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.
Neurophysiology in ALS
| Motor cortex hyperexcit. PROVEN | TMS: reduced SICI, increased MEP amplitude, shortened cortical silent period. UMN hyperexcitability detectable early — may precede clinical signs. Vucic et al. 2008 Brain |
| EMG denervation PROVEN | Most 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 TMS | Persistent inward Na current increased in ALS cortical neurons → hyperexcitability → glutamate excitotoxicity → motor neuron death. Riluzole targets this. Vucic & Kiernan 2006 Brain |
| EEG in ALS-FTD | C9orf72 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.