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CNSD Aantekeningen Hoorcolleges Thema 4-6
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Dit document bevat alle aantekeningen van de hoorcolleges van thema 4-6: 'ALS', 'stroke' en 'psychosis'.
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CENTRAL NERVOUS SYSTEM DISORDERSTHEME 4: ALS
4.1 AMYOTROPHIC LATERAL SCLEROSIS
Amyotrophic lateral sclerosis
• Progressive degeneration of central and peripheral
motor neurons
• Er zijn verschillende type ALS afhankelijk van waar de
motorneuronen zijn aangedaan. De symptomen zijn
gekoppeld aan de plek waar het begonnen is.
o Brain: cognitive defects, reflex
o Brainstem: speaking, swallowing
o Spinal cord: walking, breathing
• Symptoms: spierzwakte, atrofie, fasciculaties (spiertrillingen), reflexen, verlaagde tonus
o Fasciculations: involuntary muscle twitching; neuronen zijn overexcited waardoor er
onwillekeurige spiertrekkingen plaatsvinden
• Bulbar (30%) vs spinal (70%)
• Survival: 3 yrs (6 mo. to > 15 yrs)
o Meeste patiënten sterven doordat ze hun spieren in hun rug en borst voor het ademen niet
meer kunnen gebruiken
• Familial (5%) vs Sporadic (95%)
• Treatment: riluzole, symptomatic, LATEST! - SOD1 → Tofersen
Diagnosis
• By exclusion
o Je sluit andere ziektes uit, totdat je bij ALS uitkomt
• Different for each patient
• Laboratory studies
• MRI scans
• Electromyography
• Mimics:
o Primary lateral sclerosis (PLS)
o Lower motor neuron progressive muscular atrophy (PMA): only effects lower parts
-> Need for biomarkers!
Biomarkers
• A naturally occurring molecule, gene or characteristic by which a particular pathological or
physiological process, disease, etc. can be identified
• In medicine, a biomarker is a measurable indicator of the severity or presence of some disease
state
• More generally a biomarker is anything that can be used as an indicator of a particular disease or
some other psychological state of an organism
• Potential biomarker for ALS: neurofilament light chain (NfL) – blood/CSF
Cognitive defects in ALS
• Within spectrum of fronto-temporal dementia (FTD)
• Behaviour of language
• Cognitive impairment (50%)
,• Spectrum of diseases:
o ALS: only motor loss
o FTD: language problems, aphasia, and others
Lifestyle, BMI, energy expenditure
• Er zijn 6 stappen nodig om ALS te ontwikkelen, hiervan is er eentje genetisch en de andere zijn
environmental
o Intensieve sporters ontwikkelen vaak ALS
o Cardiovasculaire conditie is een risicofactor
o Soldaten ontwikkelen vaak ALS, aangezien zij vaak in omgevingen zijn met veel toxins
• BMI is lager voor ALS patiënten en hun daily energy intake is hoger in vergelijking met controle ->
increased presymptomatic energy expenditure
ALS genetics
• Familial (5-10%)
• Sporadic (90-95%)
o Environment, lifestyle
o Genes
o -> Conspiracy of genes, environment and time
• Er zijn de afgelopen jaren vele genen geïdentificeerd die
mogelijk geassocieerd zijn met ALS. Veel van deze genen
hebben hele verschillende functies en weinig
overeenkomsten, wat de genetica achter ALS
complex maakt.
o Implicated in protein homeostasis
o Involved in alterned RNA-binding proteins
o Involved in cytoskeletal proteins
• Analysis strategies: linkage analysis, candidate
gene analysis; GWAS; exome sequencing;
genome sequencing
o In de afgelopen jaren steeds meer genen
geïdentificeerd door de groei in analyse
strategiën
,Protein aggregation in ALS
Mutatie in SOD1, TDP-43, FUS, OPTN,
UBQLN2, ATXN2, C9ORF72, ubiquitin, p62,
VCP, VAPB, PABP1, TIA, eIF3 dan is er een
phenotype van aggregraatvorming.
TDP-43 pathology a hallmark of ALS
• In over than 95% of cases
• TDP-43 mislocalisation from nucleus to cytoplasm
• Insoluble aggregates
(A few) molecular mechanisms of ALS
• Cell autonomous (motor neurons)
o Excitotoxicity
- Bijvoorbeeld overproductie van
glutamaat
o Protein misfolding and aggregation
o Oxidative stress
- Mitochrondiën scheiden radialen uit
en dit leidt tot schade
o RNA metabolism impairment
- Transcriptie, translation en splicing
worden dan beïnvloedt
o Mitochondrial dysfunction
- Energie problemen in de cel
o Distal axonopathy
- Er vindt eerst degradation van axonen
plaats voordat neuronen afsterven
• Non-cell autonomous
o Inflammation – Gliosis
Summary
• Involvement of many rare genetic variants
• Lifestyle and environment also important
• Heterogeneity – collection of diseases
• Different subtypes related to different mutations
• Different response to therapies
• Cognitive impairment 50% patients
• Fronto-temporal dementia (FTD) 5-15% patients
ALS: challenges
• ALS is genetic but it is not clearly only familial
• Not each carrier of a mutation will develop disease
• Future:
o Increase number of patients to study genetic architecture
o Role of non-coding RNA
o Precision medicine
o Need for biomarkers
, Treatment
• Placebo vs riluzole
o Riluzole: improvement in survival
• Focus on symptomatic therapies
o Focus on quality of life
o Multidisciplinary team of
therapists
o Gastrostomy, non-invasive
ventilation
• Een behandeling vinden is erg
lastig, omdat ALS heel
heterogenous is. Je hebt te maken
met vele subtypes.
o Patiënten zouden geclusterd kunnen worden op verschillende eigenschappen (genetic risk,
brain activity, physiology, behavioral process, life experience)
o Wanneer je de behandeling richt op een bepaald subtype werkt het beter dan wanneer je je
recht op ALS in het algemeen.
Ongoing clinal trials
• No consensus what is the optimal study design
• Shift towards:
o More selected trial populations
o Primary focus on improving function rather than prolonging survival
• Clinical trials:
o Drug/compounds: lithium, edavarone, masititinb, curcumin, methylcobalamin, tamoxifen,…
o Antisense oligo/siRNA
Current gene targeting trials & treatments
• Antisense oligonucleotides (ASO) binds to target
mRNA or pre-mRNA, inducing its degradation and
preventing the mRNA from being translated into a
detrimental protein product.
• Zolgensma (AAV9-based SMN replacement) is a
prescription gene therapy for children with SMA
(spinal muscular atrophy) under 2 years old -> goede
resultaten
• Treatment
o SOD1 -> Tofersen - Biogen
• Ongoing gene-targeted trials
o FUS – lonis
o ATXN2 – Biogen
o C9orf72 – Wave/Biogen
o UNC13A – Pre-clinical
→ Hoop is hoog
• ASOs injecteer je in de spinal
cord en dan verspreid het
vanzelf richting de hersenen.
• AAV’s zijn opkomend en deze
beïnvloeden neuronen.
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