Dementia

Question 1

What is dementia?

Answer 1

clinical syndrome characterised by a cluster of symptoms manifested by difficulties in memory, language, psychological changes and impairments in daily living

Question 2

What screening tests are there for dementia?

Answer 2

1. MMSE - out of 30 and consists of 11 questions
2. Montreal cognitive assessment - out of 30; visuospatial, naming, memory, attention, language, abstraction, recall
3. GPCOG - time orientation; information; recall test; clock drawing test

Question 3

What are the modifiable and non-modifiable risk factors of dementia?

Answer 3

Modifiable:

• vascular (high cholesterol, high BP, diabetes)
• cognitive activity
• environment (head injury)
• depression

Non-modifiable:

• age
• genetic predisposition
• family history
• down’s syndrome

Question 4

List the different types of dementia from most to least common.

Answer 4

Alzheimer's
Vascular 
Mixed
Dementia with lewy bodies 
Frontotemporal

Question 5

What are the 2 hallmarks of Alzheimer’s?

Answer 5

Amyloid beta plaques

Neurofibrillary tangles

Question 6

What 3 changes to the brain structure are seen with Alzheimer’s?

Answer 6

extreme shrinkage of the hippocampus
extreme shrinkage of the cerebral cortex
severely enlarged ventricles

Question 7

What genes are associated with early and late-onset Alzheimer’s?

Answer 7

Early:
APP
PSEN1
PSEN2

Late:
ApoE4

Question 8

What is APP, and how is it associated with Alzheimer’s?

Answer 8

APP = amyloid precursor protein
it is cleaved by alpha, beta and gamma-secretase
in the normal pathway alpha and gamma-secretase will cleave APP, favouring the non-amyloidogenic pathway
in the disease pathway, beta and gamma-secretase will cleave APP, favouring the amyloidogenic pathway and the formation of plaques

**plaques are associated with synapto- and neurotoxicity and therefore cause neurodegeneration

Question 9

What are PSEN 1 and PSEN 2 a subunit of? Which one is more common in AD?

Answer 9

gamma-secretase

PSEN1 is more common (early-onset AD)

Question 10

What is tau?

Answer 10

This is a microtubule-associated protein

it is responsible for stabilisation and axonal transport

Question 11

How can tau contribute to the development of AD?

Answer 11

Tau microtubule binding is maintained by coordinated actions of kinases and phosphatases
Kinase can cause tau to become hyperphosphorylated and this results in the formation of neurofibrillary tangles

Question 12

What channels does acetylcholine bind to?

Answer 12

Nicotinic = ion gated + selective for certain cation 
Muscarinic = GPCR; M1-5; modulate a wide variety of ion channels

Question 13

When are acetylcholinesterase inhibitors used in AD? How effective are they? Give examples.

Answer 13

used for those with mild to moderate AD
improve symptoms (reduced anxiety, improve motivation, memory and concentration; improve ability to continue daily activities) but are not DMTs
examples: donepezil; galantamine; rivastigmine

Question 14

Why is acetylcholinesterase a target for treatment in AD?

Answer 14

There is degradation/loss of cholinergic neurones in the nucleus basalis of meynert, therefore preventing the breakdown of acetylcholine will alleviate the effects of the degradation/loss

Question 15

When are NMDA receptor antagonists used in AD? How effective are they? Give examples.

Answer 15

Used for moderate to severe AD + those intolerant to AChE inhibitors
Reduce glutamate excitatory neurotoxicity and have a small but clinically appreciable benefit on slowing the progression of the symptoms
Example = memantine

Question 16

What are the side effects of memantine?

Answer 16

Dizziness
headaches
tiredness

Question 17

Where are the 2 sites fo action of nitromemantine that allow antagonism of the NMDA receptors?

Answer 17

1) ion channel (memantine acts here)

2) extracellular surface –> where nitro group reacts with a cysteine-thiol group reducing NMDAR activity