Lecture 14 - Motor Neuron Disorders/ALS Flashcards
(49 cards)
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
