OSCR

What do ALS motor phenotypes measure? A population-based decomposition of their prognostic dimensions.

Overview

Authors: Andrea Calvo1,2, Cristina Moglia1,2, Stefano Callegaro1, Antonio Canosa1,2, Umberto Manera1,2, Gabriele Mora1, Sara Cabras1, Francesca Palumbo1, Enrico Matteoni1, Alessandra Maccabeo1, Giorgio Pellegrino1, Emilio Minerva1, Daniela Pascariu1, Fabrizio D’Ovidio1, Rosario Vasta1, Letizia Mazzini3,4, Fabiola De Marchi3,4, Adriano Chiò1,2
ORCID iDs: Andrea Calvo, Cristina Moglia, Stefano Callegaro, Antonio Canosa, Umberto Manera, Gabriele Mora, Sara Cabras, Francesca Palumbo, Enrico Matteoni, Alessandra Maccabeo, Giorgio Pellegrino, Emilio Minerva, Daniela Pascariu, Fabrizio D’Ovidio, Rosario Vasta, Letizia Mazzini, Fabiola De Marchi, Adriano Chiò
  1. ‘Rita Levi Montalcini’ Department of Neuroscience, University of Torino, via Cherasco 15, 10126 Turin, Italy
  2. Azienda Ospedaliero Universitaria Città Della Salute E Della Scienza, Turin, Italy
  3. Department of Translational Medicine, University of Eastern Piedmont, Novara, Italy
  4. Azienda Ospedaliero Universitaria Maggiore Della Carità Novara, Novara, Italy
Institutions: Azienda Ospedaliera Citta' della Salute e della Scienza di Torino (Italy); University of Turin (Italy); Università degli Studi del Piemonte Orientale “Amedeo Avogadro” (Italy); Azienda Ospedaliero Universitaria Maggiore della Carita (Italy)
Journal: Journal of neurology, volume 273, issue 10, article 604
Dates: received 3 August 2026; accepted 5 September 2026; published online 18 September 2026; in print 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1007/s00415-026-14134-z · PMID 42758317 · PMCID PMC13588936 · OpenAlex W7213553838
Open access: hybrid, a free copy (OpenAlex)
Status: code on request
Categories: human (organism), other condition (population), clinical / translational (subfield)
Methods: Connectivity, Machine learning, Statistics, Smoothing, state filtering, decompositions
Keywords: Amyotrophic lateral sclerosis, Motor phenotype, Prognosis, Population-based registry, Survival analysis, Disease staging
MeSH: Amyotrophic Lateral Sclerosis*, Motor Neurons*, Aged, Female, Humans, Male, Middle Aged, Phenotype, Prognosis, Prospective Studies, Registries (* major topic)
Topic: Amyotrophic Lateral Sclerosis Research (Neurology, Medicine), according to OpenAlex
Funding: Horizon 2020 Framework Programme (101017598); European Research Council (259867); Ministero della Salute (PNRR-MAD-2022-12375731, RF-2016-02362405); Ministero dell’Istruzione, dell’Università e della Ricerca (2017SNW5MB)
Citations: not cited yet (Europe PMC); 29 references in the paper

Abstract

Background: The ALS-OPM 3.3 classification stratifies incident ALS through three axes: onset region (O), propagation time (P) and motor-neuron pattern (M). We assessed whether OPM 3.3 improves prognostic discrimination over established classifications and characterised how it decomposes their prognostic signal in a population-based cohort.

Methods: In the prospective Piedmont and Aosta Valley ALS Register (2000–2022), patients were classified on the three axes; M was operationalised as M_3class (M0 balanced, M1d UMN-predominant, M2d LMN-predominant), with the PLS-spectrum M1p analysed separately. Outcome was survival (death or tracheostomy) from onset. Multivariable Cox models (O, P1(n), M_3class, age, sex) underwent bootstrap optimism-correction and fivefold cross-validation, and were compared against alternative taxonomies and clinical staging systems.

Results: Amongst 2,738 non-PLS patients (2,561 events, 93.5%), median survival differed across M classes (M0 27.0, M2d 36.0, M1d 41.9 months). OPM 3.3 outperformed the bulbar/spinal dichotomy but matched the classical phenotype (optimism-corrected C-index 0.703, 95% CI 0.685–0.719 vs 0.701). In the arm-proximal cell (95.7% M2d), the O2p protective effect vanished after M adjustment (HR 0.99, 95% CI 0.79–1.24), whilst M2d retained HR 0.83 (95% CI 0.72–0.95), showing prognosis reflects motor-neuron pattern, not anatomy. Adding King’s, Milano-Torino (MiToS), or Fine’til 9 (FT9) clinical staging further improved discrimination.

Conclusions: OPM 3.3 did not improve discrimination over established phenotypes but decomposed their prognostic signal into independently interpretable dimensions. Favourable prognosis of arm-proximal/flail-arm onset reflects the underlying LMN-predominant phenotype, not onset site. The motor-neuron axis is robust to the treatment of the propagation axis and independent of clinical staging.

Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1007/s00415-026-14134-z.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

The paper says that its authors' code is available on request: it was not published with the paper, so there is nothing to verify.

The paper's code and data availability statement is in the Data section.

Tracing map

A tracing map links a paper to the code its authors published: this paper has none (its code is available on request), so it has no map.

Data

No dataset and no data link were found in the paper.

Data availability

The PARALS clinical data and the code reproducing the analyses are available from the corresponding author upon reasonable request, subject to ethical approval.

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 3, 28 September 2026

  • Publisher: n/a → Springer Science+Business Media

Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 18 authors, 6 keywords, 11 MeSH terms, 4 funders, 29 references.

Cite

This paper

Calvo, A., Moglia, C., Callegaro, S., Canosa, A., Manera, U., Mora, G., Cabras, S., Palumbo, F., Matteoni, E., Maccabeo, A., Pellegrino, G., Minerva, E., Pascariu, D., D’Ovidio, F., Vasta, R., Mazzini, L., De Marchi, F., & Chiò, A. (2026). What do ALS motor phenotypes measure? A population-based decomposition of their prognostic dimensions. Journal of neurology, 273(10), 604. https://doi.org/10.1007/s00415-026-14134-z

BibTeX

@article{calvo2026what,
author = {Calvo, Andrea and Moglia, Cristina and Callegaro, Stefano and Canosa, Antonio and Manera, Umberto and Mora, Gabriele and Cabras, Sara and Palumbo, Francesca and Matteoni, Enrico and Maccabeo, Alessandra and Pellegrino, Giorgio and Minerva, Emilio and Pascariu, Daniela and D’Ovidio, Fabrizio and Vasta, Rosario and Mazzini, Letizia and De Marchi, Fabiola and Chiò, Adriano},
title = {{What do ALS motor phenotypes measure? A population-based decomposition of their prognostic dimensions}},
journal = {Journal of neurology},
year = {2026},
month = sep,
volume = {273},
number = {10},
pages = {604},
publisher = {Springer Science+Business Media},
issn = {0340-5354},
doi = {10.1007/s00415-026-14134-z},
url = {https://doi.org/10.1007/s00415-026-14134-z},
pmid = {42758317},
pmcid = {PMC13588936}
}

RIS

TY - JOUR
AU - Calvo, Andrea
AU - Moglia, Cristina
AU - Callegaro, Stefano
AU - Canosa, Antonio
AU - Manera, Umberto
AU - Mora, Gabriele
AU - Cabras, Sara
AU - Palumbo, Francesca
AU - Matteoni, Enrico
AU - Maccabeo, Alessandra
AU - Pellegrino, Giorgio
AU - Minerva, Emilio
AU - Pascariu, Daniela
AU - D’Ovidio, Fabrizio
AU - Vasta, Rosario
AU - Mazzini, Letizia
AU - De Marchi, Fabiola
AU - Chiò, Adriano
TI - What do ALS motor phenotypes measure? A population-based decomposition of their prognostic dimensions
T2 - Journal of neurology
J2 - J Neurol
PY - 2026
DA - 2026/09/18
VL - 273
IS - 10
SP - 604
SN - 0340-5354
PB - Springer Science+Business Media
DO - 10.1007/s00415-026-14134-z
UR - https://doi.org/10.1007/s00415-026-14134-z
LA - en
ER -

CSL-JSON

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