PH2113 - Neurodegenerative Disease and Epilepsy 5

Question 1

How long does it take for dementia to take place?

Answer 1

3 to 20 year duration
- 7 to 10 more common

Question 2

What is the incidence of dementia in the UK?

Answer 2

Increases with age
- > 65, 1 in 14 have dementia
- > 80, 1 in 6 have dementia

850,000 people in the UK

Question 3

What is Alzheimer’s disease?

Answer 3

2 types of pathology
- amyloid plaques
- extracellular
- contain beta-amyloid
- neurofibrillary tangles
- intracellular
- contain hyperphosphorylated tau

Question 4

What is the amyloid hypothesis regarding the proteins involved in Alzheimer’s disease?

Answer 4

Amyloid-beta cleaved from amyloid precursor protein (APP) by sequential action of beta and gamma secretases
- build up of amyloid-beta is crucial event
- drives Alzheimer’s disease
- normally monomeric and soluble
- oligomerises (soluble)
- toxic form
- cellular stress
- membrane
- mitochondria
- endoplasmic reticulum
- synaptic changes
- synaptic loss
- possibly changes in tau
- eventual neuronal death
- oligomers become insoluble
- insoluble
- fibrils
- plaques

Question 5

How does tau accumulation lead to Alzheimer’s disease?

Answer 5

Naturally occurring axonal protein
Stabilises microtubules
Abnormally phosphorylated in Alzheimer’s disease
- forms neurofibrillary tangles (NFTs)
- results in cytoskeletal disrupts
- altered protein transport to and from dendrites
- neuronal death

Question 6

What is the progression of Alzheimer’s disease?

Answer 6

Pathology appears sequentially
- amyloid-beta -> tau -> death
Good correlation between severity of dementia and neurofibrillary tangles
Early Alzheimer’s disease
- mild forgetfulness
Advanced Alzheimer’s disease
- limbic
- hippocampus
- amygdala
- decreased knowledge of recent/life events
- changes in behaviour
- agitation
- depression
Severe Alzheimer’s disease
- no longer recognise family and friends
- don’t understand language

Question 7

What are the causes of Alzheimer’s disease?

Answer 7

Early onset (as early as 40)
- familial
- strong genetic component
Late onset (> 65)
- sporadic

Question 8

What are the problems with diagnosing Alzheimer’s disease?

Answer 8

Amyloid-beta levels start to increase many years before memory symptoms become obvious
- 10 - 15 years
- hard to detect amyloid-beta and tau

Question 9

How is Alzheimer’s disease diagnosed?

Answer 9

Scans
- MRI
- CT
- PET
Cognitive tests
- Mini Mental State Examination (MMSE)
- MMSE 21 - 26
- mild
- MMSE < 10
- severe
Post-mortem

Question 10

What are the treatments for Alzheimer’s disease?

Answer 10

All symptomatic
- do not affect underlying disease process
- incurable
Treat cognitive symptoms
- acetylcholinesterase inhibitors
- mild
- moderate
- NMDA receptor antagonist
- severe Alzheimer’s disease
Must be started by specialist clinician
NICE
- patient-centred care
Treat non-cognitive symptoms
- behavioural
- psychological symptoms

Question 11

What is the mechanism of NMDA receptor antagonist Memantine in the role of excitotoxicity in Alzheimer’s disease? (usual MOA and drug MOA)

Answer 11

Excessive glutamate release activates NMDA receptors and voltage operated calcium channels
- VOCC
which results in Calcium influx
- toxic
leads to the Formation of reactive oxygen species
- mitochondrial damage
- oxidative stress
- activation of proteases and endonucleases
- neuronal death

This drug inhibits calcium influx into cells that is normally caused by chronic NMDA receptor activation by glutamate

Continuous activation of the N-methyl-D-aspartate (NMDA) receptors in the central nervous system caused by glutamate is thought to cause some of the Alzheimer’s disease symptoms.
the drug’s behavior as an uncompetitive (open-channel) NMDA receptor antagonist, preventing glutamate action on this receptor.

Question 12

What medications are available to treat non-cognitive symptoms of Alzheimer’s disease?

Answer 12

Anxiolytics
- anxiety
Anti-psychotics
- severe confusing
- paranoia
- hallucination
- NOT recommended for mild cognitive symptoms
- use at lowest effective dose for shortest time possible
- review every 6 weeks
- risk/benefit analysis needed
Psychological treatments
- CBT
- considered initially for mild-moderate Alzheimer’s disease with mild-moderate depression
Antidepressants
- often ineffective
- use for patients with pre-existing severe conditions

Question 13

What is the incidence of Multiple Sclerosis?

Answer 13

90,000 - 100,000 in the UK
2,000,000 Worldwide

Question 14

When is the onset of age with Multiple Sclerosis?

Answer 14

Between 20 and 40 years of age
- presentation peaks around 25 years of age

Question 15

What effect does Multiple Sclerosis have on life expectancy?

Answer 15

Reduced by 10 - 15 years
- secondary infections

Question 16

Which populations are more likely to suffer from Multiple Sclerosis?

Answer 16

More common in women
- F > M 2:1
More common in temperate regions as move away from equator

Question 17

What is Multiple Sclerosis?

Answer 17

Disturbance of immune system within CNS
Chronic, progressive neurological diseases
Characterised by scattered demyelination of nerve fibres in the brain and spinal cord

Question 18

What are the symptoms of Multiple Sclerosis?

Answer 18

Fatigue
Vision problems
Muscle weakness
- 50% need a stick to walk after 20 years
- 50% eventually have cognitive problems
Depression
- 3x more common

Depends on the location of the inflammations in the CNS
Lesions in certain sites are more common
- optic nerves
- neurones near ventricles
- axons within spinal cord