Lecture 14 - Motor Neuron Disorders/ALS Flashcards
who first diagnosed the disease now known as amyotrophic lateral sclerosis (ALS)?
Jean-Martin Charcot
describes the scarring and degeneration of the lateral corticospinal tracts in the spinal cord
the “lateral sclerosis” in ALS
a progressive neurodegenerative disorder that causes weakness and other motor impairments that eventually leads to death
amyotrophic lateral sclerosis (ALS)
how many individuals with ALS experience cognitive impairments ranging from mild to frontotemporal dementia?
~50%
what is the difference between incidence and prevalance?
incidence = fresh cases per year
prevalance = how many people experience this right now
what is the incidence rate of ALS?
~2 cases per 100 000 people per year
what is the prevalance rate of ALS?
~5 cases per 100 000 people
what is the age of onset of ALS?
55-65 years (adult onset disease)
what is the medial survival of people with ALS?
3-5 years from diagnosis
which is more common: sporadic or familial ALS?
sporadic
how many genes and loci are associated with ALS?
46
list the key genes associated with ALS
C9ORF72, SOD1, TARDBP, and FUS
a personalized survival prediction model that is used to estimate the life expectancy/prognosis of patients with ALS
the ENCALS model
where does the neurodegeneration in ALS occur?
the upper motor neurons of the motor cortex and somatosensory cortex, and their associated lower motor neurons
true or false: orphaned muscle fibers can be adopted by intact motor neurons
true
neurons in ALS are full of:
fibrils
97% of all ALS patients, regardless of the mechanisms of disease onset, have:
TDP-43 pathology (the exception includes individuals with SOD1 and FUS mutations)
a protein that is found in the nucleus of healthy cells and plays an important role in transcriptional regulation, alternative splicing, and mRNA stabilization, is present in RNA transport granules that regulate local protein synthesis in the dendrites, and is involved in cytoplasmic stress granule responses
TDP-43
in ALS, TDP-43 has an altered:
nucleocytoplasmic distribution (it is mislocalized to the cytoplasm where it starts to accumulate and clump)
why is targetting TDP-43 aggregates in the cytoplasm ineffective at treating ALS?
- by the time the aggregates are detected, nuclear function is already lost
- loss of RNA processing and splicing regulation likely contributes to neurodegeneration before aggregates appear
molecular pathophysiology is:
heterogenous (has several causes)
list the five major factor in the molecular pathophysiology of ALS
1) impaired glutamate clearance, leading to excitotoxicity
2) protein aggregate formation, RNA toxicity, and mitochhondrial dysfunction
3) pro-inflammatory cytokines from M1 activate microglia
4) failure of axonal architecture and transport
5) synaptic failure, denervation, and muscle atrophy
how does ALS initially present?
asymmetric limb weakness is the most common
- hand weakness (if it starts in the cervical region)
- weak dorsiflexion/foot drop (if it starts in the lumbosacral region)
true or false: ALS may start in any spinal segment
true
what are the lower motor neuron signs of ALS?
- flaccidity
- muscle atrophy
- fasciculations (involuntary twitches)
- weakness
what are the upper motor neuron signs of ALS?
- hyperreflexia
- spasticity
- pathogenic reflexes (Babinski, Hoffman)
- weakness
- the initial area affected seems random
- propogation radiates from the initial area at different rates
these factors both increase:
the heterogeneity of ALS
what is clinically definite ALS?
UMN and LMN clinical signs or electrophysiological evidence of ALS in 3 spinal cord regions (lumbar, throacic, cervical, bulbar)
what is lab supported clinically definite ALS?
UMN and/or LMN clinical signs in one spinal cord region and the patient carries a pathogenic SOD1 mutation
what is clinically probable ALS?
UMN and LMN clinical signs and electrophysiological evidence in two spinal cord regions with some UMN signs rostral to the LMN signs
what is clinically possible ALS?
- UMN and LMN clincal signs or electrophysiological evidence in one spinal cord region only, or
- UMN signs in two or more regions, or
- UMN and LMN signs in two regions with no UMN signs rostral to LMN signs
what electrophysiological technique is used to detect signs of ALS?
needle EMG
what does needle EMG look for?
fasciulations and fibrillations+ positive sharp waves
involuntary activation of a motor unit that happens with colateral sprouting
fasciculations (needle EMG)
involuntary activation of single muscle fibers that happens when muscle cells are orphaned
fibrillations and positive sharp waves (needle EMG)
go read the bottom of slide 372
I’m too lazy to make flashcards of that
a characteristic that is measured as an indicator of normal biological processes, pathogenic processes, or responses to an exposure or intervention, including therapeutic interventions
biomarkers
true or false: biomarkers can be molecular, histologic, radiographic, or physiologic
true
true or false: a biomarker is an assessment of how a patient feels, functions, or survives
false
what are the three major types of biomarkers that researchers are trying to develop for ALS?
- monitoring (longitudinal, status of condition)
- response (biological change, target engagement, surrogate endpoint)
- predictive (who benefits from a particular intervention)
what are the two major treatments for ALS available in Canada?
- rilutek (riluzole)
- radicava (edaravone)
ALS treatment that targets glutamate excitotoxicity pathways
rilutek (riluzole)
ALS treatment that targets oxidative stress pathways
redicava (edaravone)
an ALS treatment that was discontinued in Canada
albrioza
the first FDA approved therapy targeting a genetic cause of ALS, specifically SOD1 mutations
toferson (Valor and Atlas trials)
variants in the _____ gene are believe to cause 10-30% of familial ALS cases and 1-4% of non-famial ALS
SOD1
can individuals without mutations in the SOD1 gene receive toferson?
nope
a type of therapy where protein translation is halted due to the insertion of short DNA/RNA sequences that target and modify mRNA
antisense oligonucleotide (ASO) therapy
how do we know that toferson is working?
biomarkers provide objective measures of response, beyond clinical symptoms
