 higher concentration, less toxic than Abeta42 which is also more prone to aggregate into oligomers
- Fibrillar beta amyloid
- Form plaques, probably not toxic
- Tau pathology
- May be secondary to beta-amyloid accumulation (abnormal phosphorylated may be triggered by trimeric ABeta*56
APP (amyloid precursor protein) Ch21 – [broken down inappropriately by beta and gamma secretase] –> beta amyloid –> aggregrates causing amyloid plaques – [+tau pathology and inflammation] –> Neuronal loss and AD
- Reduced clearance of AB protein in patient with AD - many different mechanisms postulated however poorly understood
What is amyloid precursor protein and what is its involvement in the pathogenesis of AD?
- Amyloid precursor protein found on Ch21
- APP – [broken down inappropriately by beta and gamma secretase] –> beta amyloid –> aggregrates causing amyloid plaques – [+tau pathology and inflammation] –> Neuronal loss and AD
- Reduced clearance of AB protein in patient with AD - many different mechanisms postulated however poorly understoo
What is tau?
- Microtubules are held together by tau protein
- Tau protein important for integrity of cytoskeleton and transport of molecules up and down neuron
- In AD: hyperphosphorylated tau loses affinity for tubule binding domain and destabilizes tubules impairing axonal transport
- Symptoms correlate with spread
- Braak and Braak NFT stages
- Hippocampal/enterhinal –> association cortex, prefrontal cortex –> temporal lobe
Synaptic changes in AD?
- Hippocampal synapses preferentially vulnerable (activity dependent) - ? neurogenesis
- Impairs impulse transmission
- LTP loses to long term depression
- Abnormal endocytosis of NMDA and AMPA surface receptors
- Increased turnover and synapse loss is very early change (UDP, choline, DHA)
Genetics in AD?
Cause AD (almost 100% penetrance; Autosomal Dominant)
- Presenilin 1 and 2
- APP
Risk factors
- ADAM10
- ApoE4 (if 2 then higher risk)
Early onset familial AD
- ~40% of all EOAD
- Amyloid cascade hypothesis
- Increased beta-A
- Neurotoxic soluble oligomeric fibrils –> inert plaques
- APP mutations
- Ch21 (overproduction in Down’s syndrome)
- Mutations disrupt normal APP processing
- Clustered at APP secretase cleavage sites
- Genetics: Presenilin 1 most common, then Presenilin 2
What is presenilin?
- 4 proteins forming gamma-secretase (cleaves APP –> beta amyloid)
- Modulates calcium homeostasis
- Mutations result in increased beta-amyloid
- PS1 mutations = major cause of EOFAD Ch 14; develop in 20s, severely disabled by early 40s
- PS2 mutations = variable penetrance, 40-75+ years onset, 12 mutations, Ch 1
Late onset AD genetic and environment risk factors?
Genetic risk factors
- ApoE - e4 allelle Ch 19
- Age-specific risk: 10 years earlier per e4 allele
- Females increased risk (esp between 65-75)
- Accelerators of beta amyloid deposition: ABCA7, FERMT2
Environment risk factors
- AGE
- Family hx
- Female sex, singlehood/widowed
- CV risk factors, congenital heart disease
- Low education, leisure activities, socialisation, physical inactivity, cynicism, mid-life depression (higher in beta amyloid persons)
Protective factors
- Physical exercise
- ? education/stimulation
- ? Oest/HRT
- [statins, fish oil, NSAIDs] -> no benefit
