ALS-001
ALS · Motor Neuron Disease · TDP-43 + SOD1 Engine · VIZASL v1
MEBICAL · EOSE Fleet · TRB-MEBICAL-HEALTH-DOMAIN-001 · Day 90 · Real data · Cited · Sorries marked
MEBICAL · NEURO ← RESEARCH
Motor neuron axon
TDP-43 cytoplasmic aggregates
SOD1 misfolded dimer
Neuromuscular junction
γ₁ floor anchor
PHASES
RX
BIOMARKERS
NEURO
NPs
Core Pathology PROVEN
TDP-43 Nuclear Clearance (97% of ALS)
TDP-43 normally resides in nucleus: RNA splicing, transcription regulation. In ALS: TDP-43 clears from nucleus → forms hyperphosphorylated, ubiquitinated cytoplasmic aggregates → loss of nuclear function + toxic cytoplasmic gain-of-function. SORRY: why it clears is unknown.
Neumann et al. 2006 Science — TDP-43 in ALS inclusions identified
SOD1 Misfolding (20% fALS, ~2% total ALS)
Cu/Zn superoxide dismutase. Misfolded SOD1 forms toxic aggregates. 200+ mutations. Mechanism distinct from TDP-43 pathway — most fALS SOD1 cases do NOT have TDP-43 pathology. ASO targeting now proven.
Rosen et al. 1993 Nature — SOD1 mutations in fALS
C9orf72 Hexanucleotide Repeat (40% fALS, 8% sALS)
GGGGCC hexanucleotide repeat expansion in C9orf72. Largest genetic cause of ALS + FTD. Two mechanisms proposed: (1) repeat RNA foci sequester RNA-binding proteins, (2) DPR (dipeptide repeat) proteins are toxic. Both may be true — debate ongoing.
DeJesus-Hernandez et al. 2011 Neuron · Renton et al. 2011 Neuron
UMN + LMN Dual Degeneration
Upper motor neurons (cortex → spinal cord) + lower motor neurons (spinal cord/brainstem → muscle) both degenerate. Clinical signature: spasticity (UMN) + fasciculations + atrophy (LMN). El Escorial criteria for diagnosis.
Brooks et al. 2000 (revised El Escorial criteria)
Prognosis
Median survival: 2–5yr from symptom onset. Respiratory failure = most common cause of death. 10% survive >10yr. Stephen Hawking: 55yr survival — CHCHD10 variant, slow UMN predominant phenotype (outlier, not representative). Most patients progress to ventilator dependency.
Approved Treatments
Riluzole PROVEN
Glutamate release inhibitor. First ALS drug. Modest 2–3 month survival benefit. Slows disease in 2 trials. Small effect but replicated. Standard of care since 1995.
Bensimon et al. 1994 NEJM · Miller et al. 1996 NEJM
Edaravone PROVEN
Free radical scavenger. Japanese trial: 33% slower ALSFRS-R decline in early-stage, rapidly-progressive subset. FDA-approved 2017 for subset. Benefit in broader population not confirmed.
Writing Group on Behalf of ALS/MND Study Group 2017 Lancet Neurol
Tofersen (SOD1-ASO) PROVEN
ASO targeting SOD1 mRNA. Reduces CSF SOD1 protein by ~35%. Slows neurofilament rise. FDA approved 2023 for SOD1-ALS. First precision medicine win in ALS — subset of ~2% of all ALS.
Smith et al. 2022 NEJM (VALOR trial)
AMX0035 (Sodium Phenylbutyrate + TUDCA) Approved (controversial)
Mitochondrial/ER stress pathway. Canada + US approved. Phase 3 (CENTAUR) showed 2.3 point ALSFRS-R benefit. Phase 3 PHOENIX trial: failed primary endpoint 2024. Approval status under review.
Paganoni et al. 2020 NEJM · PHOENIX 2024 failure — regulatory uncertainty
Biomarkers
CSF NfL PROVENNeurofilament light chain. Highly elevated in ALS. Correlates with progression rate, survival. Best non-genetic prognostic biomarker. Lu et al. 2015
Plasma pNfH STRONGPhosphorylated neurofilament heavy. Elevated, correlates with rate. Accessible via blood draw.
EMG denervation PROVENFibrillations, positive sharp waves, fasciculations. Essential for LMN diagnosis. Awaji criteria. More sensitive than El Escorial.
TMS SICI STRONGShort-interval intracortical inhibition reduced in ALS (UMN hyperexcitability). Potential early biomarker. Vucic et al. 2008 Brain
C9orf72 PCRRepeat-primed PCR for GGGGCC expansion. Genetic test for largest ALS cause. Affects treatment (future ASO trials).
SOD1 sequencingFor tofersen eligibility. Positive = precision medicine candidate. 200+ pathogenic variants.
Neurophysiology in ALS
Motor cortex hyperexcit. PROVENTMS: reduced SICI, increased MEP amplitude, shortened cortical silent period. UMN hyperexcitability detectable early — may precede clinical signs. Vucic et al. 2008 Brain
EMG denervation PROVENMost diagnostic neurophysiology test in ALS. Fibrillations/PSWs = active denervation. Fasciculation potentials = LMN disease. Must be in ≥3 regions for El Escorial definite ALS.
Threshold tracking TMSPersistent inward Na current increased in ALS cortical neurons → hyperexcitability → glutamate excitotoxicity → motor neuron death. Riluzole targets this. Vucic & Kiernan 2006 Brain
EEG in ALS-FTDC9orf72 ALS-FTD: frontal θ slowing, reduced executive EEG correlates. FTD overlap = 15–50% of ALS. EEG diagnostically secondary to clinical assessment.
Thinkbeat Bridge
ALS motor cortex hyperexcitability = FAST_MONOTONE → motor neurons die → signal loss = SLOW_MONOTONE → NMJ silence = CHAOTIC (no output). The disease IS the δ curve: increasing excitation until the system burns out. Riluzole is a δ-reduction agent — glutamate dampening slows the convergence rate.
Novel Patterns (8)
PROVENNP-ALS-001 · TDP-43 in 97% of ALS — nuclear clearance + cytoplasmic aggregation is the near-universal ALS signature · Neumann 2006 Science
PROVENNP-ALS-002 · C9orf72 = single largest genetic cause of both ALS AND FTD · same mutation creates different syndromes · 40% fALS · DeJesus-Hernandez 2011 Neuron
PROVENNP-ALS-003 · Tofersen (SOD1-ASO) = first precision medicine win in ALS · reduces CSF SOD1 ~35% · slows NfL rise · 2023 FDA approved · Smith 2022 NEJM
PROVENNP-ALS-004 · Motor cortex hyperexcitability is an early UMN sign detectable by TMS before clinical diagnosis · Vucic 2008 Brain
OPENNP-ALS-005 · C9orf72 mechanism: DPR proteins vs RNA foci — which is primary toxic species? Both likely contribute. Debate ongoing 2026.
SORRYNP-ALS-006 · Why TDP-43 clears from nucleus — the initiating event in 97% of ALS is unknown. Stress granule hypothesis. Phase separation failure. No validated trigger.
SORRYNP-ALS-007 · AMX0035 approval controversy — CENTAUR positive, PHOENIX failed. Two trials, opposite results. Regulatory uncertainty 2024.
OPENNP-ALS-008 · ALS-FTD continuum: 15–50% ALS has FTD features. C9orf72 drives both. Shared TDP-43 pathology. One disease spectrum or two? Staging systems (King's/Milano-Torino) work but imprecise.
Open Sorries (5)
SORRY-1: Why TDP-43 clears from nucleus — the initiating event in 97% of ALS. Stress granule dysfunction? Phase separation failure? Unknown trigger.
SORRY-2: C9orf72 mechanism — DPR proteins vs RNA foci toxicity debate. Both pathways active; which dominates is unclear.
SORRY-3: AMX0035 (Relyvrio): CENTAUR trial positive 2020, PHOENIX Phase 3 failed 2024. Regulatory uncertainty — which trial is right?
SORRY-4: Individual progression rate prediction impossible. King's/Milano-Torino staging is descriptive, not predictive at individual level.
SORRY-5: Why do motor neurons die and not other TDP-43-expressing cells? Cell-type specific vulnerability mechanism unknown.
⚠ OPEN SORRIES · ALS-001
SORRY-1 · TDP-43 Nuclear Clearance (the initiating mystery)
97% of ALS has TDP-43 pathology. Why does TDP-43 leave the nucleus? Stress granule dysfunction, phase separation failure, and nuclear pore complex pathology are all proposed. No validated initiating trigger in 2026. This is the central unsolved question.

SORRY-2 · C9orf72: DPR vs RNA Foci
GGGGCC repeat expansion creates both: (1) nuclear RNA foci that sequester RNA-binding proteins, and (2) dipeptide repeat (DPR) proteins translated by RAN translation. Which toxic species dominates? Both likely contribute. The debate shapes ASO/small molecule targeting strategy.

SORRY-3 · AMX0035 Controversy
CENTAUR (2020): 2.3 point ALSFRS-R benefit, FDA approved 2022. PHOENIX Phase 3 (2024): failed primary endpoint. Two RCTs with opposite results. Regulatory agencies reviewing. Clinical uncertainty is real.

SORRY-4 · Progression Prediction
NfL correlates with rate. King's staging describes functional decline. But individual survival cannot be predicted accurately. Population statistics tell you nothing about whether this patient has 18 months or 5 years.

SORRY-5 · Motor Neuron Selectivity
TDP-43 is expressed in every cell. Motor neurons die. Why not astrocytes? Hepatocytes? Cell-autonomous (intrinsic motor neuron vulnerability) vs non-cell-autonomous (astrocyte/microglia driven) remains debated.
ALS-001 · TDP-43 NUCLEAR CLEARANCE · 2–5YR MEDIAN SURVIVAL · TOFERSEN = FIRST PRECISION WIN
γ₁ = 14.134725141734693