4. Treatment of neurodegenerative disorders

Question 1

Name 8 neurodegenerative diseases?

Answer 1

• Parkinson’sdisease
• Alzheimer’sdisease
• Huntington’sdisease
• Motorneurone diseases (Amyotrophic lateral sclerosis (ALS), Progressive bulbar atrophy; primary lateral sclerosis; spinal muscular atrophy etc)
• Spinocerebellardegenerations
• Spongiformencephalopathies
• FTD,otherdementias
• ProgressiveMS

Question 2

Genes associated with AD?

Answer 2

Amyloid precursor protein gene on Chr 21 (15% of early onset cases)

Presenilin-1 gene- Chr 14 in 80% of early onset cases

Presenilin-2 gene on Chr 2 in 5% of early onset cases

Question 3

ALS?

Answer 3

Amyotrophic lateral sclerosis

Question 4

Gene involved in ALS?

Answer 4

• Superoxide Dismutase1: Deals with Free radicals 
• TARDNA Binding
Protein (TDP-43)
• Fused in Sarcoma (FUS)
• C9orf72 (most common)

Question 5

Neuro-degeneration, effect of too much calcium?

Answer 5

Too much Ca2+ (Stimulated by too much cell excitation from Glutamate) —> Neuro degeneration
Excess Ca2+ encourages neurodegeneration by:
1. Production of protease’s and NO which DAMAGE THE MEMBRANE
2. Stimulates glutamate release which enhances cycle more

Note: Free radicals important as also cause MEMBRANE DAMAGE. Free radical scavengers used to minimise this.

Question 6

Name 5 motorneurone diseases

Answer 6

• Amyotrophic Lateral Sclerosis (UMN &LMN)
• Progressive Muscular Atrophy (LMN)
• Primary Lateral Sclerosis (UMN)
• Spinal Muscular Atrophy
• Lou Gehrig’s disease

Question 7

Drug used for ALS?

Answer 7

Riluzole

Can prolong likfe by 3 months, is expensive

Question 8

Mechanism of Riluzole?

Answer 8

• Blocks TTX Na channels
• Reduces Glutamate release (? Calcium block) • Increases astrocyte glutamate uptake
• Enhances GABA activity (inhibitory pathway)
• Enhances BDNF action (NF= neurotrophic factor)

Question 9

Epidemiology of Alheimzers disease?

Answer 9

• 70% all cases of dementia
• Prevalence of AD 1% at 65, 40% at 90 (doubles every 5 years)
• Female predominance
• 10% familial

Question 10

Presentation of alheizmers?

Answer 10

• Presents with early memory disturbance, progressing to dyspraxia and dysphasia, eventually immobile and mute

Question 11

Histological identifiers of AD?

Answer 11

1. Neurofibrillary tangles
   • predominantly composed of tau
   • normal tau stabilises microtubules
   • tau is hyperphosphorylated in NFTs and forms paired helical filaments
2. Amyloid plaques
   • Extracellular proteinaceous deposits
   • Largely composed of Aβ peptides – either diffuse or neuritic (surrounded by dystrophic neurites)

Question 12

What is the main component of amyloid plaques?

Answer 12

a-Beta peptide –> A-betta aggregates –> Amyloid fibrils

Due to cleavage at beta-secretase and gamma-secretase cleavage sites.

Question 13

History of immunisation against beta amyloid/Tau as a treatment for AD

Answer 13

• AN 1792 active immunisation —> 2002: 18/300 developed MENINGO-ENCEPHALITIS
Result from post mortem: Amyloid removed but neurodegeneration continued
• Bapineuzumab (aab-001) passive transfer in phase III ineffective, some inflammation
• New trials using anti-Tau and anti-Ab

Question 14

In the brains of people with alzheimers disease, what are the neurochemical changes seen?

Answer 14

• Loss of ACh (due to neuronal loss from nucleus basalis of Meynert)
• Loss of GABA from cortex secondary to neuronal loss
• Loss of Serotonin (5HT) input from dorsal raphe nuclei.
• Loss of Noradrenaline input from locus ceruleus

Question 15

Treatment of dementia

Answer 15

• Acetylcholinesterase inhibitors; donepezil, galantamine, rivastigmine used in mild to moderate dementia.
• NMDA receptor antagonists e.g. memantine used in moderate to severe DAT.

Question 16

What is the ADAS-cog?

Answer 16

Alzheimer’s Disease Assessment Scale-Cognitive Subscale test
• measure of cognitive performance

In many different actions:
It primarily measures language and memory. The ADAS-Cog consists of 11 parts and takes approximately 30 minutes to administer. Tests cognitive and non-cognitive function (e.g. mood and behaviour)
Looks at...
1. Word Recall Task
2. Naming Objects and Fingers
3. Following Commands
4. Constructional Praxis
5. Ideational Praxis
6. Orientation
7. Word Recognition Task
8. Remembering Test Directions
9. Spoken Language
10. Comprehension
11. Word-Finding Difficulty

Question 17

What is the best place of measurement for the ADAS-cog?

Answer 17

Not mild dementia.

Pretty demented

Question 18

Problem with ADAS-cog?

Answer 18

Not specific, two point different have unknown meaning

Can only be used for patients that are relatively demented.

Question 19

What is the current knowledge of MS disease progression?

Answer 19

MS usually starts with relapses and remissions
From scanning and pathology, there is initially non presenting inflammation. Over years there is slow degeneration
Then relapses stop, you just get progressively worse.
Treatment in relapsing phase but not in deterioration stage.

Question 20

Cannasbis as a treatment for MS?

Answer 20

Treats pain and spasticity

Question 21

Role of endogenous cannabinoid in brain injury

Answer 21

2-AG release after head injury = neuroprotection

Evidence to suggst these drugs encourage myelination and repair of nerve cells after damage.

Question 22

Disease modification as a result of cannabinoids?

Answer 22

Anti-inflammatory
Anti-exoidant
Anti-apoptotic
Microglial activation
Microglial migration
Ca2+ flux

Question 23

EDSS scale for MS?

Answer 23

0 = normal
10= death from MS

Between the walking phase is becoming increasingly impaired.

Question 24

Possible explanations for MS drug trials being unsuccessful?

Answer 24

• Drug doesn’t work
• Population not changing, so won’t see effect
• Measurement instruments inadequate
• Higher levels disability beyond potential help
• Differential effects at different levels (e.g anti- spasticity effect)