L2 Motor System Disorders

Question 1

2 groups of neurodegenerative diseases

Answer 1

1. Conditions affecting memory and conditions related to dementia
2. Conditions causing problems with movements

Question 2

Examples of NDDs

Answer 2

Alzheimer’s, vascular dementia, Parkinson’s, Huntington’s

Question 3

What do NDDs have in common?

Answer 3

• Role of aging
• Glutamate excitotoxicity
• Mitochondrial dysfunction → oxidative stress
• Apoptosis
• Protein misfolding & aggregation
• Disruption of intracellular transport
• Neuroinflammation

Question 4

Average age of onset of PD

Answer 4

55

Question 5

What percentage of PD cases are familial?

Answer 5

~10%

Question 6

What genes are involved in autosomal dominant PD cases (rare)?

Answer 6

LRRK2
SNCA (encodes for α-synuclein production)

Question 7

What genes are involved in autosomal recessive PD cases?

Answer 7

Parkin, PINK-1, DJ-1

Question 8

Exposure to what toxin induces Parkinson’s-like symptoms?

Answer 8

MPTP

Question 9

Neuronal pathways affected by PD

Answer 9

Selective loss of dopaminergic neurons (therefore less GABA inhibition), while cholinergic neurons remain intact

Question 10

Main treatment for PD until L-DOPA was discovered

Answer 10

Atropine and related drugs

Question 11

What reestablish the balance between DA and ACh?

Answer 11

Muscarinic receptor antagonists

Question 12

What is the problem with anti-muscarinics?

Answer 12

Associated with troublesome side effects and are therefore now rarely used, except to treat Parkinsonian symptoms in patients on anti-psychotics (DA receptor antagonists → nullify effect of L-DOPA)

Question 13

Treatment strategies for PD to increase DA signalling

Answer 13

1. Increasing DA synthesis: L-DOPA (administered with DDC inhibitor)
2. Inhibiting DA catabolism: Selegiline (MAOB inhibitor), COMT inhibitors (Tolcapone, Entacapone)
3. Blocking uptake & enhancing release of DA: Amantadine
4. DA receptor agonists: Bromocriptine & Pramipexole

Question 14

Examples of DDC inhibitors

Answer 14

• Carbidopa
• Benserazide
• Methyldopa

Question 15

What type of disease is Huntington’s?

Answer 15

AD inherited NDD (no sporadic form)

Question 16

What causes HD?

Answer 16

An insertion of multiple CAG repeats in the huntingtin (HTT) gene, resulting in an N-terminal polyglutamine expansion of HTT

Question 17

What does disease severity in HD depend on?

Answer 17

the length of the polyQ stretch

Question 18

What suggests that HTT has a central role in cell functioning?

Answer 18

• HTT is highly conserved from Drosophila to humans
• HTT KO mice die at embryonic stage

Question 19

Neuronal pathways affected by HD

Answer 19

Some cholinergic neurons may be lost, but even more GABAergic neurons degenerate → more DA signalling

Question 20

Approved treatment for chorea (and hyperkinetic disorders similar to HD)

Answer 20

Tetrabenazine

Question 21

How does Tetrabenazine work?

Answer 21

Mainly as a VMAT-2 inhibitor, promoting the degradation of monoamines (in particular, DA)

Question 22

What was the first deuterated drug to have received FDA approval (in 2017)?

Answer 22

Deutetrabenazine (Austedo)

Question 23

All anti-psychotic drugs block __ receptors

Answer 23

D2

Question 24

200mg daily of what NMDA receptor antagonist likely moderately decreases HD chorea?

Answer 24

Riluzole

Question 25

Use of Amantadine in HD

Answer 25

Likely effective in decreasing chorea, but high doses can worsen cognitive function

Question 26

What is the most common motor neuron disease?

Answer 26

Amyotrophic lateral sclerosis

Question 27

What do most ALS patients die from?

Answer 27

Respiratory failure (usually within 3-5 yrs from onset of symptoms)

Question 28

True or False: Most ALS cases are sporadic.

Answer 28

True

Question 29

What is the only probable risk factor identified for ALS?

Answer 29

Smoking

Question 30

Most common causative gene mutation in ALS

Answer 30

SOD1

Question 31

Only approved drug for ALS in Europe

Answer 31

Riluzole

Question 32

How does Riluzole work?

Answer 32

- blocks NMDA receptors (inhibits Glu release, stimulates reuptake) - blocks voltage-gated Na⁺ channels

Question 33

What is Edaravone?

Answer 33

A potent radical scavenger used to treat ALS in Japan & US

Question 34

What is Albrioza?

Answer 34

Sodium phenylbutyrate and taurursodiol combination used to treat ALS

Question 35

4 main types of multiple sclerosis

Answer 35

- Progressive relapsing (PRMS) - Relapsing remitting (RRMS): ~80% of patients - Secondary progressive (SPMS) - Primary progressive (PPMS)

Question 36

What cells of MS patients are more reactive toward myelin components?

Answer 36

T cells (Th1, Th17)

Question 37

Examples of disease-modifying therapies for MS

Answer 37

- Fingolimod (Gilenya) - IFN-β (Avonex, Betaferon) - Nataliuzumab (Tysabri): anti-VLA4 mAb - Alemtuzumab (Lemtrada): anti-CD52 mAb

Question 38

Only FDA-approved DMT for PPMS

Answer 38

Ocrelizumab (Ocrevus): anti-CD20 mAb

Question 39

Agents targeting nucleic acid metabolism

Answer 39

- Mitoxantrone (Novantrone) infusion: topoisomerase II inhibitor - Oral Cladribine (Mavenclad): purine analog - Oral Teriflunomide (Aubagio): active metabolite of leflunomide, inhibits de novo pyrimidine synthesis

Question 40

Synthetic protein that mimics myelin basic protein

Answer 40

Glatiramer acetate (Copaxone) - induces switch from pro- to anti-inflammatory pathways

Question 41

What DMT for MS is based on a psoriasis treatment and induces a Th2 phenotype to cause immunosuppression?

Answer 41

Dimethyl fumarate (Tecfidera)

Question 42

__ are major targets for effective immunotherapy in relapsing MS

Answer 42

Memory B cells