Alzheimers Disease Flashcards
What are the incidence rates of alzheimers
age related cognitive decline:
10% over 85
40% over 85
How are the different stages of Alzheimers explained in terms of symptoms
early = symptoms can resemble other neurological and psychological conditions (personality and memory changes)
middle = deficits start to appear, seen on neuropsychological tests, mainly in episodic memory.
end stage = global deficits
general causes/pathology of alzheimers
- neurofibrillary tangles
- senile plaques
- neuronal loss
- cholinergic depletions
Explain pathology of neurofibrillary tangles
are abnormal accumulations of tau protein that collect inside neurons. the overproduction leads to dissociation of portions of microtubules and form into filaments. The filaments are composed of pairs that wound around each other in a helical arrangement. These are found in the brain of AD patients caused by the hyperphosphorylated tau protein
Explain pathology of senile plaques
plaque formation is caused by abnormal processing of amyloid precursor protein (APP). APP broken down by cleavage processes, can either be harmless or at other sites can produce beta-amyloid. beta-amyloid is difficult to get rid of and therefore starts accumulating
Explain pathology of neuronal loss
first stage of neuronal loss is in the medial temporal lobe (hippocampus and entorhinal cortex) and also lateral temporal lobe
Explain pathology of cholinergic depletions
As you age, cholinergic depletions happen anyway (even without having alzheimers), every decade.
results in cognitive decline
What are the two versions of the genetic contributions of alzheimers
- familial version - abnormalities on chromosomes 1, 14, 19, & 21
- sporadic version - no real known genetic contribution to this kind. 95% of people have this type. etiology not well understood. gene polymorphism of APOE 4, meaning there are multiple variant forms of this specific gene that causes different phenotypes/results
What does the dominant theory of the etiology of alzheimers argue
that genetic mutations results in pathology of plaques or tangles which cause cognitive impairments
ex. get gene mutation -> get associated pathology -> results in neurodegeneration/dementia
What is the most sophisticated etiology model of alzheimers
that the AD population could have an interaction between beta-amyloid and cholinergic depletions that cause the dementia
what are the barriers that inhibited progress of SAD learning and research after that one paper
- no distinction between familial vs sporadic version of AD
- lack of specificity and sensitivity of functional assessments
- a reliance on inappropriate animal models (the rat experiments dont work the same as humans)
Furthermore, what does it mean that there was a lack of specificity of functional assessments in rats which was a barrier to research
tasks were used not good, ex. were testing areas that shouldn’t even be altered with AD. saw that SAD deficits were more subtle and found that placing hide demand on hippocampal function are sensitive to even subtle hippocampal disruption (bad?)
Familial versus sporadic versions of AD
FAD - genetic mutations, pathology, then disease happens (5%)
SAD - unknown etiological (cause), descent into dementia, unpredictably (95%)
Furthermore, what does it mean that there was a reliance on inappropriate animal models causing barrier for research
only would focus on a single factor being the cause (ex. tau or beta-amyloid)
the mice produce high levels of pathology compared to humans, overexpress protein fragments that aren’t even found in humans
define circadian rhythms
mental, physical, and behavioural changes that follow a 24 hour cycle with peaks and valleys of function. ex. when asleep body has less function and is fasting, dont need lots of activity in G1 tract
how are circadian rhythms observed
through hormone profiles, gene and protein expression, dendritic morphology, activity patterns, cognitive function, etc.
what generates circadian rhythms
suprachiasmatic nucleus (SCN) of the anterior hypothalamus
what is the breakdown in circadian rhythms a characteristic of
AND what hypothesis was created from this characteristic connection
aging
that circadian rhythm decreases with aging is connected to hippocampal memory loss and AD
experiment to test circadian rhythm and aging to hippocampal memory loss
created “days” for the hamsters and would track when they would run on a wheel. (darkness is when they normally run on a wheel and in light they don’t)
healthy rats did this, unhealthy rats were not good and started even being active in the day time!
What does this tell us about hippocampal damage??
experiment to test circadian rhythm and aging to hippocampal memory loss
created “days” for the hamsters and would track when they would run on a wheel. (darkness is when they normally run on a wheel and in light they don’t)
healthy rats did this, unhealthy rats were not good and started even being active in the day time!
What does this tell us about hippocampal damage??
Appetitive context conditioning - learning and memory behaviour task
to test functions of hippocampus and amygdala through circadian rhythms
two different contexts, different things happen in each chamber, do test (ex. put a wheel in a chamber which they like) then take out the wheel/US, see what associations hamsters make and where they spend the most of their time
healthy rhythms showed HUGE preference
unhealthy did not
CONCLUSION = circadian dysfunction is better predictor or cognitive decline than age
what is the relation between circadian rhythms and cognitive decline/AD
changes in circadian rhythms have consistently been report in AD patients
due to function decay of the suprachiasmatic nucleus (seen in AD patients)
circadian rhythms/ decline is important factor in AD patients, PERIOD
Many other combinations of co-factors can produce variants of age-related cognitive decline in AD patients such as
(hippocampal formation damage is essential and result in neurodegeneration and/or brain dysfunction)
stress hormones, circadian decline, cholinergic depletion, neurofibrillary tangles, senile plaques, head trauma, environmental toxins, diet, etc.
explain what the proof of principle means for the multiple combinations of co-factors model
that we are testing that the model is practical, specifically that a combinations of factors can cause age related cognitive decline
multiple combinations of cofactors experiment: stress and stroke
stress them out and give them a ministroke, they gave the amount of stress in a range from 5minutes to 1hour to keep it variable so they didn’t habituate to it.
results was that corticosterone levels was highest for combination of stress stroke compared to just stress, just stroke, or control
was massive degeneration in hippocampus, specifically C3 of dentate in the combination group, lots of hippocampal brain damage, lots more cell death, flouro-jade B is also indicator of cell death which was higher in stroke stress combination
behaviour task - morris water maze
phase 1 = initial location - 4days
phase 2 = different location - 1day
phase 3 = platform back in original location and see which one the rat would swim to (competition test)
for phase 1, normal data for both control and treatments
differences emerge with phase 2
competition test, the stress stroke combination were only going to original location, could not go to new one.
Conclusions??
define cholinergic system
controls acetylcholine and these cells can project up to the hippocampus
3 experiments for proof of principle for acetylcholine effects (cholinergic)
- cholinergic depletions and stress
- and seizures
- and stroke
what was the basic protocol for all acetylcholine experiments
cholinergic depletion or vehicle - recover for 2 weeks - co factor (stress, stroke, seizure) or control - 1 week - then behavioural testing of either water maze or fear conditioning - then see changes/histology
saporin
used to cause lesions specifically in cholinergic neurons of the medial septum and killed many neurons in there
explain fear conditioning task for these experiments
day1 = 2 min habituation, 5 tone shock pairings
day2 = 2 minutes habituation, 8 min tone presentation
day3 = 5 minutes, no tone or shock
multiple combinations of cofactors - cholinergic depletions and stress (on both water task and freezing)
generally, higher corticosterone levels and chAT cells are lower, meaning the neurons were properly killed (in both stress and AC and just AC treatment)
water task = AC and stress groups were IMPAIRED, not to new or old platform place, just random
fear task = ?? double check
didnt show neurodegeneration in hippocampus but still are impaired at learning and memory in the hippocampus
Conclusions: impairment was not due to hippocampal damage, actually due to cholinergic depletion impact on plasticity. which then increases hippocampus vulnerability to secondary insults
what negative effect does the cholinergic system/ acetylcholine cause
decreases threshold of seizure activity, neurogenesis, neurotrophic levels, alterations, plasticity LTP potentiation (BAD)
What were the patterns found in multiple combinations of co-factors experiments
no effects on neurodegeneration or learning and memory from some combinations, some effects, and some effects on only learning and memory but not neurodegeneration
Conclusions of multiple combinations theory
different mechanisms = different treatments for disease
not always a clear relationship between neurodegeneration and function impairments
new genetic approaches about SAD
revealed set of gene polymorphisms associated with SAD, such polymorphisms include inflammation, lipid metabolism, immune responses, and endocytosis
(polymorphisms increase susceptibility of disease)
