{ "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.\n\nMethods: 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.\n\nResults: 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).\n\nConclusions: 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.", "abstract_shown": true, "affiliations": [ "Department of Neurology, Center for ALS and Other Motor Neuron Disorders Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt‐Universität Zu Berlin, and Berlin Institute of Health Berlin Germany", "APST Research Berlin Germany", "Department of Neurology, Center for ALS and Other Motor Neuron Disorders Alfried Krupp Krankenhaus Essen Germany", "Department of Neurology, BG University Hospital Bergmannsheil Ruhr University Bochum Bochum Germany", "Department of Neurology Jena University Hospital Jena Germany", "ZSE, Zentrum für Seltene Erkrankungen Jena University Hospital Jena Germany", "Department for Neuromuscular Disorders Bonn University Bonn Germany", "DZNE, Deutsches Zentrum für Neurodegenerative Erkrankungen, Research Site Bonn Germany", "Department of Neurology Universitätsmedizin Göttingen Göttingen Germany", "Department of Neurology Hannover Medical School Hannover Germany", "Department of Neurology Diakovere Henriettenstift and Friederikenstift Hannover Germany", "PRACTIS Clinician Scientist Program, Dean's Office for Academic Career Development Hannover Medical School Hannover Germany", "Department of Neurology Universitätsmedizin Schleswig‐Holstein Lübeck Germany", "Department of Neurology Medical University of Vienna Vienna Austria", "Comprehensive Center for Clinical Neurosciences and Mental Health Medical University of Vienna Vienna Austria", "Department of Neurology Münster University Hospital Münster Germany", "Department of Neurology Medical University Innsbruck Innsbruck Austria", "Department of Neurology University of Regensburg Regensburg Germany", "Department of Molecular Neurology Friedrich‐Alexander‐University Erlangen‐Nürnberg Erlangen Germany", "Center for Rare Diseases Erlangen (ZSEER) University Hospital Erlangen Erlangen Germany", "Department of Neurology University Hospital Leipzig Leipzig Germany", "Department of Neurology, Klinikum Rechts der Isar Technical University of Munich Munich Germany", "DZNE, Deutsches Zentrum für Neurodegenerative Erkrankungen, Research Site Munich Germany", "Academic Unit of Neurology, Trinity Biomedical Sciences Institute, School of Medicine Trinity College Dublin, The University of Dublin Dublin Ireland", "Neuromedizinisches Zentrum Klinikum Osnabrück Osnabrück Germany" ], "article_type": "research article", "arxiv": null, "author_total": 33, "authors": [ { "affs": [ 0, 1 ], "name": "Thomas Meyer", "orcid": "0000-0002-2736-7350" }, { "affs": [ 2 ], "name": "Torsten Grehl", "orcid": "0000-0002-0631-6976" }, { "affs": [ 0, 1 ], "name": "Peggy Schumann", "orcid": "0009-0003-4936-7225" }, { "affs": [ 3 ], "name": "Ute Weyen" }, { "affs": [ 4, 5 ], "name": "Annekathrin Rödiger" }, { "affs": [ 4 ], "name": "Uta Smesny" }, { "affs": [ 4 ], "name": "Benjamin Ilse", "orcid": "0000-0002-2260-0803" }, { "affs": [ 6, 7 ], "name": "Patrick Weydt", "orcid": "0000-0003-2344-5662" }, { "affs": [ 0, 6, 7 ], "name": "Sarah Bernsen", "orcid": "0000-0001-7485-2626" }, { "affs": [ 6, 7 ], "name": "Rachel Fabian" }, { "affs": [ 8 ], "name": "Bettina Göricke" }, { "affs": [ 9, 10 ], "name": "Susanne Petri" }, { "affs": [ 9 ], "name": "Rea Lumi", "orcid": "0009-0003-9248-4099" }, { "affs": [ 9, 11 ], "name": "Bogdan Bjelica", "orcid": "0000-0002-1783-703X" }, { "affs": [ 12 ], "name": "Julian Großkreutz" }, { "affs": [ 13, 14 ], "name": "Hakan Cetin", "orcid": "0000-0001-9009-7261" }, { "affs": [ 13, 14 ], "name": "Omar Keritam", "orcid": "0000-0002-6819-5006" }, { "affs": [ 13, 14 ], "name": "Friedrich Haimberger" }, { "affs": [ 15 ], "name": "Catharina Korsukewitz" }, { "affs": [ 16 ], "name": "Wolfgang Löscher", "orcid": "0000-0002-7593-3222" }, { "affs": [ 17 ], "name": "Zaharias Kohl", "orcid": "0000-0002-4147-8866" }, { "affs": [ 18, 19 ], "name": "Martin Regensburger", "orcid": "0000-0002-2172-7386" }, { "affs": [ 20 ], "name": "Petra Baum" }, { "affs": [ 21 ], "name": "Moritz Metelmann", "orcid": "0000-0002-8670-6148" }, { "affs": [ 0 ], "name": "Dagmar Kettemann" }, { "affs": [ 0 ], "name": "Jenny Norden" }, { "affs": [ 4 ], "name": "Robert Steinbach", "orcid": "0000-0003-3936-6010" }, { "affs": [ 0 ], "name": "Péter Körtvélyessy", "orcid": "0000-0003-1262-6169" }, { "affs": [ 21, 22 ], "name": "Paul Lingor", "orcid": "0000-0001-9362-7096" }, { "affs": [ 0, 23 ], "name": "Robert McFarlane", "orcid": "0000-0001-7380-4219" }, { "affs": [ 0, 1 ], "name": "Christoph Münch" }, { "affs": [ 24 ], "name": "Matthias Boentert" }, { "affs": [ 0 ], "name": "André Maier", "orcid": "0000-0003-2473-4116" } ], "bibtex": "https://research.draconitic.com/paper/4ncz1dj14pn1a.bib", "cited_by": 0, "doi": "10.1111/ene.70798", "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13714081/", "id": "4ncz1dj14pn1a", "issns": [ "1351-5101", "1468-1331" ], "landing_url": "https://doi.org/10.1111/ene.70798", "language": "en", "licence": "CC-BY-4.0", "licence_label": "CC BY 4.0", "licence_source": "article", "licence_url": "https://creativecommons.org/licenses/by/4.0/", "metadata_licence": null, "native_subjects": [ [ "heading", "Original Article" ], [ "openalex", "2728|Amyotrophic Lateral Sclerosis Research" ] ], "openalex": "W7224108841", "pdf_url": "https://onlinelibrary.wiley.com/doi/pdfdirect/10.1111/ene.70798", "pmcid": "PMC13714081", "pmid": "42947290", "published": "2026-10-27", "publisher": "Wiley", "ris": "https://research.draconitic.com/paper/4ncz1dj14pn1a.ris", "sources": [ { "first_seen": "2026-11-01T12:21:38Z", "native_id": "PMC13714081", "source": "pmc", "url": "https://doi.org/10.1111/ene.70798" } ], "subjects": [ { "field": "medicine", "origin": "openalex:2728|Amyotrophic Lateral Sclerosis Research", "subfield": "neurology" } ], "title": "Anatomically Defined Motor Phenotypes Reveal Dissociated Trajectories of Progression, Neurofilament Profiles, and Survival in ALS", "title_text": "Anatomically Defined Motor Phenotypes Reveal Dissociated Trajectories of Progression, Neurofilament Profiles, and Survival in ALS", "type": "peer-reviewed", "updated_at": "2026-11-01T12:21:38Z", "url": "https://research.draconitic.com/paper/4ncz1dj14pn1a", "venue": "European Journal of Neurology", "versions": [] }