Alzheimers Disease

Question 1

What are the incidence rates of alzheimers

Answer 1

age related cognitive decline:
10% over 85
40% over 85

Question 2

How are the different stages of Alzheimers explained in terms of symptoms

Answer 2

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

Question 3

general causes/pathology of alzheimers

Answer 3

1. neurofibrillary tangles
2. senile plaques
3. neuronal loss
4. cholinergic depletions

Question 4

Explain pathology of neurofibrillary tangles

Answer 4

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

Question 5

Explain pathology of senile plaques

Answer 5

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

Question 6

Explain pathology of neuronal loss

Answer 6

first stage of neuronal loss is in the medial temporal lobe (hippocampus and entorhinal cortex) and also lateral temporal lobe

Question 7

Explain pathology of cholinergic depletions

Answer 7

As you age, cholinergic depletions happen anyway (even without having alzheimers), every decade.
results in cognitive decline

Question 8

What are the two versions of the genetic contributions of alzheimers

Answer 8

1. familial version - abnormalities on chromosomes 1, 14, 19, & 21
2. 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

Question 9

What does the dominant theory of the etiology of alzheimers argue

Answer 9

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

Question 10

What is the most sophisticated etiology model of alzheimers

Answer 10

that the AD population could have an interaction between beta-amyloid and cholinergic depletions that cause the dementia

Question 11

what are the barriers that inhibited progress of SAD learning and research after that one paper

Answer 11

1. no distinction between familial vs sporadic version of AD
2. lack of specificity and sensitivity of functional assessments
3. a reliance on inappropriate animal models (the rat experiments dont work the same as humans)

Question 12

Furthermore, what does it mean that there was a lack of specificity of functional assessments in rats which was a barrier to research

Answer 12

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?)

Question 13

Familial versus sporadic versions of AD

Answer 13

FAD - genetic mutations, pathology, then disease happens (5%)
SAD - unknown etiological (cause), descent into dementia, unpredictably (95%)

Question 14

Furthermore, what does it mean that there was a reliance on inappropriate animal models causing barrier for research

Answer 14

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

Question 15

define circadian rhythms

Answer 15

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

Question 16

how are circadian rhythms observed

Answer 16

through hormone profiles, gene and protein expression, dendritic morphology, activity patterns, cognitive function, etc.

Question 17

what generates circadian rhythms

Answer 17

suprachiasmatic nucleus (SCN) of the anterior hypothalamus

Question 18

what is the breakdown in circadian rhythms a characteristic of
AND what hypothesis was created from this characteristic connection

Answer 18

aging
that circadian rhythm decreases with aging is connected to hippocampal memory loss and AD

Question 19

experiment to test circadian rhythm and aging to hippocampal memory loss

Answer 19

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??

Question 19

experiment to test circadian rhythm and aging to hippocampal memory loss

Answer 19

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??

Question 20

Appetitive context conditioning - learning and memory behaviour task

Answer 20

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

Question 21

what is the relation between circadian rhythms and cognitive decline/AD

Answer 21

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

Question 22

Many other combinations of co-factors can produce variants of age-related cognitive decline in AD patients such as

Answer 22

(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.

Question 23

explain what the proof of principle means for the multiple combinations of co-factors model

Answer 23

that we are testing that the model is practical, specifically that a combinations of factors can cause age related cognitive decline

Question 24

multiple combinations of cofactors experiment: stress and stroke

Answer 24

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

Question 25

behaviour task - morris water maze

Answer 25

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??

Question 26

define cholinergic system

Answer 26

controls acetylcholine and these cells can project up to the hippocampus

Question 27

3 experiments for proof of principle for acetylcholine effects (cholinergic)

Answer 27

1. cholinergic depletions and stress
2. and seizures
3. and stroke

Question 28

what was the basic protocol for all acetylcholine experiments

Answer 28

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

Question 29

saporin

Answer 29

used to cause lesions specifically in cholinergic neurons of the medial septum and killed many neurons in there

Question 30

explain fear conditioning task for these experiments

Answer 30

day1 = 2 min habituation, 5 tone shock pairings
day2 = 2 minutes habituation, 8 min tone presentation
day3 = 5 minutes, no tone or shock

Question 31

multiple combinations of cofactors - cholinergic depletions and stress (on both water task and freezing)

Answer 31

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

Question 32

what negative effect does the cholinergic system/ acetylcholine cause

Answer 32

decreases threshold of seizure activity, neurogenesis, neurotrophic levels, alterations, plasticity LTP potentiation (BAD)

Question 33

What were the patterns found in multiple combinations of co-factors experiments

Answer 33

no effects on neurodegeneration or learning and memory from some combinations, some effects, and some effects on only learning and memory but not neurodegeneration

Question 34

Conclusions of multiple combinations theory

Answer 34

different mechanisms = different treatments for disease
not always a clear relationship between neurodegeneration and function impairments

Question 35

new genetic approaches about SAD

Answer 35

revealed set of gene polymorphisms associated with SAD, such polymorphisms include inflammation, lipid metabolism, immune responses, and endocytosis
(polymorphisms increase susceptibility of disease)