Lecture 45: Amytrophic Lateral Sclerosis

Question 1

ALS is the most common form of what disease?

Answer 1

Motor neuron disease (75%)

Question 2

What part of the motor tract experiences symptoms from ALS?

Answer 2

UMNS and LMNS

• Limb onset (~70%)
• Bulbar onset (~25%)
• Resp onset (~2-3%)

Question 3

What is the general onset/prognosis of ALS?

Answer 3

Limbs/Speech and swallowing/breathing issues

• Cognitive decline (FTD)
• Median life expectancy (3 years)

Question 4

What are the risk factors for ALS?

Answer 4

5-10% is familial (Gene mutations not the only factor)

Multistep hypothesis (environment + genetics, six steps or exposures required)

Question 5

What are the environmental risk factors for ALS?

Answer 5

• US military service
• Electromagnetic fields
• Agricultural chemicals
• Head injuries
• Smoking
• Professional football

Question 6

What can the symptoms of ALS be divided into?

Answer 6

UMN signs and LMN signs

Question 7

What are the UMN signs of ALS?

Answer 7

• Spasticity / Stiffness
• Increased stretch (tendon) reflexes
• Babinksi reflex (upwards?)

Question 8

What are the LMN signs of ALS?

Answer 8

• Weakness
• Muscle atrophy
• Decreased muscle tone (flaccidity)
• Decreased stretch reflexes
• Muscle dennervation;
  -> Fasiculations
  -> Fibrillations
  Normal flexor plantar response i.e no babinski reflex

Question 9

Describe the specific components of the motor pathway impacted in ALS:

Answer 9

UPN (glutamatergic, betz cell layer)
Corticobulbar (bublar, CN symptoms)
Corticospinal
LMN (Brainstem motor nuclei and SC AHC)
-> Ach, alpha motor neuron (fast type) most affected

Question 10

In bulbar onset ALS which cranial nerves are affected?

Answer 10

Motor components of:

• Trigeminal (Chewing/Biting)
• Facial (Expressions)
• Glossopharyngeal (Swallowing)
• Vagus (Swallowing/speech)
• Accessory (Head/shoulder movements)
• Hypoglossal (Tongue movement)

Question 11

When it comes to LMN, which groups of muscles are preserved?

Answer 11

• Occular CNs preserved
• Onufs nucleus preserved = anal and urinary sphincter functions

Slow twitch motor units can compensate by re-innervating the denervated fibres by surviving MNs)

Question 12

Describe the pathogenesis of ALS:

Answer 12

Lateral sclerosis
- Loss of neurons (early and substantial loss of LMN and UMN)
Remaining neurons have protein aggregates in them (also glia)
-> TDP-43 protein aggregates most common

Muscles
- Denervation/NMJs compromised

Question 13

Given the that genetic mutations tend to result in TDP-43 aggregates, whats do aggregates indicate?

Answer 13

Aggregates indicate presence of toxic soluble oligomers

Question 14

What do TDP-43 aggregates correspond with?

Answer 14

• Disabling motor symptoms (weakness, atrophy)

- ~50% also have mild FTD

Question 15

What can cells do to try and protect itself from TDP-43 aggregates?

Answer 15

• TDP-43 is clumped into globular or filamentous shapes in the cytoplasm, instead of diffuse in the nucleus
• TDP-43 in aggregates is hyperphosphorylated and decorated with waste disposal markers