L24 - Alzheimers Disease Flashcards
x% of all cases of dementia are caused by AD - it is also the most common cause of dementia among >65 year olds
60
If you have Amyloid-Beta in your brain, does this mean you have AD?
Not necessarily
Majority of neurons affected in AD is in which brain region?
PFC
What 2 abnormal structures are seen in brains of people with AD?
1) Beta-amyloid plaques - dense deposits of protein and cellular material that accumulate around nerve cells, WE THINK it creates a toxic environment
2) Neurofibrillary tangles - twisted fibres that build up inside the nerve cell caused by hyperphosphorylation of tau protein
What is the precursor to amyloid peptide (A-beta)?
APP - amyloid precursor protein, it has 3 cleavage sites alpha, beta and gamma
What enzymes do you need to cleave APP to A-Beta (beta-amyloid protein)?
Beta-secretase AND Gamma-secretase
If you have mutation in the A-Beta gene, you get greater cleavage where?
Beta-secretase so you produce more A-beta toxic fragment
Which secretase combination: alpha, beta, gamma is neuroprotective?
alpha and gamma
T/F - Hyperphosphorylation of tau is in same regions to the amyloid plaques in the brain
F- different
T/F -Higher incidence of AD in people that drink, smoke, inactive, overweigh
T
How are neurofibrillary tangles formed?
Tau protein stabilizes the cell usually, in AD, abnormal tau fall apart from microtubules - destroying the transport system. Strands of the abnormal tau then form neurofibrillary tangles
How does the PET scan of AD-affected brain differ from normal brain? MRI?
PET - Decreased cellular activity (not using as much glucose)
MRI - atrophy present in AD brain
Using specific ligands that can bind to amyloid - in AD brain, there is more amyloid present
Using specific ligands that can bind to amyloid - in AD brain, there is more amyloid present
Preclinical AD - in which areas are the first signs of AD seen?
Entorhinal cortex -> then hippocampus (BOTH MEMORY-IMPORTANT REGIONS)
- Affected regions shrink as nerve cells die
- Changes can begin 10-20 years before symptoms appear
You can take CSF and look at ____ which is the toxic component - these are also found in presymptomatic individuals
ABeta42
AD is linked with deficiency of what NT?
Ach - basal forebrain inputs to hippocampus and cerebral cortex impaired
Donepezil (Aricept is brand name)
a) What is it?
b) Features - comp/non-comp, reversible/irreversible, half life?
c) Dosage?
d) Metabolised by?
e) Delays AD by how long?
f) Adverse effects?
a) Anticholinesterase used to treat AD
b) Non-comp and irreversible in terms of binding and have similar efficacy, with half life of 70 hours
c) Once a day 5 to 10 mg
d) Metab by cytochrome P450 isoenzymes CYP3A and CYP2D6
e) Delays deterioration by 6- 12 months
f) SE: Nausea, diarrhoea, anorexia, headache, insomnia, depression, drowsiness, dizziness, fatigue, sweating, tremor, muscle cramps
Does vitamin E have an effect in AD or CV disease?
No
There is quite a few antidepressants and antipsychotics that are used to treat the symptoms of AD
There is quite a few antidepressants and antipsychotics that are used to treat the symptoms of AD
In AD patients, there is a dramatic decrease in levels of _____ in the cortex and hippocampus due to the atrophy of _____ where the cholinergic inputs are primarily from
Choline acetyltransferase, nucleus basalis of Meynert in basal forebrain
Cholinergic hypothesis
Loss of ACh in AD correlates with impairment of memory - hence enhancement of cholinergic function may improve cognitive function
Another drug approved for AD?
Memantine - NMDA antagonist, reduce glutamate-induced neuronal degeneration
Current treatment summary of AD
Cholinergic agents initially improve and transiently maintain cognitive abilities in patients with mild to moderate AD.
However, cognitive abilities worsen over time, treatment may delay but does not stop AD progression
New treatments that maintain cognitive ability and stop the progression of AD are needed
If you have a higher incidence of APOE4, there is a higher incidence in AD but we are not sure how it works - could have to do with endogenous clearance mechanisms
If you have a higher incidence of APOE4, there is a higher incidence in AD but we are not sure how it works - could have to do with endogenous clearance mechanisms
