Lecture 2- Motor Neurone Disease

Question 1

Onset of MND

Answer 1

50-60 years of age, onset rarer as you age

Question 2

lifetime risk of MND

Answer 2

1 in 300

Question 3

symptoms of MND

Answer 3

• loss of motor neuron circuitry- upper (motor cortex) and lower (brainstem)
• loss of voluntary motor function in bulbar, upper limbs, lower limbs

Question 4

regions of motor neuron loss

Answer 4

bulbar- speech, swallowing, face muscle, eye movement
upper limbs- paralysis and muscle wasting in hands, arms, chest
lower limbs- paralysis and muscle wasting in legs, trunk

Question 5

ALS functional rating scale

Answer 5

monitors loss of function over time by asking same questions

Question 6

respiratory function

Answer 6

loss of function is 100% fatal

Question 7

motor neuron degeneration

Answer 7

selective death of motor neurons, no transmission through circuitry, loss of muscle movement
neurogenic atrophy of skeletal muscles
- anterior ventral horn

Question 8

protein aggregation

Answer 8

genetic mutation or oxidation causes protein folding–>cytoplasmic accumulation and aggregation
TDP-43

Question 9

pathological protein in MND

Answer 9

TDP-43

Question 10

neuroinflammation

Answer 10

proliferation and activation of astrocytes and microglia

reactive gliosis, leads to glial scar (sclerosis)

Question 11

crossover with dementia

Answer 11

many MND patients, also experience FTD

Question 12

ALS-FTD spectrum

Answer 12

mutations that are more likely to result in symptoms of ALS or FTD
e.g . C9ORF72- 50% of either

Question 13

sporadic MND

Answer 13

90% of MND cases

Question 14

possible contributing factors to sporadic MND

Answer 14

genetic background, somatic mutation, development

Question 15

possible environmental factors for sporadic MND

Answer 15

smoking, chemical exposure, deployment, virus (integrate into DNA), blue-green algae, elite sports

Question 16

sporadic MND hypothesis

Answer 16

6 factors required to initiate disease process, towards end, rapid motor neuron loss

Question 17

familial MND

Answer 17

10% of cases, 25 genes identified so far

Question 18

6 implicated mechanisms in pathophysiology of MND

Answer 18

oxidative stress, mito dysfunction, excitotoxicity, protein aggregation, impaired axonal transport, neuroinflammation

Question 19

oxidative stress

Answer 19

ROS generation not controlled, reduced capacity to remove, oxidative damage

Question 20

mito dysfunction

Answer 20

ROS accumulation, mtDNA and protein damage, mito calcium homeostasis disrupted, apoptotic cell death

Question 21

excitotoxicity

Answer 21

elevated synaptic glumate levels and receptors on motor neurons
- excessive stimulation–>calcium influx–>neuronal injury

Question 22

protein aggregation

Answer 22

TDP-43

-defects in protein degradation e.g. ubiquitin proteasome system, autophagy

Question 23

impaired axonal transport

Answer 23

axonal transport of cargoes for motor neurons that are highly polarised and long projection cells
- slowing of axonal transport–>deficiency of cargoes in axons and distal synapses

Question 24

neuroinflammation

Answer 24

innate- CNS resident astrocyte and microglial activation
adaptive- peripheral lymphocytes e.g. T cells into CNS
- production of pro-inflammatory cytokines

Question 25

2 clinically approved drugs

Answer 25

Riluzole

edaravone

Question 26

riluzole

Answer 26

glutamate receptor antagonist

• attentuates excitotoxicity
• blocks Na channels, enhance glutamate uptake

Question 27

edaravone

Answer 27

antioxidant and free radical scavenger (removes ROS)

-may slow physical decline when administered early

Question 28

2 cell therapies using stem cells

Answer 28

1. replace lost neurons- but can’t reconnect motor neuron circuit
2. support surviving motor neurons- effectiveness not demonstrated