Anatomically Defined Motor Phenotypes Reveal Dissociated Trajectories of Progression, Neurofilament Profiles, and Survival in
ALS
Thomas Meyer, Torsten Grehl, Peggy Schumann, Ute Weyen, Annekathrin Rödiger, Uta Smesny, Benjamin Ilse, Patrick Weydt, Sarah Bernsen, Rachel Fabian, Bettina Göricke, Susanne Petri, Rea Lumi, Bogdan Bjelica, Julian Großkreutz, Hakan Cetin, Omar Keritam, Friedrich Haimberger, Catharina Korsukewitz, Wolfgang Löscher, Zaharias Kohl, Martin Regensburger, Petra Baum, Moritz Metelmann, Dagmar Kettemann, Jenny Norden, Robert Steinbach, Péter Körtvélyessy, Paul Lingor, Robert McFarlane, Christoph Münch, Matthias Boentert, André Maier ABSTRACT
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.