Journal Article

DZNE-2026-01118

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Anatomically Defined Motor Phenotypes Reveal Dissociated Trajectories of Progression, Neurofilament Profiles, and Survival in ALS.

Meyer, T. ; Grehl, T. ; Schumann, P. ; Weyen, U. ; Rödiger, A. ; Smesny, U. ; Ilse, B. ; Weydt, P.DZNE* ; Bernsen, S.DZNE* ; Fabian, R.DZNE* ; Göricke, B. ; Petri, S. ; Lumi, R. ; Bjelica, B. ; Großkreutz, J. ; Cetin, H. ; Keritam, O. ; Haimberger, F. ; Korsukewitz, C. ; Löscher, W. ; Kohl, Z. ; Regensburger, M. ; Baum, P. ; Metelmann, M. ; Kettemann, D. ; Norden, J. ; Steinbach, R. ; Körtvélyessy, P.Extern* ; Lingor, P.DZNE* ; McFarlane, R. ; Münch, C. ; Boentert, M. ; Maier, A.

2026
Wiley-Blackwell Oxford [u.a.]

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Please use a persistent id in citations: doi:10.1111/ene.70798

Abstract: 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.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.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).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.

Keyword(s): Humans (MeSH) ; Amyotrophic Lateral Sclerosis: mortality (MeSH) ; Amyotrophic Lateral Sclerosis: blood (MeSH) ; Amyotrophic Lateral Sclerosis: pathology (MeSH) ; Amyotrophic Lateral Sclerosis: physiopathology (MeSH) ; Amyotrophic Lateral Sclerosis: classification (MeSH) ; Disease Progression (MeSH) ; Neurofilament Proteins: blood (MeSH) ; Female (MeSH) ; Phenotype (MeSH) ; Male (MeSH) ; Middle Aged (MeSH) ; Motor Neurons: pathology (MeSH) ; Aged (MeSH) ; Cohort Studies (MeSH) ; amyotrophic lateral sclerosis ; motor phenotypes ; neurofilament light chain ; propagation ; survival ; Neurofilament Proteins ; neurofilament protein L

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Contributing Institute(s):

1. Clinical Research Coordination (Clinical Research (Bonn))
2. Clinical Neuroimaging (AG Radbruch)
3. Clinical Research (Munich) (Clinical Research (Munich))

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

Appears in the scientific report 2026

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; ; Article Processing Charges ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; DEAL Wiley ; DOAJ Seal ; Ebsco Academic Search ; Essential Science Indicators ; Fees ; IF >= 5 ; JCR ; PubMed Central ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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