Lecture 13; Movement disorders 2

Question 1

What conditions affect neuron cell bodies?

Answer 1

ALS (mainly looked at)

Poliomyelitis

Question 2

What is poliomyelitis?

Answer 2

Oral viral infection that acutely degenerates motor neurons

Question 3

What is polio?

Answer 3

RNA virus, highly contagious

Question 4

When and how was polio brought under control?

Answer 4

1950s by vaccination

Question 5

What is a modern application now of polio virus?

Answer 5

Genetically modified polio virus treatment of glioblastoma.

• Rapid growing tumor
• Stereotaxic injection

Question 6

What are some other names for ALS?

Answer 6

MND motor neuron disease

Lou Gehrigs disease

Question 7

What is ALS?

Answer 7

Motor neuron disease

- Affects cell bodies

Question 8

Describe the progression of ALS;

Answer 8

Develops slowly over months/years

Progressive disease

Starts at a very young age

Question 9

How does polio affect MNs?

Answer 9

Acute damage to cell bodies

- Virus is specific to cell bodies and these dont regenerate

Question 10

What is the symptoms of polio?

Answer 10

Paralysis, atrophy, but do survive

Question 11

Describe where ALS affects;

Answer 11

Sclerosis = hardening

ALS = Hardening of the lateral aspect of the spinal cord, glial cells replace dead motor neurons (gliosis)

Question 12

Whats the incidence of ALS?

Answer 12

5/100,000

Typically onsets at 5th decade of life

Question 13

Is ALS genetic?

Answer 13

90% non family history

Question 14

Describe the genetic variant of ALS;

Answer 14

Rare familial form of ALS with dominant inheritance

Mutation of some genes i.e superoxide dismutase

Question 15

Describe the symptoms of ALS;

Answer 15

Progressive wasting, weakness and atrophy of muscles leading to paralysis

• Weakness of legs, arms and hands
• Difficulty with speech and swallowing
• Impairment of respiration

Smooth muscle affected
Muscle stretch reflexes exaggerated and muscle (tone) spasticity

Question 16

Whats the survival outcomes of ALS?

Answer 16

Death usually 2-3 years, rare benign forms that last 10+ years

Question 17

What are some EMG affects of ALS?

Answer 17

Muscle denervation; Fasiculations and Fibrillations

Fasciculation’s : Twitching ; electrophysiologically unstable motor units

Fibrillation ; Individual muscle fibres (spontaneous AP)

Question 18

What are the exceptions in ALS?

Answer 18

• No involvement of extraocular muscles
• No involvement of sphincters
• Usually no intellectual or sensory deficits

Motor neurons of extraocular muscles are protected, this is unknown why

Lots of other diseases have sensory affects

Question 19

Describe specifically what is degenerated that leads to the muscle wasting and atrophy?

Answer 19

a) Motor neurons of the spinal cord with the exception of those controlling sphincters
b) Motor neurons in the brain stem ; with the exception of CN 3,4,6

a+b degeneration = muscle wasting + paralysis

Question 20

What does the degeneration of upper motor neurons lead to?

Answer 20

** misleading, it is actually pyramidal cells in the cortex, they become more excitable = increase reflexes, tone, spasticity DESPITE degeneration

Question 21

What is the current pathogenesis hypothesis regarding ALS?

Answer 21

Oxidative stress hypothesis

Excitotix hypothesis

TDP 43 / FUS mutation

Question 22

Describe the oxidative stress hypothesis;

Answer 22

Damage to neurons by free radicals (reactive oxygen and nitrogen species) when radical production exceeds the detoxification capacity of the specific enzymes (glutathione oxidase, superoxide dismustase, catalase

Question 23

What is a rare familial form of ALS?

Answer 23

Mutations of superoxide dismutase (10%)

Question 24

What is the excitotoxic hypothesis?

Answer 24

Excessive AMPA and NMDA activation by glutamate

Question 25

What is the first possible cause of the excitotoxic hypothesis?

Answer 25

1) Increased EC glutamate because of decreased activity of astrocytic glutamate transporter GLT-1

Question 26

What is the second possible cause of the excitotoxic hypothesis?

Answer 26

Decreased GluR2 expression (as a subunit of the AMPA receptor)

Motor neurons of ALS have lower GluR2 subunits in their AMPA receptors, predisposing them to higher Ca influx

(GluR2 mutation results in the AMPA becoming permeable to Ca)

Question 27

What is the TDP-43/FUS mutation hypothesis?

Answer 27

TDP-43 and FUS are proteins involved in protein processing and are normally found in the nucleus.

In some forms of FAMILIAL ALS genes for these proteins mutate and they are shifted to the cytoplasm and form agregates the affect motorneuron function (Choke Function)

Question 28

What are the treatments for ALS?

Answer 28

No effective drugs available to alter or halt the disease progress

but can fix symptoms and improve the quality of life.

Question 29

Do antioxidants help?

Answer 29

No clear effects (vitamin C,E)

Question 30

Whats a drug that can target glutamate release?

Answer 30

Riluzole (small benefit) blocks glutamate release and can slow the disease progress by a couple of months

Question 31

Whats a drug that is in phase 3 clinical trial?

Answer 31

Dexpramipexole; improves mitochondiral function and reduces oxidative stress

Question 32

Whats a drug that reduces spasticity?

Answer 32

Baclophen (GABA-B agonist), reduces spasticity

Question 33

What is some other experimental treatments?

Answer 33

Experimental replacement or trophic therapy using genetically modified cells or stem cells. (replace the defective astrocytes that dont transport glutamate)