Dementia Pathophysiology and Pharmacology

Question 1

what is dementia?

Answer 1

A disorder associated with impairment of memory, speech and language, comprehension, motor skills, judgement and orientation

Question 2

what is the pathology of dementia characterised by?

Answer 2

cell death in areas of the brain

Question 3

what age group are mainly affected by dementia?

Answer 3

over 65years

Question 4

what is the most common form of dementia?

Answer 4

Alzheimer’s disease

Question 5

what is Alzheimer’s disease?

Answer 5

an irreversible progressive disease that slowly destroys memory and thinking skills

Question 6

what are the senile plaques found in the cerebral cortex of alzheimers patients made of?

Answer 6

• extracellular - accumulation of insoluble fragments of beta-amyloid
• intracellular - accumulation of hyperphosphorylated tau strands

Question 7

what is the macro characteristic pathology of Alzheimer disease?

Answer 7

Ventricular enlargement, & hippocampal entorhinal and temporal cortex atrophy

Question 8

what is the micro characteristic pathology of Alzheimer disease?

Answer 8

Amyloid plaques, neurofibrillary tangles, neuronal loss in the hippocampus, Locus Coerulus, and raphe nuclei

Question 9

what is the molecular characteristic pathology of Alzheimer disease?

Answer 9

β-amyloid deposition (plaques), abnormal tau (tangles), synaptophysin (a synaptic vesicle protein) loss

Question 10

what is the neurochemical characteristic pathology of Alzheimer disease?

Answer 10

Cortical cholinergic loss (correlates with dementia), also see loss of 5-HT, NA

Question 11

what are β-amyloid plaques?

Answer 11

Dense deposits of protein and cellular material that accumulate outside the neurone

Question 12

what are neurofibrillary tangles?

Answer 12

Twisted fibers that build up inside the neurone

Question 13

what is the precursor to amyloid plaques?

Answer 13

amyloid precursor protein (APP)

Question 14

how does APP cause plaque formation?

Answer 14

1. APP sticks through the neuron membrane
2. enzymes cut the APP into fragments of protein including beta-amyloid
3. this leads to extracellular deposition of β-pleated assemblies of Aβ-peptides hence forming plaques
4. plaques in the hippocampus and cerebral cortex inhibit neuronal activity

Question 15

what is the role of tau

Answer 15

to stabilise the microtubules of neurones

Question 16

what happens to tau in alzheimers disease?

Answer 16

• it is abnormally phosphorylated and assembles into paired helical filaments.
• this causes the microtubles to collapse and the tau proteins aggregate into neurofibrillary tangles

Question 17

what are the 2 main acetyl choline pathways?

Answer 17

1. Nucleus basalis to the cortex

2. Pedunculopontine nucleus to thalamus

Question 18

what role does acetyl choline play in the Nucleus basalis to the cortex pathway?

Answer 18

learning and memory and is impaired in Alzheimer’s

Question 19

what role does acetyl choline play in the Pedunculopontine nucleus to thalamus pathway?

Answer 19

sleep, wake and sensory filtering

Question 20

what happens to acetyl choline (ACh) in alzheimers disease (AD)?

Answer 20

• atrophy of the nucleus basalis of Meynert causes reduced activity of the choline acetyltransferase enzyme
• resulting in reduced acetyl choline synthesis
• this then causes impaired memory in AD patients

Question 21

what do we give to tackle the depletion of acetyl choline levels in AD?

Answer 21

-acetylycholine esterase inhibitors

Question 22

give examples of acetylycholine esterase inhibitors?

Answer 22

1. donepezil
2. rivastigmine
3. galantamine
4. tacrine

Question 23

what are side effects to taking acetylycholine esterase inhibitors?

Answer 23

Bradycardia, GI complaints, Sleep disturbance

Question 24

why do we no longer use Tacrine as an acetylycholine esterase inhibitor?

Answer 24

because of its hepatotoxicity profile

Question 25

acetylycholine esterase inhibitors don’t treat alzheimes disease. So why do we give them to patients?

Answer 25

because they are efficacious in treating cognitive symptoms in Alzheimer’s

Question 26

where are donepezil and galantamine metabolised?

Answer 26

in the liver

Question 27

what hydrolyses rivastigmine?

Answer 27

cholinesterase (which is found in the synapse of ACh neurones)

Question 28

what are the adverse effects of donepezil?

Answer 28

nausea, vomiting, diarrhoea, muscle cramps

Question 29

what are the adverse effects of rivastigmine?

Answer 29

nausea, vomiting, diarrhoea, headache, dizzy

Question 30

what are the adverse effects of Galantamine?

Answer 30

nausea, vomiting, agitation, sleep disturbances

Question 31

what is given as an adjunct to cholinesterase inhibitors?

Answer 31

memantine which blocks glutamate excitotoxicity -NMDA antagonist