Alzheimer's & cognitive function Flashcards
What are the definitions for Dementia?
-
Multiple Cognitive Deficits
* Memory dysfunction - Especially new learning
* At least 1 additional cognitive deficit -
Cognitive disturbances
* Sufficiently severe to cause impairment of occupational or social functioning
* Must rep a decline from prev level of func
What is Alzheimer’s disease?
- Progressive deterioration of cognitive function without antecedent cause, such as stroke
- Early (familial) & Late (Sporadic)
Describe progression of AD symptoms
What are Extracellular Amyloid plaques?
- Main marker of AD
- Large neurotoxic aggregates of insoluable amyloid protein
- Extracellular deposits + Gliosis
What are Intraneuronal Neurofibrillary tangles?
Not only found in AD
- Disorganised bundles of filaments in neuronal cytoplasm formed by hyperphsophrylated tau proteins
What are the consequences of Amyloid plaques and neurofibrilary tangles?
- Disruption of neurotransmission
- Brain atrophy
How does the brain atrophy in Alzheimer’s?
- Starts with synapse loss
- Enlargement of ventricles
Early AD
* Degeneration of cells in hippocampus
1. Mild forgetfulness
2. Difficulty solving simple maths
Mild-Moderate AD
* Atrophy of Cerebral Cortex
1. Dec in reading judgement
2. Forget how to do simple tasks
Adv-Final AD
* Death of more nerve cells
1. Agitation, wandering
2. Inability to recognise people
Breifly metion the link between NT and Alzheimer’s
- Loss of specific NT pathways to cortex and hippocampus
- Cholinergic ACh (correlated with dementia)
- Noradrenaline
- Serotonin
- Loss of cortical interneurons
What cholinergic changes are there in ADs?
- Loss of forebrain cholinergic neurons
- Reduced activity of choline acetyltransferase (Synth of acetylcholine)
- Selective loss of nicotinic rec subtypes in hippo and cortex
What are the benefits of Acetylcholinesterase inhibitors?
- Increase ACh at synapses
- May imp, maintain or slow decline of cognitive, behavioural, and functional performance in patients with mild-moderate AD
- Slow diesease course - Earlier the better
Why do nerve cells die?
Due to loss of intacellular Ca2+ homeostsis
How does this happen?
* Mis-metabolism of amyloid precursor protein
* Oxidative stress
* Neurotoxic insult
* Excessive excitatory AA rec activation
* Apoptosis
Explain the metabolism of amyloid precursor protein
- Can be cleaved at three sites: alpha, beta, and gamma-secretase which play key roles in the non-amyloidogenic (good) and amyloidogenic (bad) metabolism of APP
- Non-amyloidogenic = if APP is cleaved by alpha and gamma-secretase
- Amyloidogenic = if APP is cleaved by beta and gamma-secretase – leads to the formation of plaques
- 3 mutation types are associated with familial Alzheimer’s
What is the secreted forms of APPb?
- Protective
* E.g. Reg proteases, promotes neuronal survival, mod glutamate resp etc
What is the secreted forms of b-amyloid peptide?
- Neurotoxic
* E.g. Renders neurons vulnerable to excitoxicity, disrupts Ca2+ homeostasis etc
What are the genetics of ADs?
- Autosomal dominant disease - familial AD=5-10% of cases
3 imp genetc loci identified in familia form
1. APP gene on chromosome
2. Presenilin (PS1) gene on chromosome 14
3. Presenilin (PS2) gene on chromosome 1
- favour production of the long amyloid Aß42 which aggregates more readily than the normal short Aß40 form
What are risk factors for ADs?
What is the Amyloid Cascade hypothesis?
How do you halt disease process?
