Dementia

Question 1

What differences between a dementia and a non dementia brain can be seen on a PET scan?

Answer 1

Neuronal loss
Hypometabolism
Loss of grey matter
Ligher

Question 2

In which 3 areas of function is there a progressive decline in ability in dementia

Answer 2

• Decline in memory and reasoning
• Decline in communication skills
• Inability to carry out daily activities

Question 3

What behavioural and psychological symptoms are seen in dementia

Answer 3

Agitation
Aggression
Wandering
Shouting
Repeated questioning
Sleep disturbance
Depression

Question 4

4 non-modifiable risk factors for dementia

Answer 4

• Age
• Genetic predisposition
• Family history
• Downs syndrome

Question 5

4 modifiable risk factor for dementia

Answer 5

• Vascular risk factor
• Cognitive inactivity
• Environment
• Depression

Question 6

What 2 structures can be seen in the brain in dementia

Answer 6

Plaques

Tangles

Question 7

What protein is present in senile plaques and cerebral vessels in alzheimers disease

Answer 7

Beta-amyloid peptide

Question 8

What protein is present in neurofibrillary tangles

Answer 8

Hyperphosphorylated tau protein

Question 9

Do cholinergic cells increase or decrease in number in AD

Answer 9

Decrease significantly

Question 10

What % of AD cases are classified as early onset

Answer 10

<5%

Question 11

Name the 3 genes identified to be involved in early onset AD

Answer 11

Amyloid precursor protein (APP)
Presenilin 1 (PSEN1)
Presenilin 2 (PSEN2)

Question 12

What kind of protein is amyloid precursor protein

Answer 12

Single transmembrane protein

Question 13

Where is APP expressed normally (4)

Answer 13

Neurones
Glial cells
Endothelial cells
SMC

Question 14

What is APP cleaved to form

Answer 14

Amyloidogenic A-beta peptides

Question 15

What are mutations in APP associated with

Answer 15

Familial forms of early onset Alzheimers

Cerebral amyloid angiopathy

Question 16

What does A673T mutation do

Answer 16

Decreases a-beta production and it protective of AD

Question 17

What does PSEN1 encode for

Answer 17

PSEN1 encoding presenilin-1

This is a subunit of gamma secretase

Question 18

How much mutations have been reported in

a) PSEN1
b) PSEN2
c) APP

Answer 18

a) 189
b) 24
c) 29

Question 19

What does PSEN2 encode for

Answer 19

Gamma sacretase- aspartyl protease responsible for A-beta generation

Question 20

What enzymes cleave APP (transmembrane polypeptide)

Answer 20

alpha, beta and gamma secretase

Question 21

Describe the APP processing pathway that is non-pathogenic

Answer 21

• Alpha and gamma secretase cleave APP
• Derives P3 and C83
• No AD

Question 22

Describe APP processing pathway that is pathogenic

Answer 22

• Beta and gamma secretase and generates a beta amyloid peptide (39-43)
• This is a pathogenic peptide

Question 23

What 2 explanations have been suggested to explain amyloid proteins involvement in AD

Answer 23

• Overproduction of amyloid and oligomers

- Inability to remove amyloid

Question 24

What are the sequence of steps that result in familial forms of AD (10)

Answer 24

• Genetic missence mutations in APP, PS1, PS2
• Increased proteolysis and production of APP
• Progressive accumulation of a-beta in brain interstitial fluid
• Deposition of aggregated A-beta40/ a-beta42 as plaques
• Inflammatory response
• Progressive neuritic injury within amyloid plaques
• Disruption of neuronal metabolism and ionic homeostasis
• Altered kinase/ phosphatase activity– hyperphosphorylated tau
• Formation of hyperphosphorylated tau protein
• Widespread neuronal/ neuritic dysfunction and death in hippocampus and cerebral cortex

Question 25

What is the inflammatory response seen in familial forms of AD

Answer 25

microglial activation | astrocytosis and acute phase protein release

Question 26

What gene is the strongest genetic risk factor for late onset AD

Answer 26

Apolipoprotein E

Question 27

What is apolipoprotein E

Answer 27

Secreted lipoprotein involved in cholesterol metabolism

Question 28

What are the 3 isoforms of ApoE and which is the greatest risk

Answer 28

ApoE2, E3 and E4

Question 29

Where is ApoE4 polymorphorphism located

Answer 29

Chromosome 19

Question 30

What does ApoE4 protein do

Answer 30

Decreases clearance of extracellular a beta

Question 31

What is the normal function of Tau protein

Answer 31

Stabilises microtubules through 4 tubulin binding domains in case of the longer isoform

Question 32

What is the effect of phosphorylating tau

Answer 32

- Binding of tau to microtubules normally maintained in equilibrium by kinases and phosphatases - Phosphorylation regulates activity to bind to microtubules and can affect axonal transport

Question 33

What is MAPT

Answer 33

Encodes microtubule associated protein Tau

Question 34

What form of dementia are MAPT mutations related to

Answer 34

Frontotemporal dementia

Question 35

How do amyloid csf levels change as disease progresses and why

Answer 35

They decrease because all amyloid goes into the plaques

Question 36

How do tau csf levels change as disease progresses

Answer 36

Increases

Question 37

3 blood based biomarkers seen in AD

Answer 37

Protein DNA/ RNA Lipids

Question 38

What are MRI used for in AD?

Answer 38

See things such as hippocampal loss | Ruling out of other causes

Question 39

Which cholinergic pathways degenerate in AD

Answer 39

Forebrain pathways innervating cortical and limbic structures

Question 40

Effect of blocking acetylcholinesterase

Answer 40

Increases failing cholingeric signal

Question 41

2 categories of drugs used to treat AD

Answer 41

Acetylcholinesterase inhibitors | NMDA receptor antagonists

Question 42

Name 3 acetylcholinesterase inhibitors | When are they used

Answer 42

Donepezil, galantamine and rivastigmine | Used for management for mild to moderate Alzheimers disease

Question 43

Name a NMDA receptor antagonist | When is it used

Answer 43

Memantine | Moderate Alzheimer's disease who are intolerant/ contraindication to AChE inhibitors

Question 44

Name some examples of disease modification therapies

Answer 44

``` Anti-fibrillation Secretase inhibitors Increased clearance Immunisation GSK3 inhibitors ```