{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T04:50:40Z","timestamp":1791262240751,"version":"4.1.0"},"reference-count":10,"publisher":"Springer Science and Business Media LLC","issue":"10","license":[{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T00:00:00Z","timestamp":1791244800000},"content-version":"vor","delay-in-days":5,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100000406","name":"Motor Neurone Disease Association","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000406","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000971","name":"ALS Association","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000971","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Neurol"],"published-print":{"date-parts":[[2026,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder with substantial clinical heterogeneity, complicating the design and interpretation of clinical trials. Two strategies have been proposed to address this variability: phenotype-based prognostic modelling and biomarker-based stratification using neurofilaments. We aimed to determine whether a widely used phenotype-based method, the TRICALS risk score, could substitute for neurofilament biomarkers in a clinical trial.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We used data from the MIROCALS phase 2b randomised controlled trial of low-dose interleukin-2 in ALS (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u2009220). The TRICALS risk score was calculated for each participant. The published biomarker model includes CSF phosphorylated neurofilament heavy chain (pNFH) and a pNFH\u2009\u00d7\u2009treatment interaction. We analysed the effects of replacing CSF pNFH with the TRICALS risk score and of adding TRICALS score as an additional covariate to the original model. Model performance was assessed using likelihood ratio \u03c7\n                      <jats:sup>2<\/jats:sup>\n                      statistics and\u2009\u2212\u20092 log likelihood (\u2212\u20092LL). The primary outcome was survival.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      TRICALS risk score was moderately correlated with CSF pNFH (\n                      <jats:italic>r<\/jats:italic>\n                      \u2009=\u20090.357), explaining 12.7% of shared variance. Substituting CSF pNFH with TRICALS score reduced model performance (\u2212\u20092LL 928.25 vs 793.36). The TRICALS\u2009\u00d7\u2009treatment interaction was statistically significant (hazard ratio [HR] 0.72, 95% CI 0.54\u20130.96\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.025), but contributed modestly to model fit (\u0394\u03c7\n                      <jats:sup>2<\/jats:sup>\n                      \u2009=\u20094.76), compared with the pNFH\u2009\u00d7\u2009treatment interaction (\u0394\u03c7\n                      <jats:sup>2<\/jats:sup>\n                      \u2009=\u200914.24). Incorporating the pNFH\u2009\u00d7\u2009treatment interaction significantly improved model fit and identified a treatment effect (HR 0.28, 95% CI 0.12\u20130.63;\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.002).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>The TRICALS risk score does not substitute for CSF neurofilament biomarkers as a prognostic or stratification variable but provides complementary information.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00415-026-14040-4","type":"journal-article","created":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T03:57:09Z","timestamp":1791259029000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["TRICALS risk score augments but cannot replace neurofilament as a prognostic biomarker in ALS"],"prefix":"10.1007","volume":"273","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7406-9831","authenticated-orcid":false,"given":"Ahmad","family":"Al Khleifat","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Malaspina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janine","family":"Kirby","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy","family":"Tree","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pamela J.","family":"Shaw","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P. Nigel","family":"Leigh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ammar","family":"Al-Chalabi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,10,6]]},"reference":[{"key":"14040_CR1","doi-asserted-by":"publisher","DOI":"10.12688\/f1000research.10476.1","volume":"6","author":"S Martin","year":"2017","unstructured":"Martin S, Al Khleifat A, Al-Chalabi A (2017) What causes amyotrophic lateral sclerosis? F1000Res 6:371. https:\/\/doi.org\/10.12688\/f1000research.10476.1","journal-title":"F1000Res"},{"key":"14040_CR2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2024.105323","author":"M Benatar","year":"2024","unstructured":"Benatar M, Macklin EA, Malaspina A et al (2024) Prognostic clinical and biological markers for amyotrophic lateral sclerosis disease progression: validation and implications for clinical trial design and analysis. EBioMedicine. https:\/\/doi.org\/10.1016\/j.ebiom.2024.105323","journal-title":"EBioMedicine"},{"key":"14040_CR3","doi-asserted-by":"publisher","DOI":"10.1186\/s40035-021-00257-y","author":"S Witzel","year":"2021","unstructured":"Witzel S, Frauhammer F, Steinacker P et al (2021) Neurofilament light and heterogeneity of disease progression in amyotrophic lateral sclerosis: development and validation of a prediction model to improve interventional trials. Transl Neurodegener. https:\/\/doi.org\/10.1186\/s40035-021-00257-y","journal-title":"Transl Neurodegener"},{"key":"14040_CR4","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(18)30089-9","author":"H-J Westeneng","year":"2018","unstructured":"Westeneng H-J, Debray TPA, Visser AE et al (2018) Prognosis for patients with amyotrophic lateral sclerosis: development and validation of a personalised prediction model. Lancet Neurol. https:\/\/doi.org\/10.1016\/S1474-4422(18)30089-9","journal-title":"Lancet Neurol"},{"key":"14040_CR5","doi-asserted-by":"publisher","DOI":"10.1177\/22143602251336058","author":"T Simkins Lead","year":"2025","unstructured":"Simkins Lead T, Shefner JM, Kupfer S et al (2025) Application of the ENCALS predictive survival model in assessing the effect of the 24 44 inclusion criteria in FORTITUDE ALS. J Neuromuscul Dis. https:\/\/doi.org\/10.1177\/22143602251336058","journal-title":"J Neuromuscul Dis"},{"key":"14040_CR6","doi-asserted-by":"publisher","DOI":"10.1080\/21678421.2019.1632899","author":"J Gold","year":"2019","unstructured":"Gold J, Rowe DB, Kiernan MC et al (2019) Safety and tolerability of Triumeq in amyotrophic lateral sclerosis: the Lighthouse trial. Amyotroph Lateral Scler Frontotemporal Degener. https:\/\/doi.org\/10.1080\/21678421.2019.1632899","journal-title":"Amyotroph Lateral Scler Frontotemporal Degener"},{"key":"14040_CR7","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(25)00262-4","author":"G Bensimon","year":"2025","unstructured":"Bensimon G, Leigh PN, Tree T et al (2025) Efficacy and safety of low-dose IL-2 as an add-on therapy to riluzole (MIROCALS): a phase 2b, double-blind, randomised, placebo-controlled trial. Lancet. https:\/\/doi.org\/10.1016\/S0140-6736(25)00262-4","journal-title":"Lancet"},{"key":"14040_CR8","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2025.1636303","author":"T Roy","year":"2025","unstructured":"Roy T, Al-Chalabi A, Iacoangeli A et al (2025) Biomarkers in ALS trials: from discovery to clinical utility. Front Neurosci. https:\/\/doi.org\/10.3389\/fnins.2025.1636303","journal-title":"Front Neurosci"},{"key":"14040_CR9","doi-asserted-by":"publisher","DOI":"10.1186\/s13024-025-00890-5","author":"F Theunissen","year":"2025","unstructured":"Theunissen F, Flynn L, Iacoangeli A et al (2025) Entering the era of precision medicine to treat amyotrophic lateral sclerosis. Mol Neurodegener. https:\/\/doi.org\/10.1186\/s13024-025-00890-5","journal-title":"Mol Neurodegener"},{"key":"14040_CR10","doi-asserted-by":"publisher","DOI":"10.1038\/s41582-020-00434-z","author":"MC Kiernan","year":"2021","unstructured":"Kiernan MC, Vucic S, Talbot K et al (2021) Improving clinical trial outcomes in amyotrophic lateral sclerosis. Nat Rev Neurol. https:\/\/doi.org\/10.1038\/s41582-020-00434-z","journal-title":"Nat Rev Neurol"}],"container-title":["Journal of Neurology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00415-026-14040-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00415-026-14040-4","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00415-026-14040-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T03:57:10Z","timestamp":1791259030000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00415-026-14040-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10]]},"references-count":10,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2026,10]]}},"alternative-id":["14040"],"URL":"https:\/\/doi.org\/10.1007\/s00415-026-14040-4","relation":{},"ISSN":["0340-5354","1432-1459"],"issn-type":[{"value":"0340-5354","type":"print"},{"value":"1432-1459","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10]]},"assertion":[{"value":"11 April 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 July 2026","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 July 2026","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 October 2026","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"AA-C declares contracts with the MRC, NIHR and Darby Rimmer Foundation; consulting fees from Amylyx, Apellis, Biogen, Clene Therapeutics, Cytokinetics, GenieUs, GSK, Lilly, Mitsubishi Tanabe Pharma, Novartis, OrionPharma, Quralis, Sano, Sanofi and Vecalis, and is a judge for the Longitude Prize in ALS. AAK declares contracts with the UK National Endowment for Science, Technology and the Arts (NESTA) and Black Swan Biotech. AM, JK, TT, PNL, and AAC have intellectual property rights for licensing MIROCALS trial data for exploitation by ILTOO Pharma, and are named on 2 patent applications\u00a0(AAC on 1) related to the use of IL2\n                      LD\n                      in ALS.","order":1,"name":"Ethics","label":"Conflicts of interest","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"643"}}