Anatomically Defined Motor Phenotypes Reveal Dissociated Trajectories of Progression, Neurofilament Profiles, and Survival in ALS

@article{meyer2026anatomically,
  title = {{Anatomically Defined Motor Phenotypes Reveal Dissociated Trajectories of Progression, Neurofilament Profiles, and Survival in ALS}},
  author = {Thomas Meyer and Torsten Grehl and Peggy Schumann and Ute Weyen and Annekathrin Rödiger and Uta Smesny and Benjamin Ilse and Patrick Weydt and Sarah Bernsen and Rachel Fabian and Bettina Göricke and Susanne Petri and Rea Lumi and Bogdan Bjelica and Julian Großkreutz and Hakan Cetin and Omar Keritam and Friedrich Haimberger and Catharina Korsukewitz and Wolfgang Löscher and Zaharias Kohl and Martin Regensburger and Petra Baum and Moritz Metelmann and Dagmar Kettemann and Jenny Norden and Robert Steinbach and Péter Körtvélyessy and Paul Lingor and Robert McFarlane and Christoph Münch and Matthias Boentert and André Maier},
  journal = {European Journal of Neurology},
  year = {2026},
  month = oct,
  doi = {10.1111/ene.70798},
  url = {https://doi.org/10.1111/ene.70798},
  note = {CC BY 4.0},
}

TY  - JOUR
TI  - Anatomically Defined Motor Phenotypes Reveal Dissociated Trajectories of Progression, Neurofilament Profiles, and Survival in ALS
AU  - Thomas Meyer
AU  - Torsten Grehl
AU  - Peggy Schumann
AU  - Ute Weyen
AU  - Annekathrin Rödiger
AU  - Uta Smesny
AU  - Benjamin Ilse
AU  - Patrick Weydt
AU  - Sarah Bernsen
AU  - Rachel Fabian
AU  - Bettina Göricke
AU  - Susanne Petri
AU  - Rea Lumi
AU  - Bogdan Bjelica
AU  - Julian Großkreutz
AU  - Hakan Cetin
AU  - Omar Keritam
AU  - Friedrich Haimberger
AU  - Catharina Korsukewitz
AU  - Wolfgang Löscher
AU  - Zaharias Kohl
AU  - Martin Regensburger
AU  - Petra Baum
AU  - Moritz Metelmann
AU  - Dagmar Kettemann
AU  - Jenny Norden
AU  - Robert Steinbach
AU  - Péter Körtvélyessy
AU  - Paul Lingor
AU  - Robert McFarlane
AU  - Christoph Münch
AU  - Matthias Boentert
AU  - André Maier
PY  - 2026
DA  - 2026/10/27
JO  - European Journal of Neurology
DO  - 10.1111/ene.70798
UR  - https://doi.org/10.1111/ene.70798
AB  - Background: Clinical heterogeneity in amyotrophic lateral sclerosis (ALS) may reflect structured disease trajectories. This study investigated whether anatomically defined motor phenotypes capture reproducible patterns associated with progression, serum neurofilament light chain (NfL), and survival.  Methods: In a multicenter cohort of 1307 ALS patients, motor phenotypes were classified by region of onset, timing of propagation to a vertically distant body region (early ≤ 12 months vs. later), and the degree of upper (UMN) and lower motor neuron (LMN) dysfunction. Intercenter consistency was assessed using the Friedman test and Kendall's W. Associations with ALS progression rate (ALSPR), NfL, and survival were analyzed using group comparisons and Cox regression models.  Results: Phenotype classification was consistent across centers (Kendall's W 0.75–0.89). Onset phenotypes were significantly associated with ALSPR, NfL, and survival (p < 0.001). Trunk onset showed the lowest log(NfL/ALSPR), indicating dissociation between rapid progression and relative NfL elevation. Early propagation was the strongest marker of disease aggressiveness, with higher ALSPR, elevated NfL, and reduced survival (HR 2.93, p < 0.001). In early propagation, NfL disproportionally increased with progression indicating a relative uncoupling of NfL from functional decline. Phenotypes with balanced UMN/LMN and predominant LMN involvement were associated with shorter survival (HR 2.51, p < 0.001).  Conclusions: Anatomically defined motor phenotypes identify reproducible ALS trajectories with distinct clinical and neurofilament profiles. Early propagation provides an actionable risk marker of disease aggressiveness, while combined upper and lower motor neuron dysfunction or lower motor neuron predominance is prognostically unfavorable. These findings support integrating structured phenotyping into prognostic models and clinical trial stratification.
SN  - 1351-5101
SN  - 1468-1331
ER  -