Alzheimer's. Flashcards
How can you define dementia?
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.
What are causes of cognitive deterioration?
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.
What is the life expectancy of someone with alzheimer;s after diagnosis?
5-8 years.
What is the main marker of AD?
Extracellular amyloid plaques.
What is another main cause of AD?
Intraneural neurofibrillary tangles = disorganised bundles of filaments in neuronal cytoplasm - formed by hyperphosphorylated tau proteins - causes hyperactivation and degenerate neurone.
What is the differential diagnosis of Alzheimers?
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.
What is the differential diagnosis of vascular demntia?
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.
What are the 3 stages of brain atrophy in AD? Describe each stage.
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.
In AD, specific neurotransmitter pathways are lost between where? What neurotransmitters are involved?
Cortex and Hippocampus. ACh, NA, 5HT.
What else is there reduced activity of?
Acetyltransferase and selective loss of nicotinic receptor subtypes in hippocampus/cortex.
What are the benefits of acetylcholinesterase inhibitors?
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.
Why do nerve cells die?
Loss of intracellular Ca2+ homeostasis - causes toxicity.
Mis metabolism of APP - amyloid precursor protein.
Oxidative stress, neurotoxic insult, apoptosis.
What are the genetic risk factors for AD?
Familial AD - APP mutaion and presenilins 1 and 2 (increase beta-amyloid production)
Sporadic AD - Apo E4 and other genes. ( decrease beta-amyloid clearance).
What are the biochemical risk factors for AD?
Inflammation (glial cells involved in beta-amyloid clearance). Free radicals and NGF.
What are ‘other’ risk factors for AD?
Age, gender, HEAD SIZE LOL, educational level and stress.
All the risk factors lead to what?
Beta-amyloid plaque formation, neurofibrillary tangles, neuronal loss, synaptic loss. These all cause neurotransmitter deficit.
APP is cleaved at how many sites?
3.
What are the 3 enzymes involved in amyloidogenic and non-amyloidogenic metabolism of APP
Alpha, Beta and Gamma secretase.
What happens in non-amyloidogenic metabolism?
APP cut into large peptide by alpha and gamma secretase and smaller cell associated peptide has neuroprotective role and can be further degraded.
What happens in amyloidogenic metabolism?
Beta-amyloid formed by beta-secretase and gamma secretase.
What effects does the beta-amyloid peptide have?
Neurotoxic!! - renders neurons vulnerable, disrupts neuronal Ca++ homeostasis, aggregation of beta-amyloid increases toxicity, promotes cytokine release = inflammatory.
In the amyloid cascade hypothesis, what is different between the dominant inherited forms of AD and the non-dominant inherited form of AD?
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.
What are the next steps in the amyloid cascade hypothesis?
- 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.
What drugs improve blood flow by vasodilating effects on monamine receptors?
Dihydroergotoxine, Pentoxyfylline.
What drugs enhance glutamate mechanisms?
Piracetam and Aniracetam.
What is cholinergic replacement therapy and what drugs are used?
- 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.
