Dementia Pathophysiology Flashcards
Give 4 key post mortem findings for AD
Neurofibrillary tangles within neurones
Extra-cellular senile “plaques”
Cerebral Cortex + cerebrum atrophy
Hippocampus (memory) shrinks the most - almost lost altogether. Explains the symptoms of dementia
how are beta amyloid plaques formed + describe them?
Start as short peptides - then aggregate + form insoluble protein deposits.
Not toxic, just useless as they clog up the brain & NS!
Explain genetic components for AD risk
Amyloid Precursor Protein, APP gene is on chromosome 21, expressed mostly in nerve cells. 40 amino acid stretch
Presenilin-1 and presenelin-2 also have familial AD mutations
AD mutations mean the APP cleaves to form amyloid beta deposits
These mutations associated w familial, early-onset AD
e.g. Swedish mutation: double mutation aa670-671 in APP
Down’s= extra chromosome 21, third allele of APP, increasing AD risk
What is sporadic, late onset AD?
Much more common; age > 65 y
However still has a genetic component:
ApoE (chr 19) Lipid transport protein
Alleles APOE E2, E3, E4
If you have 2 APOE E2 alleles =, you are less likely to develop AD
2 APOE E4 alleles= greater AD risk
therefore APOE is a risk factor, not a deterministic gene!
compare 2 molecular pathologies of AD?
We mentioned senile plaques are Aβ peptide fibrils.
How are these cleaved and involved in plaque formation?
Aβ fibrils are cleaved from APP by α, β, gamma secretase
β-secretase (bad guy) + gamma-secretase produce Aβ42 and Aβ40 amyloid peptides–> amyloid plaque formation
Preselinin co-factors needed to make gamma secretase work
The brain tries to rid Aβ + excess waste products thru perivascular system, but si hay risk factors (eg APOE 4), this is less likely–> plaque formation
What is Tau? + how can it go wrong?
Explain the hyperphosphorylation concept of Tau
Tau (encoded by MAPT) stabilises the axon cytoskeleton + maintains helical structure. Tau= parallel filaments located inside neurons & axons in the cerebral cortex
Multiple tau kinases (e.g GSK-3b, Cdk5) add phosphatases
If tau gets too many phosphates/HYPERphosphorylated, it can’t contain its linear structure - gets kinked + forms neurofibrillary tangles
These tangles impair axon function + can no longer hold the helix together!
fronto-temporal dementia
cause of this + when is it seen
3 other mutations which cause this
Less common + seen earlier in life
Mutations in Tau forms Pick bodies (arrows) - aka aggregations of excess non-functional Tau in their cytoplasm
TDP-43, FUS, C9orf72 mutations also cause fronto-temporal dementia
lewy body dementia
who is this commonly seen in?, mechanism + what is formed?
Often seen in people with PD
Misfolding and aggregation of α-synuclein protein forms Lewy bodies. This is encoded by SNCA + again forms useless sphere protein deposits.
These can be used diagnostically, see top right image
Most types of AD are…
Most alzheimer’s diseases are probably mixed dementia
Vascular contributions speed up process of disease progression + is VERY common
Vascular pathologies = small vessel disease
small vessel disease?
causes + what it can lead to?
2 things which aren’t SVD?
This is a concentric fibrous thickening of penetrating arteries–> loss of elasticity + can no longer provide circulation to internal structures of brain -> Leads to multiple white matter lesions ( lacunar infarcts)
Can be post stroke, leads to patchy deficits
often due to Occlusion of single deep perforating artery
Not atheroma or cerebral amyloid angiopathy
What is a way to screen for AD?
PET ligand - sticks to A-beta peptides, is a way to screen for AD
Compare large vs small vessel disease
LVD has 1 Strategic single infarct - leading to multiple cortical grey matter infarcts (MID)
20-30% post-stroke develop dementia (not immediately after the stroke)
SVD has as multiple lacunar infarcts (white matter) - but with occlusion of single deep perforating artery
Often mixed with Alzheimer’s = “mixed” type
how to differentiate diagnosis of PDD vs DLB?
Alzheimers vs FTD vs LBD vs Vascular Dementia
