Alzheimer's disease Flashcards

1
Q

Dementia statistics

A

1/11 Canadians over 65 affected by dementia

Estimated lifetime risk: 10-12%

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2
Q

Clinical features of Alzheimer’s disease

A
insidious onset
slowly progressive
memory loss
aphasia, apraxia
changes in judgment/reasoning
spatial disorientation, behavioural changes
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3
Q

Disease duration of Alzheimer’s disease

A

variable

avg time between diagnosis and death: 8-9 years

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4
Q

Age of onset of AD

A

Early =65

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5
Q

Dementia causes

A
AD (66%)
Vascular (10-20)
LBD (10-20)
Frontotemporal dementia (5-15)
Others: infection, diabetes, thyroid, vitamin deficiency, etc
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6
Q

Pathology of Alzheimer’s disease

A
Accumulation of beta amyloid plaques
neurofibrillary tangles of Tau protein
Loss of cerebral cortex volume due to cell death
Senile plaques
Gliosis
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7
Q

Diagnosis of Alzheimer’s disease

A
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
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8
Q

AD genetics

A
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
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9
Q

Sporatic AD genetics

A
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!
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10
Q

Environmental factors implicated in sporadic AD

A
mental stimulation
head injury
mood disorders/stress
vitamins/herbal remedies?
vascular health - exercise, diet, hypertension, high cholesterol, diabetes
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11
Q

Familial AD

A

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

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12
Q

Familial AD genetics

A

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

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13
Q

Genetic testing for familial AD

A

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

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14
Q

AD gross pathology

A
general brain atrophy
cerebral hemispheres more involved
cerebellum spared 
Hydrocephalus due to increase in size of ventricles
cerebral cortical atrophy
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15
Q

AD distribution of pathology

A

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

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16
Q

Amyloid protein

A

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

17
Q

Amyloid precursor protein

A

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

18
Q

APP in early-onset ADD

A

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
Q

AD in Down’s syndrome

A

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

20
Q

Tau protein

A

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
Q

Inflammation in AD

A

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

22
Q

NTs in AD

A

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

23
Q

Pharmacological treatment of AD

A

cholinesterase inhibitors

NMDA receptor antagonists

24
Q

Cholinesterase inhibitors

A

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
Q

NMDA receptor antagonist

A

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

26
Q

Glutamatergic therapy

A

Glutamate is the major excitatory NT in CNS

increase glutamate –> excessive activation of NMDA, intracellular Ca accummulation –> neuronal death