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

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.

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Publication Details

Journal
European Journal of Neurology
Published
2026-10-27
DOI
https://doi.org/10.1111/ene.70798
Primary Topic
Amyotrophic Lateral Sclerosis Research
Type
article
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article

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

Wolfgang N. Löscher, Susanne Petri, Patrick Weydt, Petra Baum et al.
European Journal of Neurology
Amyotrophic Lateral Sclerosis Research
article

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

Wolfgang N. Löscher, Susanne Petri, Patrick Weydt, Petra Baum, Sarah Bernsen, Jenny Nordén, Robert Steinbach, Catharina Korsukewitz, Omar Keritam, Benjamin Ilse, Bogdan Bjelica, Christoph Münch, Péter Körtvelyessy, Bettina Göricke, Peggy Schumann, Paul Lingor, Hakan Çetin, Thomas Meyer, Matthias Boentert, Zacharias Kohl, Dagmar Kettemann, André Maier, Torsten Grehl, Moritz Metelmann, Ute Weyen, Julian Großkreutz, Martin Regensburger, Robert M. McFarlane, Uta Smesny, Rea Lumi, Friedrich Haimberger, Annekathrin Rödiger, Rachel Fabian
article en

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.

European Journal of NeurologyVol. 33(11)
University of Bonn (DE), Innsbruck Medical University (AT), Friedrich-Alexander-Universität Erlangen-Nürnberg (DE), Universität Innsbruck (AT), Trinity College Dublin (IE), University of Münster (DE), German Center for Neurodegenerative Diseases (DE), TUM Klinikum (DE), Medizinische Hochschule Hannover (DE), Humboldt-Universität zu Berlin (DE), Universitätsklinikum Erlangen (DE), University Hospital Münster (DE), Diakovere (DE), University Hospital Schleswig-Holstein (DE), Universitätsmedizin Göttingen (DE), University Hospital Leipzig (DE), Jena University Hospital (DE), Klinikum Osnabrück (DE), Berlin Institute of Health at Charité - Universitätsmedizin Berlin (DE), BG University Hospital Bergmannsheil Bochum (DE), Alfried Krupp Hospital (DE), University of Regensburg (DE), Technical University of Munich (DE), Freie Universität Berlin (DE), Medical University of Vienna (AT), Charité - Universitätsmedizin Berlin (DE), Ruhr University Bochum (DE), University of Lübeck (DE)
Openalex Percentile: Top 13%
Amyotrophic Lateral Sclerosis Research
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