Neurodegeneration three - Alzheimer part one

Question 1

What is the definition of dementia?

Answer 1

Loss of intellectual functions (thought, memory) severe enough to interfere with daily living.

Question 2

Is dementia a disease?

Answer 2

No, it is a collection of symptoms that accompany various diseases or conditions

Question 3

What do the symptoms of dementia include?

Answer 3

Changes in mood, personality and behaviour

Question 4

Is dementia reversible?

Answer 4

Not when caused by disease or injury

However if caused by drugs, alcohol, hormone/vitamin imbalance or dementia then it is.

Question 5

Whats the prevalence of dementia?

Answer 5

Strongly correlates with age, nearly 70% by age 100 but beyond this it appears to plateau

Question 6

Whats a major cause of dementia?

Answer 6

Alzhiemers

Question 7

Whats the time course for dementia?

Answer 7

Around a nine year progressive deterioration in cognitive ability.

Question 8

Whats a common disorder of dementia?

Answer 8

Behavioural disorders

Question 9

What are some biomarkers/pathology for dementia?

Answer 9

Amyloid protein
Tau protein
Brain Atrophy

Question 10

What are some characterisitic pathologies of alzhiemers?

Answer 10

Senile plaques (amyloid)
Neuronal loss (frontal/temporal cortices and hippocampus) - brain atrophy
Nueorfibrillary tangles (tau)

Question 11

Do normal people have amyloid in their brain?

Answer 11

Yes-required protein

Question 12

Whats the amyloid theory?

Answer 12

When theres too much amyloid protein it deposits elsewhere and is toxic (not where it should be)

Question 13

Why is amyloid metabolism important?

Answer 13

Amyloid PRECURSOR protein is normally broken down by Alpha -secretase but if BEta or Gamma secretase get in there then it cuts it into very small fragments which form plaques

B-amyloid protein fragments coalesce into plaques

Question 14

What forms senile plaques?

Answer 14

Beta amyloid fragments that have coalesced from amyloid precursor protein

Question 15

What are the neurofibrillary tangles?

Answer 15

Microtubules of tau protein that have disintergrated and clumped together (hyperphosphorylated) (intracellular)

Question 16

Why do amyloid plaques and neurofibrillary tangles form?

Answer 16

No known cause yet

Question 17

How are amyloid plaques toxic?

Answer 17

They disrupt Ca homeostasis and induce apoptosis.

Lot of build up of amyloid in mitochnodria too

Question 18

What are some additional pathologies in AD?

Answer 18

Marked increase in inflammatory markers

Alteration of distribution of trophic factors such as BDNF too…

Question 19

Describe the neuroanatomy progression of AD

Answer 19

Starts deep in the medial temporal cortex migrates to the frontal cortex then posteriorly to the occipital cortex

In general, can start in the occipital cortex etc.

Question 20

With regards to neuroanatomy what is the first major symptom and why?

Answer 20

Memory loss as deep inside the medial temporal cortex is the hippocampus which has a very important role in memory

He calls it a global retrograde amnesia (progressive loss)- technically anteretrograde

Question 21

What are the symptoms of dementia then?

Answer 21

Depends on where is damaged but associate the lobes with their functions por favor

parietal lobe - senosry dysfunction

Question 22

Whats a major pathology of the brain?

Answer 22

Atrophy

on ct we can observe greater invaginations of sulci

Question 23

What are some imaging tehcniques for Dementia?

Answer 23

MRI
CT
PET

Imaging used preferentially to confirm disease

Question 24

Is AD or dementia genetic?

Answer 24

Yes they can be

Question 25

Which chromosome are the genes for AD located?

Answer 25

21 which is why down syndrome people have early onset

Question 26

What is the first target in the treatment of AD?

Answer 26

The cholinergic system

Question 27

Why is the cholinergic system used to treat AD?

Answer 27

It produces symptomatic improvements

Question 28

What happens when you decrease ACh production?

Answer 28

Sweating, salivation problems

Question 29

What do you want to do to ACh transmission in AD?

Answer 29

INcrease it

Question 30

How do you increase ACh transmission?

Answer 30

1. ) Use ACh agonists 2. ) Inhibit ACh esterase (most sucessful) 3. ) Increase presynaptic activation 4. ) Tweak the receptor, make it hypersenitive, or express its expression

Question 31

Whats the only drug used in AD for cholinergic system?

Answer 31

ACh esterase inhibitor

Question 32

Why target the cholinergic system?

Answer 32

Cholinergic neurons are preferentially lost especially in the synapse

Question 33

What is the choloinergic system important for?

Answer 33

memory, sleep, arousal etc Mostly alertness - which is why we target it, but has limited potential

Question 34

What are some risk factors for AD?

Answer 34

``` Family history (10%) (non-mendellian inheritance) Down syndrome (100% over 40) Chronic hypertension/diabetes head injuries (2-3x more likely) ```

Question 35

What are the characteristics of early stage AD?

Answer 35

- Begins with forgetfulness - Progresses to disorientation and confusion - personality changes - Symptoms of depression/manic behaviour

Question 36

What are the medical interventions of AD?

Answer 36

Medication - ACh inhibitors i.e aricept and cognex | Therapy for depression and counselling for families

Question 37

What is the most common cause of death for AD?

Answer 37

Aspiration pneumonia

Question 38

What is a new innervate treatment?

Answer 38

Monoclonal antibodies used to increase removal of amyloid small proteins