Neurodegeneration three - Alzheimer part one Flashcards
What is the definition of dementia?
Loss of intellectual functions (thought, memory) severe enough to interfere with daily living.
Is dementia a disease?
No, it is a collection of symptoms that accompany various diseases or conditions
What do the symptoms of dementia include?
Changes in mood, personality and behaviour
Is dementia reversible?
Not when caused by disease or injury
However if caused by drugs, alcohol, hormone/vitamin imbalance or dementia then it is.
Whats the prevalence of dementia?
Strongly correlates with age, nearly 70% by age 100 but beyond this it appears to plateau
Whats a major cause of dementia?
Alzhiemers
Whats the time course for dementia?
Around a nine year progressive deterioration in cognitive ability.
Whats a common disorder of dementia?
Behavioural disorders
What are some biomarkers/pathology for dementia?
Amyloid protein
Tau protein
Brain Atrophy
What are some characterisitic pathologies of alzhiemers?
Senile plaques (amyloid) Neuronal loss (frontal/temporal cortices and hippocampus) - brain atrophy Nueorfibrillary tangles (tau)
Do normal people have amyloid in their brain?
Yes-required protein
Whats the amyloid theory?
When theres too much amyloid protein it deposits elsewhere and is toxic (not where it should be)
Why is amyloid metabolism important?
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
What forms senile plaques?
Beta amyloid fragments that have coalesced from amyloid precursor protein
What are the neurofibrillary tangles?
Microtubules of tau protein that have disintergrated and clumped together (hyperphosphorylated) (intracellular)
Why do amyloid plaques and neurofibrillary tangles form?
No known cause yet
How are amyloid plaques toxic?
They disrupt Ca homeostasis and induce apoptosis.
Lot of build up of amyloid in mitochnodria too
What are some additional pathologies in AD?
Marked increase in inflammatory markers
Alteration of distribution of trophic factors such as BDNF too…
Describe the neuroanatomy progression of AD
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.
With regards to neuroanatomy what is the first major symptom and why?
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
What are the symptoms of dementia then?
Depends on where is damaged but associate the lobes with their functions por favor
parietal lobe - senosry dysfunction
Whats a major pathology of the brain?
Atrophy
on ct we can observe greater invaginations of sulci
What are some imaging tehcniques for Dementia?
MRI
CT
PET
Imaging used preferentially to confirm disease
Is AD or dementia genetic?
Yes they can be
Which chromosome are the genes for AD located?
21 which is why down syndrome people have early onset
What is the first target in the treatment of AD?
The cholinergic system
Why is the cholinergic system used to treat AD?
It produces symptomatic improvements
What happens when you decrease ACh production?
Sweating, salivation problems
What do you want to do to ACh transmission in AD?
INcrease it
How do you increase ACh transmission?
- ) Use ACh agonists
- ) Inhibit ACh esterase (most sucessful)
- ) Increase presynaptic activation
- ) Tweak the receptor, make it hypersenitive, or express its expression
Whats the only drug used in AD for cholinergic system?
ACh esterase inhibitor
Why target the cholinergic system?
Cholinergic neurons are preferentially lost especially in the synapse
What is the choloinergic system important for?
memory, sleep, arousal etc
Mostly alertness - which is why we target it, but has limited potential
What are some risk factors for AD?
Family history (10%) (non-mendellian inheritance) Down syndrome (100% over 40) Chronic hypertension/diabetes head injuries (2-3x more likely)
What are the characteristics of early stage AD?
- Begins with forgetfulness
- Progresses to disorientation and confusion
- personality changes
- Symptoms of depression/manic behaviour
What are the medical interventions of AD?
Medication - ACh inhibitors i.e aricept and cognex
Therapy for depression and counselling for families
What is the most common cause of death for AD?
Aspiration pneumonia
What is a new innervate treatment?
Monoclonal antibodies used to increase removal of amyloid small proteins
