Motorneurone disease (done) Flashcards
What are the 3 most prevalent neurodegenerative disorders?
AD & PD
MND is 3rd most common
What is the prevalence of MND?
0.4-1.8/100,000 ppl
1.6 male : 1 female
What is the avg age of onset of MND?
40-60 yrs
What are the main symptoms of MND?
- Muscle contractions weakness
- Loss of muscle mass
- Inability to control movement
What are the general causes of MND?
Progressive DEGENERATION of MNs in brain & SC innervating (skeletal) voluntary muscles
What is the median survival of MND?
4 years (up to 20 yrs)
What are the general causes of death in MND?
- Respiratory weakness
- Pneumonia
There are currently no effective treatments
How did we know that is was degeneration of Mrs causing MND?
Duchenne = 19th century
Found muscle could still contract, so MN innervation must be impaired
What are the 4 major types of MND & why do are they different?
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
What is the most common type of MND & when is the median onset of it?
ALS –> median onset ~60 y/o
What are the symptoms of ALS?
Weakness & wasting in limbs
Muscle stiffness & cramps
Affects tongue, hand & leg muscles first
What is the mechanism of ALS?
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
What is the median survival of ALS?
2-5 yrs
What are the 2 types of MNs that can be affected & where of each of them originate & run to?
- 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
What is the:
- Prevalence
- Onset
- Symptoms
- Mechanisms & regions
- Special characteristics
- Life expectancy
of Progressive Bulbar Palsy (PBP)?
- 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
What is the:
- Prevalence
- Onset
- Symptoms
- Mechanisms & regions
- Special characteristics
- Life expectancy
of Progressive Muscular Atrophy (PMA)?
- 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
What is the:
- Prevalence
- Onset
- Symptoms
- Mechanisms & regions
- Special characteristics
- Life expectancy
of Primary Lateral Sclerosis?
- 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
What is Spinobulbar muscular atrophy (SBMA)?
- Not MND - similar but not the same w similar prevalence to MND
- Lower MNs & peripheral muscles affected
- Does not affect life expectancy
Physical symptoms are not the only symptoms that occur in MND - what are the other ones?
Cognitive & behavioural
What are the cognitive symptoms of MND?
- 35% of ppl have mild cog change affecting executive functions
- Such as planning, decision making & language
What are the behavioural symptoms that can occur w MND?
- 5-10% show signs of frontotemporal dementia (FTD)
- This results in pronounced behavioural changes
How do symptoms vary in MND patients?
- Not all symptoms will affect everyone or in the same order
- Symptoms will progress at varying speeds –> makes disease difficult to predict
What are the 6 methods that can be used to diagnose MND?
1 - Clinical examination
2 - Blood tests
3 - Electromyography (EMG)
4 - nerve conduction tests
5 - Transcranial Magnetic Stimulation (TMS)
6 - MRI
How is a clinical examination used to diagnose MND?
Main way to diagnose
Physical examination to identify cardinal symptoms –> muscle weakness/wasting
How can blood tests be used to diagnose MND?
- Inc levels of creatine kinase (muscle breakdown releases this)
- Problem = not specific to MND –> (also from heart attack, muscle injury, alcohol abuse & medicine)
How can electromyography (EMG) be used to diagnose MND?
- Fine needles record impulses w/in certain muscles
- Good for detecting early changes - even if muscle activity seems normal
How can nerve conduction tests be used to diagnose MND?
- Electrical impulse applied thru a small pad on skin
- Measures compound muscle AP, condition velocity & latency
How can transcranial magnetic stimulation (TMS) be used to diagnose MND?
- 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)
How can MRI be used to diagnose MND?
- Not actually used to diagnose MND itself –> used to rule out other diseases
- (e.g. AD, PD, MS, tumours or brain injury)
What does the World Federation of Neurology El Escorial criteria for ALS look for in general?
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)
What are the 5 main descending motor pathways that undergo neurological changes in MND?
- Brain stem & cranial MNs
- Corticospinal tract
- Spinal a-motor neurons
- Bulbospinal neurons
- Ventral horn
What happens in MND when there is changes in the Brain stem & cranial MNs?
Upper MNs:
- Eyelids start to droop
- Speech impaired
Brian stem:
- Tongue & facial muscles
What happens in MND when there is changes in the corticospinal tract?
- Degeneration in ALS
- Causes spasticity
Bc messages cannot get down from upper MNs or bulbospinal tract
What happens in MND when there is changes in a-motor neurons?
Issues w legs arms & diaphragm
Changes in these MNs lead to:
- Fasticulation (muscle twitching)
- Muscle wasting
- Weakness
- Hypertonia
- Eventually respiratory failure
How does the ventral horn of SC change in MND?
- Ventral horn shrinks
- You get ghost cells & filaments, theses = spheroids
What are ghost cells & spheroids (found in ventral horn of SC in MND)?
Got cells = lost the contract around outside of the cells
Spheroids = occur inside these & are created by misfolded proteins
What does the changes in the ventral horn lead to, causing MND?
- 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
What % of ALS cases are genetic?
5-10% –> can be autosomal dominant mutation or autosomal recessive
What are the AD mutations known to cause ALS (MND)?
1 - A9ofr72 gene, chromosome 9
2 - SOD1 (superoxide dismutase), chromosome 21
How common is the A9ofr72 gene, chromosome 9 (AD) mutation in ALS (MND)?
- Mutations found in 25-40% familial
- 7% sporadic ALS
- 25% FTD cases
How does the A9ofr72 gene, chromosome 9
mutation (AD) cause ALS?
- Highly expressed in MNs - influences mRNA production
- Mutations in GGGGCC expansion –> 30+ in ALS
What is the prevalence of the SOD1 mutation (AD) in MND (ALS)?
- 10-15% familial
- 1-2% sporadic
How does the SOD1 mutation (AD) cause MND?
- SOD1 is an anti-oxidant –> converts superoxide (O-2) to hydrogen peroxide & oxygen (H2O2 & O2)
- Mutant SOD1 aggregates & forms clumps –> affects all MNs
What is the autosomal recessive mutations known to cause ALS (MND)?
1 - ALS2, chromosome 2q33
How does the ALS2 (AR) mutation cause ALS?
- 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
What form of ALS does the Vesicle-asociated membrane protein B, chromosome 20q13.3 mutation cause?
Atypical late-onset form of ALS
(Not sure if AD or AR)
What does the Vesicle-asociated membrane protein B mutation do to cause ALS?
Causes dysfunction of intracellular membrane trafficking
What sort of ALS is the Sentaxin gene, chromosome 9 (AR) mutation linked to?
Rare, autosomal dominant juvenile ALS
How does the Sentaxin gene mutation cause ALS?
It affects DNA/RNA helices controlling RNA processing
What mutation leads to atypical late-onset form of ALS?
Mutation in
Vesicle-asociated membrane protein B, chromosome 20q13.3
What mutation causes rare, AD juvenile ALS?
Sentaxin gene, chromosome 9
Name 2 other mutations involved in ALS?
- TARDEP
- FUS
How does the TARDEP mutation cause ALS?
TAR DNA binding protein, involved in transcription –> forms aggregates in ALS
How does the FUS mutation cause ALS?
Fused in sarcoma
RNA binding protein, involved in: transcription, DNA repair & RNA splicing
FUS aggregates found ing MNs in sporadic ALS
What % of MND cases have no known family history (sporadic)?
90%
What are the 5 known causes of sporadic MND?
- Gene mutations
- Chemical imbalances (glutamate)
- Protein mishandling
- Disorganised immune response
- Environmental toxin
How are gene mutations known to cause sporadic MND?
Twin studies have shown 60% heritability
These gene mutation occur during lifetime - must be some sort of genetic element
How can chemical imbalance cause sporadic MND?
Ppl w MND have high glutamate levels in CSF
Too much glutamate = toxic to nerve cells
How can protein mishandling cause sporadic MND?
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
How does disorganised immune response lead to MND?
- 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
How does environmental toxin exposure cause sporadic MND?
& evidence for this
- 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
What is an example of an environmental cause of MND (ALS)?
ALS-like disorders in the Western Pacific (Guam, Kia peninsula Japan & West Papua) after WW2
Describe the ALS-like disorders in the Western Pacific that occurred after WW2
- 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
What was the determined cause of the ALS-like disease in the Western Pacific post WW2?
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
What are the 3 major suggested reasons for damage to/death of MNs?
1 - Activation of glutamate receptors
2 - Superoxide Dismutase 1 (SOD1) mutation
3 - Mutation of neurofilament genes
How does activation of glutamate receptors cause damage to/death of MNs?
- Activation of glutamate receptors =
- Excitotoxicity =
- Inc intralleuluar Calcium =
= Motor neurone apoptosis
How does Superoxide dismutase 1 (SOD1) mutation cause damage to/death of MNs?
- 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
How does mutation of neurofilament genes cause damage to/death of MNs?
- Mutation of neurofilament genes =
- Disorganised neurofilament =
- Blocks axonal transport =
= MN apoptosis
What evidence is there from transgenic mouse studies for the mechanisms of MN degeneration?
- 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
What are the only 2 treatments we have at the moment for MND?
Symptomatic treatments & slowing progression
What are the symptomatic treatments we have for MND?
- Respiratory support –> airway clearance, ventilation & rest strength training
- Pain –> standard analgesics, particularly opiates
- Spasticity –> Baclofen (GABA-B agonist)
What are the treatments we have for slowing progression of MND?
- 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
What are the 2 types of disease modifying approaches for MND?
- Gene therapy
- Stem cells
What is an example of a gene therapy that can be used as an approach for MND?
Anti-sense oligonucleotide (ASO) downregulation of SOD1 (2% of MND cases)
Approved by FDA in 2023 & under review by EMA in 2024
How does ASO (anti-sense oligonucleotide) gene therapy work to treat MND?
- 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
How are stem cells being used to treat MND?
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
What are BMSCs?
Bone marrow mesenchymal stem cells
Used for stem cell treatment of MND
Has transplantation of BMSCs been shown to work in ALS?
- 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
What is Myasthenia Gravis?
A differential presentation of a similar disorder
Typically affects muscle of the eye - but can affect any skeletal muscle
What are the symptoms of Myasthenia Gravis?
Muscle weakness but fatiguable
Worsen w use unlike MND
Muscles that control breathing & neck can be affected as well
What is the cause of Myasthenia Gravis?
- Antibodies produced against nicotinic receptors at NMJ
or
- MuSK protein - receptors tyrosine kinase involved in NMJ development
What type of disorder is Myasthenia Gravis?
A chronic autoimmune (AChR/ms-TyrK) neuromuscular disorder
More prevalent in women (<40) than men (>60)
PURE MOTOR DISORDER –> no effect on sensation
How can Myasthenia Gravis be treated?
Treatable with AChE inhibitors & immunomodulation
What are the mechanisms of Myasthenia Gravis?
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)
Hoe does the NMJ change in Myasthenia Gravis?
The junctional folds degrade
(On the muscle there are grooves, these become smaller and less indented into the muscle = less connection)
What are the treatments for Myasthenia Gravis?
- Edrophonium
- ACh esterase inhibitors (AChE-Is)
- Immunosuppressants
- Plasmapheresis
- Removal of thymus gland
- Monoclonal antibody (mAB) treatments
How can Edrophonium be used as a treatment for Myasthenia Gravis?
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
How can Acetylcholine Esterase Inhibitors (AChE-Is) be used to treat Myasthenia Gravis?
- Slow the breakdown of ACh
- e.g. Neostigmine
How can immunosuppressants be used to treat Myasthenia Gravis?
- e.g. corticosterone, prednisone
- Improve symptoms by suppressing antibody production
How can plasmapheresis be used to treat Myasthenia Gravis?
Remove antibodies from circulation
How can removal of the thymus gland be used to treat Myasthenia Gravis?
Rebalance the immune system
How can monoclonal antibody (mAB) treatments be used to treat Myasthenia Gravis?
mABs target immune cells to reduce production of autoantibodies (clinical trials ongoing)
