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Flashcards in Alzheimer's disease Deck (26):
1

Dementia statistics

1/11 Canadians over 65 affected by dementia
Estimated lifetime risk: 10-12%

2

Clinical features of Alzheimer's disease

insidious onset
slowly progressive
memory loss
aphasia, apraxia
changes in judgment/reasoning
spatial disorientation, behavioural changes

3

Disease duration of Alzheimer's disease

variable
avg time between diagnosis and death: 8-9 years

4

Age of onset of AD

Early =65

5

Dementia causes

AD (66%)
Vascular (10-20)
LBD (10-20)
Frontotemporal dementia (5-15)
Others: infection, diabetes, thyroid, vitamin deficiency, etc

6

Pathology of Alzheimer's disease

Accumulation of beta amyloid plaques
neurofibrillary tangles of Tau protein
Loss of cerebral cortex volume due to cell death
Senile plaques
Gliosis

7

Diagnosis of Alzheimer's disease

typically a diagnosis of exclusion
clinical diagnosis ~90% correct
Neuropathological diagnosis certain (suspicion until then)
may involve:
- neurological examination
- CT/MRI
- SPECT
- blood work
- neuropsychological, neuropsychiatric evaluation
- functional assessment
- family history

8

AD genetics

Most are sporadic: 75-95%
Multifactorial
susceptibility genes
enviornmental factors
aging is greatest risk factors
affected first degree relative: 15-30% recurrence risk
15-30 to

9

Sporatic AD genetics

ApoE gene
one of 40+ susceptibility genes identified, shows strongest effect
exact role unclear
3 alleles: APOE2, 3, 4
APOE4 greatest risk for sporadic AD
- heterozygote: 3x popn risk
- homozygote: 8x pon risk
clinical genetic testing not recommended
NOT causative!

10

Environmental factors implicated in sporadic AD

mental stimulation
head injury
mood disorders/stress
vitamins/herbal remedies?
vascular health - exercise, diet, hypertension, high cholesterol, diabetes

11

Familial AD

rare, 5-25% of all cases
Clinically indistinguishable from sporadic
Can be early or late onset
Hallmarks:
- multiple family members with AD
- affected parents having affected children over many generations
- multiple siblings affected
- similar age of symptom onset within family

12

Familial AD genetics

autosomal dominant
almost complete penetrance (50% recurrent risk in first degree relatives)
3 causative genes identified:
- Presenilin 1, 2, amyloid precursor protein
Affect processing of APP and increase in beta amyloid peptide
Only for early-onset
No genes identified for late-onset familial AD yet

13

Genetic testing for familial AD

UT - strict inclusion criteria, no cost, 12 mo turnaround time
Clinical testing from US, 2500$, 2-4 wks
relevant ONLY if early-onset familial AD
negative: does not R/O possibility

14

AD gross pathology

general brain atrophy
cerebral hemispheres more involved
cerebellum spared
Hydrocephalus due to increase in size of ventricles
cerebral cortical atrophy

15

AD distribution of pathology

predominantly in association cortices
no blindness/numbness in AD
loss of planning
loss of hippocampus: mood, personality, emmory

16

Amyloid protein

extracellular
8- 10 nm in diameter, can aggregate into beta-pleated sheets
characteristic birefringence on Congo Red stain

17

Amyloid precursor protein

gene on chromosome 21
family of membrane-inserted glycoproteins
expressed by neurons/other cells
fxn unknown

18

APP in early-onset ADD

Mutations near enzymatic cleavage site
--> increased production of A beta
PS-1 and PS-2 part of gamma-secretase complex
mutations result in more A beta

19

AD in Down's syndrome

all adults with Down's syndrome develop pathologic changes of AD
earliest recognizable change = Abeta deposition
trisomy 21 --> extra copy of APP

20

Tau protein

microtubule associated protein on chromosome 17
alternate splicing --> 6 isoforms
Abnormal hyperphosphorylation --> formation of paired helical filaments (PHF) and striaght filaments
PHF is a major constituent of neurofibrillary tangles, plaque-associated neurites and neuropil threads

21

Inflammation in AD

IgG
complement proteins, receptors
cytokines, cytokine receptors
microglia (MHC II)

22

NTs in AD

reduced cholinergic neurons (nucleus basalis)
reduced ACh, ChAT, AChE
reduced serotonin, dopamine
reduced norepinephrine

23

Pharmacological treatment of AD

cholinesterase inhibitors
NMDA receptor antagonists

24

Cholinesterase inhibitors

Donepezil
Galantamine
Rivastigmine
start low, titrate up, watch for side effects - sludge (N/V/diarrhea)
possible CIs: bradycardia, active peptic ulcers, uncontrolled asthma, seizure

25

NMDA receptor antagonist

memantine
moderate to severe AD
renal excretion
side effects: dizziness, confusion, headache, constipation

26

Glutamatergic therapy

Glutamate is the major excitatory NT in CNS
increase glutamate --> excessive activation of NMDA, intracellular Ca accummulation --> neuronal death