Alzheimer's. Flashcards

1
Q

How can you define dementia?

A

Multiple cognitive deficits - memory dysfunction eg: new learning (prominent early symptom).
At least one additional cognitive deficit eg: aphasia, agnosia.
Cognitive disturbances - sufficiently severe to cause impairment of occupational/social functioning. Must represent a decline from a previous level of functioning.

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2
Q

What are causes of cognitive deterioration?

A

Alzheimers (40%), vascular disease, multi-infarct dementia (5-20%), drugs, depression, delirium, ethanol (5-15%), medical metabolic systems, neurological, tumour-toxin-trauma, infection-idiopathic-immunologic, amnesia-autoimmune-age associated memory impairment.

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3
Q

What is the life expectancy of someone with alzheimer;s after diagnosis?

A

5-8 years.

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4
Q

What is the main marker of AD?

A

Extracellular amyloid plaques.

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5
Q

What is another main cause of AD?

A

Intraneural neurofibrillary tangles = disorganised bundles of filaments in neuronal cytoplasm - formed by hyperphosphorylated tau proteins - causes hyperactivation and degenerate neurone.

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6
Q

What is the differential diagnosis of Alzheimers?

A

A) Multiple cognitive deficits - memory impairment/other cognitive impairments.
B) Deficits impairing social life/occupational life.
C) Course shows gradual onset and decline
D) Deficits are not due to -other CNS condition or substance induced condition.
E) Do not occur exclusively during delirium
F) Not due to another psychiatric disorder.

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7
Q

What is the differential diagnosis of vascular demntia?

A

A) Multiple cognitive deficits - memory impairment/other cognitive impairments.
B) Deficits impairing social life/occupational life.
C) Focal neurological signs and symptoms or lab evidence indicating cerebrovascular disease etiologically related to deficits.
D) Not due to delirium.

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8
Q

What are the 3 stages of brain atrophy in AD? Describe each stage.

A

Early AD - degeneration of cells in hippocampus, mild forgetfulness, repeating themselves.
Mild AD - atrophy of cerebral cortex, decline in reading judgement and language, emotional outbursts. Forget how to do simple tasks.
Advanced AD - Death of more nerve cells, agitation, wondering, inability to recognise faces and communicate.

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9
Q

In AD, specific neurotransmitter pathways are lost between where? What neurotransmitters are involved?

A

Cortex and Hippocampus. ACh, NA, 5HT.

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10
Q

What else is there reduced activity of?

A

Acetyltransferase and selective loss of nicotinic receptor subtypes in hippocampus/cortex.

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11
Q

What are the benefits of acetylcholinesterase inhibitors?

A

Increases ACh at synapses. May improve, maintain/slow decline of cognitive, behavioural and functional performance in patients with mild/moderate AD. Slows the course of the disease.

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12
Q

Why do nerve cells die?

A

Loss of intracellular Ca2+ homeostasis - causes toxicity.
Mis metabolism of APP - amyloid precursor protein.
Oxidative stress, neurotoxic insult, apoptosis.

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13
Q

What are the genetic risk factors for AD?

A

Familial AD - APP mutaion and presenilins 1 and 2 (increase beta-amyloid production)
Sporadic AD - Apo E4 and other genes. ( decrease beta-amyloid clearance).

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14
Q

What are the biochemical risk factors for AD?

A

Inflammation (glial cells involved in beta-amyloid clearance). Free radicals and NGF.

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15
Q

What are ‘other’ risk factors for AD?

A

Age, gender, HEAD SIZE LOL, educational level and stress.

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16
Q

All the risk factors lead to what?

A

Beta-amyloid plaque formation, neurofibrillary tangles, neuronal loss, synaptic loss. These all cause neurotransmitter deficit.

17
Q

APP is cleaved at how many sites?

A

3.

18
Q

What are the 3 enzymes involved in amyloidogenic and non-amyloidogenic metabolism of APP

A

Alpha, Beta and Gamma secretase.

19
Q

What happens in non-amyloidogenic metabolism?

A

APP cut into large peptide by alpha and gamma secretase and smaller cell associated peptide has neuroprotective role and can be further degraded.

20
Q

What happens in amyloidogenic metabolism?

A

Beta-amyloid formed by beta-secretase and gamma secretase.

21
Q

What effects does the beta-amyloid peptide have?

A

Neurotoxic!! - renders neurons vulnerable, disrupts neuronal Ca++ homeostasis, aggregation of beta-amyloid increases toxicity, promotes cytokine release = inflammatory.

22
Q

In the amyloid cascade hypothesis, what is different between the dominant inherited forms of AD and the non-dominant inherited form of AD?

A

The initial step
Dominant - increase in beta-amyloid42 production throughout life due to missense mutations in APP/PS1/PS2.
Non-dominant - Failure of beta-amyloid clearance mechanisms and gradual rise of beta-amyloid42 levels in the brain.

23
Q

What are the next steps in the amyloid cascade hypothesis?

A
  • Accumulation and oligomerisation of beta-amyloid42 in limbic and association cortices.
  • Subtle effects of beta-amyloid oligomers on synaptic efficacy.
  • Gradual deposition of beta-amyloid42 oligomers as diffuse plaques.
  • Microglial and astrocyte activation and attendant inflammatory responses.
  • Altered neuronal ionic homeostasis, oxidative injury.
  • Altered kinase/phosphatase activities lead to tangles.
  • Widespread neuronal/synaptic dysfunction and selective neuronal loss with attendant neurotransmitter deficits.
24
Q

What drugs improve blood flow by vasodilating effects on monamine receptors?

A

Dihydroergotoxine, Pentoxyfylline.

25
Q

What drugs enhance glutamate mechanisms?

A

Piracetam and Aniracetam.

26
Q

What is cholinergic replacement therapy and what drugs are used?

A
  • Cholinesterase inhibitors - tacrine (associated with hepatotoxicity but has modest efficacy) and donepezil.
  • Muscarinic agonists - Arecoline and pilocarpine - some efficacy in animal models, peripheral side effects.