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Motorneurone disease (done) Flashcards

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1
Q

What are the 3 most prevalent neurodegenerative disorders?

A

AD & PD

MND is 3rd most common

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2
Q

What is the prevalence of MND?

A

0.4-1.8/100,000 ppl

1.6 male : 1 female

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3
Q

What is the avg age of onset of MND?

A

40-60 yrs

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4
Q

What are the main symptoms of MND?

A
  • Muscle contractions weakness
  • Loss of muscle mass
  • Inability to control movement
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5
Q

What are the general causes of MND?

A

Progressive DEGENERATION of MNs in brain & SC innervating (skeletal) voluntary muscles

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6
Q

What is the median survival of MND?

A

4 years (up to 20 yrs)

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7
Q

What are the general causes of death in MND?

A
  • Respiratory weakness
  • Pneumonia

There are currently no effective treatments

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8
Q

How did we know that is was degeneration of Mrs causing MND?

A

Duchenne = 19th century

Found muscle could still contract, so MN innervation must be impaired

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9
Q

What are the 4 major types of MND & why do are they different?

A

There are 4 types of MND depending on which MNs are affected:

  • Amyotrophic Lateral Sclerosis (ALS)
  • Progressive Bulbar Palsy (PBP)
  • Progressive Muscular Atrophy (PMA)
  • Primary Lateral Sclerosis
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10
Q

What is the most common type of MND & when is the median onset of it?

A

ALS –> median onset ~60 y/o

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11
Q

What are the symptoms of ALS?

A

Weakness & wasting in limbs

Muscle stiffness & cramps

Affects tongue, hand & leg muscles first

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12
Q

What is the mechanism of ALS?

A

Degeneration of all MNs, both upper & lower

Loss of ACh tone at NMJ = loss of muscle tone

Eye movement (extra-ocular muscles) usually spared –> preserves sensations & cognitive function

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13
Q

What is the median survival of ALS?

A

2-5 yrs

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14
Q

What are the 2 types of MNs that can be affected & where of each of them originate & run to?

A
  • Upper MNs = come down from cell bodies in primary motor cortex –> into SC
  • Lower MNs = Alpha MNs that go from central horn of SC to muscle
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15
Q

What is the:

  • Prevalence
  • Onset
  • Symptoms
  • Mechanisms & regions
  • Special characteristics
  • Life expectancy

of Progressive Bulbar Palsy (PBP)?

A
  • Prevalence = common (~10%)
  • Onset = ~70
  • Symptoms = No peripheral/spinal symptoms in first 6 months –> tongue wasting & fasciculation
  • Mechanisms & regions = Brainstem MNs
  • Special characteristics = Rapidly progressing form of ALS (begins w upper NMs)
  • Life expectancy = 0.5-3 yrs
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16
Q

What is the:

  • Prevalence
  • Onset
  • Symptoms
  • Mechanisms & regions
  • Special characteristics
  • Life expectancy

of Progressive Muscular Atrophy (PMA)?

A
  • Prevalence = rare (4-5% MND)
  • Onset = ~60
  • Symptoms = Wasting & functional disability of arms/legs - other regions spared
  • Mechanisms & regions = Lower MNs only
  • Special characteristics = Flail arm more common in men - slower progression
  • Life expectancy = 4-6 yrs
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17
Q

What is the:

  • Prevalence
  • Onset
  • Symptoms
  • Mechanisms & regions
  • Special characteristics
  • Life expectancy

of Primary Lateral Sclerosis?

A
  • Prevalence = V rare (1-3& MND)
  • Onset = >50
  • Symptoms = Little/no muscle wasting, stiffness, pain & spasticity in lower limbs
  • Mechanisms & regions = Upper MNs only
  • Special characteristics = Slow progressing - mild cog changes –> may progress to ALS
  • Life expectancy = progressive but non fatal
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18
Q

What is Spinobulbar muscular atrophy (SBMA)?

A
  • Not MND - similar but not the same w similar prevalence to MND
  • Lower MNs & peripheral muscles affected
  • Does not affect life expectancy
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19
Q

Physical symptoms are not the only symptoms that occur in MND - what are the other ones?

A

Cognitive & behavioural

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20
Q

What are the cognitive symptoms of MND?

A
  • 35% of ppl have mild cog change affecting executive functions
  • Such as planning, decision making & language
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21
Q

What are the behavioural symptoms that can occur w MND?

A
  • 5-10% show signs of frontotemporal dementia (FTD)
  • This results in pronounced behavioural changes
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22
Q

How do symptoms vary in MND patients?

A
  • Not all symptoms will affect everyone or in the same order
  • Symptoms will progress at varying speeds –> makes disease difficult to predict
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23
Q

What are the 6 methods that can be used to diagnose MND?

A

1 - Clinical examination

2 - Blood tests

3 - Electromyography (EMG)

4 - nerve conduction tests

5 - Transcranial Magnetic Stimulation (TMS)

6 - MRI

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24
Q

How is a clinical examination used to diagnose MND?

A

Main way to diagnose

Physical examination to identify cardinal symptoms –> muscle weakness/wasting

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25
Q

How can blood tests be used to diagnose MND?

A
  • Inc levels of creatine kinase (muscle breakdown releases this)
  • Problem = not specific to MND –> (also from heart attack, muscle injury, alcohol abuse & medicine)
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26
Q

How can electromyography (EMG) be used to diagnose MND?

A
  • Fine needles record impulses w/in certain muscles
  • Good for detecting early changes - even if muscle activity seems normal
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27
Q

How can nerve conduction tests be used to diagnose MND?

A
  • Electrical impulse applied thru a small pad on skin
  • Measures compound muscle AP, condition velocity & latency
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28
Q

How can transcranial magnetic stimulation (TMS) be used to diagnose MND?

A
  • Stimulates & measure threshold & response of upper MNs
  • More modern technique - strong mag field is used to dampen/induce activity in brain (so can look at upper MNs properly)
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29
Q

How can MRI be used to diagnose MND?

A
  • Not actually used to diagnose MND itself –> used to rule out other diseases
  • (e.g. AD, PD, MS, tumours or brain injury)
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30
Q

What does the World Federation of Neurology El Escorial criteria for ALS look for in general?

A

There are many criteria but the main thing looked for is:

For the symptoms to be progressive & spreading (can also look for problems in certain areas)

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31
Q

What are the 5 main descending motor pathways that undergo neurological changes in MND?

A
  • Brain stem & cranial MNs
  • Corticospinal tract
  • Spinal a-motor neurons
  • Bulbospinal neurons
  • Ventral horn
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32
Q

What happens in MND when there is changes in the Brain stem & cranial MNs?

A

Upper MNs:
- Eyelids start to droop
- Speech impaired

Brian stem:
- Tongue & facial muscles

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33
Q

What happens in MND when there is changes in the corticospinal tract?

A
  • Degeneration in ALS
  • Causes spasticity

Bc messages cannot get down from upper MNs or bulbospinal tract

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34
Q

What happens in MND when there is changes in a-motor neurons?

A

Issues w legs arms & diaphragm

Changes in these MNs lead to:
- Fasticulation (muscle twitching)
- Muscle wasting
- Weakness
- Hypertonia
- Eventually respiratory failure

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35
Q

How does the ventral horn of SC change in MND?

A
  • Ventral horn shrinks
  • You get ghost cells & filaments, theses = spheroids
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36
Q

What are ghost cells & spheroids (found in ventral horn of SC in MND)?

A

Got cells = lost the contract around outside of the cells

Spheroids = occur inside these & are created by misfolded proteins

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37
Q

What does the changes in the ventral horn lead to, causing MND?

A
  • Dec activity of ChAT (this makes ACh)
  • Nerve conduction is mostly normal
  • But there is decreased MN terminal sprouting
  • Also see inc glutamate levels in CSF
38
Q

What % of ALS cases are genetic?

A

5-10% –> can be autosomal dominant mutation or autosomal recessive

39
Q

What are the AD mutations known to cause ALS (MND)?

A

1 - A9ofr72 gene, chromosome 9

2 - SOD1 (superoxide dismutase), chromosome 21

40
Q

How common is the A9ofr72 gene, chromosome 9 (AD) mutation in ALS (MND)?

A
  • Mutations found in 25-40% familial
  • 7% sporadic ALS
  • 25% FTD cases
41
Q

How does the A9ofr72 gene, chromosome 9
mutation (AD) cause ALS?

A
  • Highly expressed in MNs - influences mRNA production
  • Mutations in GGGGCC expansion –> 30+ in ALS
42
Q

What is the prevalence of the SOD1 mutation (AD) in MND (ALS)?

A
  • 10-15% familial
  • 1-2% sporadic
43
Q

How does the SOD1 mutation (AD) cause MND?

A
  • SOD1 is an anti-oxidant –> converts superoxide (O-2) to hydrogen peroxide & oxygen (H2O2 & O2)
  • Mutant SOD1 aggregates & forms clumps –> affects all MNs
44
Q

What is the autosomal recessive mutations known to cause ALS (MND)?

A

1 - ALS2, chromosome 2q33

45
Q

How does the ALS2 (AR) mutation cause ALS?

A
  • Encodes ALSIN - found in all MNs
  • Guanine exch factor involved in recycling of G protein
  • Involved in development of axon & dendrites. Essential for transmission of nerve impulses

2 forms:
- Long form = neuroprotective
- Short form = ALS

46
Q

What form of ALS does the Vesicle-asociated membrane protein B, chromosome 20q13.3 mutation cause?

A

Atypical late-onset form of ALS

(Not sure if AD or AR)

47
Q

What does the Vesicle-asociated membrane protein B mutation do to cause ALS?

A

Causes dysfunction of intracellular membrane trafficking

48
Q

What sort of ALS is the Sentaxin gene, chromosome 9 (AR) mutation linked to?

A

Rare, autosomal dominant juvenile ALS

49
Q

How does the Sentaxin gene mutation cause ALS?

A

It affects DNA/RNA helices controlling RNA processing

50
Q

What mutation leads to atypical late-onset form of ALS?

A

Mutation in

Vesicle-asociated membrane protein B, chromosome 20q13.3

51
Q

What mutation causes rare, AD juvenile ALS?

A

Sentaxin gene, chromosome 9

52
Q

Name 2 other mutations involved in ALS?

A
  • TARDEP
  • FUS
53
Q

How does the TARDEP mutation cause ALS?

A

TAR DNA binding protein, involved in transcription –> forms aggregates in ALS

54
Q

How does the FUS mutation cause ALS?

A

Fused in sarcoma

RNA binding protein, involved in: transcription, DNA repair & RNA splicing

FUS aggregates found ing MNs in sporadic ALS

55
Q

What % of MND cases have no known family history (sporadic)?

A

90%

56
Q

What are the 5 known causes of sporadic MND?

A
  • Gene mutations
  • Chemical imbalances (glutamate)
  • Protein mishandling
  • Disorganised immune response
  • Environmental toxin
57
Q

How are gene mutations known to cause sporadic MND?

A

Twin studies have shown 60% heritability

These gene mutation occur during lifetime - must be some sort of genetic element

58
Q

How can chemical imbalance cause sporadic MND?

A

Ppl w MND have high glutamate levels in CSF

Too much glutamate = toxic to nerve cells

59
Q

How can protein mishandling cause sporadic MND?

A

Ubiquitin2 –> a system used to clear out misfiled proteins

MNs more susceptible to tangles & misforms as they are long –> ubiquitin2 fails to repair MNs = MND

60
Q

How does disorganised immune response lead to MND?

A
  • Leads to improper function of ubiquitin2 in protein degradation via autophagosomes

How does it happen:

  • Damaged proteins & ubiquitin2 build up in MNs & the brain
  • Immune system attacks healthy cells
61
Q

How does environmental toxin exposure cause sporadic MND?

& evidence for this

A
  • Exposure to toxins such at metals, radiation, solvents & electromagnetic fields
  • Two-fold inc in ALS incidence in the military due to exposure to certain metals or chemicals, injuries, viral-infections & intense exertion
62
Q

What is an example of an environmental cause of MND (ALS)?

A

ALS-like disorders in the Western Pacific (Guam, Kia peninsula Japan & West Papua) after WW2

63
Q

Describe the ALS-like disorders in the Western Pacific that occurred after WW2

A
  • High rates of ALS-PDC (ALS-Parkinsonism Dementia Complex) after WW2 –> known as lytico-bodig
  • Incidence = 87:100,000
  • Male:Female = 2.5:1
  • Mean age of onset = much younger

Was a slowly progressive degenerative disease w spectrum of clinical presentation (ALS, Parkinson’s & dementia)

Thought to be environmental cause bc incidence dec to 5:100,000 in 1985

64
Q

What was the determined cause of the ALS-like disease in the Western Pacific post WW2?

A

All 3 cultures it was seen in used cycad (palm) seeds for medicinal and/or food

Seeds contained bMAA - an excitatory amino acid & neurotoxin (mimics actions of glutamate) = toxic → when given to monkeys for a month they get a Parkinson’s like tremor

In one culture they used to make stew out of fruit bats & this was major cause of them getting the ALS like syndrome → from the original source, the fruit bats would concentrate the BMAA so ppl who ate it got this disorder, when they were hunted to extinction the prevalence dropped

65
Q

What are the 3 major suggested reasons for damage to/death of MNs?

A

1 - Activation of glutamate receptors

2 - Superoxide Dismutase 1 (SOD1) mutation

3 - Mutation of neurofilament genes

66
Q

How does activation of glutamate receptors cause damage to/death of MNs?

A
  • Activation of glutamate receptors =
  • Excitotoxicity =
  • Inc intralleuluar Calcium =

= Motor neurone apoptosis

67
Q

How does Superoxide dismutase 1 (SOD1) mutation cause damage to/death of MNs?

A
  • SOD1 mutation =
  • Hyperactive anti-oxidant =

1 - Dec zinc binding

2 - Inc toxicity –> inc peripheral (intermediate filament) –> leads to disorganised neurofilament (which blocks axonal transport)

= MN apoptosis

68
Q

How does mutation of neurofilament genes cause damage to/death of MNs?

A
  • Mutation of neurofilament genes =
  • Disorganised neurofilament =
  • Blocks axonal transport =

= MN apoptosis

69
Q

What evidence is there from transgenic mouse studies for the mechanisms of MN degeneration?

A
  • Inc peripheral OR inc SOD both cause MND symptoms

Other KO mouse studies provide additional evidence of:
- Dec glial glutamate transporter EAAT2 in astrocytes

  • Inc glutamate mat cause excitotoxicity
70
Q

What are the only 2 treatments we have at the moment for MND?

A

Symptomatic treatments & slowing progression

71
Q

What are the symptomatic treatments we have for MND?

A
  • Respiratory support –> airway clearance, ventilation & rest strength training
  • Pain –> standard analgesics, particularly opiates
  • Spasticity –> Baclofen (GABA-B agonist)
72
Q

What are the treatments we have for slowing progression of MND?

A
  • Sodium Phenylbutyrate & Taurusodiol = reduces ER stress & mitochondrial dysfunction
  • Riluzole = decreases glutamate release, may slow symptoms, approved by both FDA & EMA
  • Edaravone = scavenges free radicals, may slow disease progression, approved in US (iv & oral) –> but not Europe due to lack of efficacy
73
Q

What are the 2 types of disease modifying approaches for MND?

A
  • Gene therapy
  • Stem cells
74
Q

What is an example of a gene therapy that can be used as an approach for MND?

A

Anti-sense oligonucleotide (ASO) downregulation of SOD1 (2% of MND cases)

Approved by FDA in 2023 & under review by EMA in 2024

75
Q

How does ASO (anti-sense oligonucleotide) gene therapy work to treat MND?

A
  • ASOs bind to specific mRNAs & reduce or alter translation into proteins
  • Will only work for patients w mutations/deficits in these genes
  • Multiple other approaches being trailed - failure of C9orf72 ASO trials show precise knowledge of gene function req
76
Q

How are stem cells being used to treat MND?

A

Adult multi-potent stem cells (e.g. BMSCs) - can differentiate into many different cell types

  • Not possible to replace lost MNs, but can differentiate into astrocytes & microglia & perform neurotrophic functions
77
Q

What are BMSCs?

A

Bone marrow mesenchymal stem cells

Used for stem cell treatment of MND

78
Q

Has transplantation of BMSCs been shown to work in ALS?

A
  • Effective in animal models (SOD1), some small clinical trials conducted
  • Appears safe, limited benefits reported
  • Newer approaches use IPSCs from patients to model the disease - may be possible to use therapeutically in the future
79
Q

What is Myasthenia Gravis?

A

A differential presentation of a similar disorder

Typically affects muscle of the eye - but can affect any skeletal muscle

80
Q

What are the symptoms of Myasthenia Gravis?

A

Muscle weakness but fatiguable

Worsen w use unlike MND

Muscles that control breathing & neck can be affected as well

81
Q

What is the cause of Myasthenia Gravis?

A
  • Antibodies produced against nicotinic receptors at NMJ

or

  • MuSK protein - receptors tyrosine kinase involved in NMJ development
82
Q

What type of disorder is Myasthenia Gravis?

A

A chronic autoimmune (AChR/ms-TyrK) neuromuscular disorder

More prevalent in women (<40) than men (>60)

PURE MOTOR DISORDER –> no effect on sensation

83
Q

How can Myasthenia Gravis be treated?

A

Treatable with AChE inhibitors & immunomodulation

84
Q

What are the mechanisms of Myasthenia Gravis?

A

1 - B-cells produce immunoglobulins against proteins at NMJ —> prevent ACh release from MN terminals causing muscle fibre depolarisation

2 - End plate potential less post-synaptic depolarisation

3 - Miniature end plate potential also reduced –> reduction in storage of ACh in vesicles

(Caused by the Anti-AChR or MuSK Abs)

85
Q

Hoe does the NMJ change in Myasthenia Gravis?

A

The junctional folds degrade

(On the muscle there are grooves, these become smaller and less indented into the muscle = less connection)

86
Q

What are the treatments for Myasthenia Gravis?

A
  • Edrophonium
  • ACh esterase inhibitors (AChE-Is)
  • Immunosuppressants
  • Plasmapheresis
  • Removal of thymus gland
  • Monoclonal antibody (mAB) treatments
87
Q

How can Edrophonium be used as a treatment for Myasthenia Gravis?

A

It is an anti cholinesterase diagnostic test

  • Edrophonium does little in normal patients - can cause temp dramatic improvement in muscle strength in MG patients
  • Differential diagnosis w Lambert-Eaton myasthenia syndrome –> same symptoms but inability to produce ACh
88
Q

How can Acetylcholine Esterase Inhibitors (AChE-Is) be used to treat Myasthenia Gravis?

A
  • Slow the breakdown of ACh
  • e.g. Neostigmine
89
Q

How can immunosuppressants be used to treat Myasthenia Gravis?

A
  • e.g. corticosterone, prednisone
  • Improve symptoms by suppressing antibody production
90
Q

How can plasmapheresis be used to treat Myasthenia Gravis?

A

Remove antibodies from circulation

91
Q

How can removal of the thymus gland be used to treat Myasthenia Gravis?

A

Rebalance the immune system

92
Q

How can monoclonal antibody (mAB) treatments be used to treat Myasthenia Gravis?

A

mABs target immune cells to reduce production of autoantibodies (clinical trials ongoing)

Disease in the brain (22 decks)

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