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In the Donepezil and Memantine treatment paper, what mechanism(s) were these drugs intended to address/fix? [the nts (acetylcholine and glutamate) nor the mechanisms were mentioned in the paper. I’m pulling this from my presentation]
- Donepezil mechanism: Acetycholinesterase INHIBITOR (increases acetylcholine in synaptic cleft by SLOWING its breakdown)
- Memantine: NMDA type-glutamate receptor – works to BLOCK excitatory effects of glutamate. Excess glutamate signaling can lead to NERVE cell DEATH & excitotoxicity
What effect did each of the drugs, Donepezil and Memantine, have on cognitive and non-cognitive functions? Was one particularly better than the other or was there a synergistic relationship? How was this measured/determined?
- COGNITIVE FXN:
- 1. Donepezil treatment alone resulted in benefits with regards to COGNITIVE fxn
- 2. Memantine treatment had NO significant cognitive fxnl benefit
- 3. NO synergistic benefit seen by utilizing combinations of both donepezil and memantine
- In looking at cognitive functions, SMMSE and BADLS scores were used
- NON-COGNITIVE FXN:
- 1. Donepezil showed NO significant effect on NON-COGNITIVE fxn
- 2. Memantine had SMALL but insignif. Effect on non-cognitive aspects
- 3. NO synergistic benefit by adding memantine treatment to donepezil
- Non-cognitive function was measured using Minimal clinical difference in Mean NPI scores.
What is Aβ42? Explain how the Aβ42 plaques are formed and what their effect is on the cholinergic pathway? What changes in Aβ42 in the CSF and plasma did the authors identify in their study of Dominantly inherited Alzheimer’s disease?
- Abeta42 is an amyloid beta peptide that is PROCESSED FROM APP (amyloid precursor protein).
- Ab42 is responsible for the plaque buildup in the brain assoc. w alzheimers. These Plaques are formed when APP processing undergoes the DISEASE causing pathway, aka BETA pathway. This pathway involves APP cleaved by BETA secretase (not alpha, as in healthy pathway, resulting in p3 subunit release), then cleavage by GAMMA secretase, resulting in Abeta42.
- Effects on Cholinergic pathway: Reduced activity of PYRUVATE DEHYDROGENASE (normally produces acetyl). This results in Reduced Uptake of choline -> reduced acetylcholine conent -> reduced acetylcholine released from synaptic vesicle
- CSF levels of Ab42 DEcreased in carriers at 25yrs prior to onset of AD
- Plasma levels of Ab42 showed INcrease from 10 years prior to onset until death
Multiple factors influence whether a specific complex genetic disease develops. What are these factors and what influences them? Describe the variability found in complex diseases because of the relationship between the factors needed for the disease to occur.
- 1. Genetic makeup of individual: predetermined and changed thru mutation in DNA. Based on inherited traits
- 2. Environment of individual: Helpful, if live in area with no pollution and abundant natural resources or harmful if inhaling toxic pollution and living with limited resources
- 3. Lifestyle of individual: includes characteristics of individual such as amount of exercise, food choices (Organic or non-GMO vs alternative, meat eater vs vegetarian)
- Because of the variability in each of the three factors, it is very hard to pinpoint specific causes of these complex diseases. It is a unique set of circumstances for each individual that determines if a complex disease will persist or not, so not to be simplified with an easy treatment or prevention strategy.