{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T14:40:15Z","timestamp":1792593615495,"version":"4.5.0"},"reference-count":51,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2025,9,29]],"date-time":"2025-09-29T00:00:00Z","timestamp":1759104000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2025,9,29]],"date-time":"2025-09-29T00:00:00Z","timestamp":1759104000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2026,2]]},"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Biomarkers with clear contexts of use are important tools for amyotrophic lateral sclerosis (ALS) therapy development. Understanding their longitudinal trajectory in the untreated state is key to their use as potential markers of pharmacodynamic response. To this end, we undertook a large\u2010scale proteomic study in well\u2010phenotyped cohorts to identify biomarker candidates of ALS disease state and disease progression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Clinical phenotypic data and biofluid samples, collected from patients with ALS and healthy controls through multiple longitudinal natural history studies, were used to identify biomarker candidates. Slow off\u2010rate modified aptamer (SOMAmer)\u2010based relatively quantitative measurement of ~7,000 proteins was performed in plasma and cerebrospinal fluid (CSF), with immunoassay validation of candidates of interest.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We identified 329 plasma proteins significantly differentially regulated between ALS and controls (adjusted\n                      <jats:italic>p<\/jats:italic>\n                      \u2010value &lt;0.05), with 25 showing &gt;40% relative abundance. PDLIM3, TNNT2, and MYL11 had the greatest log\u2010fold elevation, whereas ANTXR2 and ART3 had the greatest log\u2010fold reduction. A similar set of plasma proteins was found to increase (eg, PDLIM3, TNNT2, and MYL11) or decrease (eg, ANTXR2, ART3, and MSTN) with disease progression. CSF proteins with the greatest log\u2010fold elevation included NEFL, NEFH, CHIT1, CA3, MYL11, and GPNMB. These results were confirmed in an independent replication cohort. Moreover, tissue\u2010specific signature enrichment suggests a significant contribution of muscle as a source of these biomarkers. Plasma KCNIP3 was elevated by ~60% in those on riluzole. Immunoassays provided orthogonal validation of plasma TNNT2 and CSF GPNMB.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Interpretation<\/jats:title>\n                    <jats:p>We identified an array of novel biomarkers with the potential to serve as response biomarkers to aid therapy development, as well as to shed light on the underlying biology of disease. ANN NEUROL 2026;99:393\u2013407<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ana.78046","type":"journal-article","created":{"date-parts":[[2025,9,29]],"date-time":"2025-09-29T11:10:26Z","timestamp":1759144226000},"page":"393-407","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Skeletal Muscle Biomarkers of Amyotrophic Lateral Sclerosis: A Large\u2010Scale, Multi\u2010Cohort Proteomic Study"],"prefix":"10.1002","volume":"99","author":[{"given":"Oleksandr","family":"Dergai","sequence":"first","affiliation":[{"name":"Diseases of Aging and Regenerative Medicine Novartis Biomedical Research  Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-9643-9855","authenticated-orcid":false,"given":"Joanne","family":"Wuu","sequence":"additional","affiliation":[{"name":"Department of Neurology and ALS Center University of Miami Miller School of Medicine  Miami FL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magdalena","family":"Koziczak\u2010Holbro","sequence":"additional","affiliation":[{"name":"Diseases of Aging and Regenerative Medicine Novartis Biomedical Research  Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8020-7567","authenticated-orcid":false,"given":"Andrea","family":"Malaspina","sequence":"additional","affiliation":[{"name":"UCL Queen Square Motor Neuron Disease Center, UCL Queen Square Institute of Neurology, University College London, Queen Square  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6519-7225","authenticated-orcid":false,"given":"Volkan","family":"Granit","sequence":"additional","affiliation":[{"name":"Department of Neurology and ALS Center University of Miami Miller School of Medicine  Miami FL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica P.","family":"Hernandez","sequence":"additional","affiliation":[{"name":"Department of Neurology and ALS Center University of Miami Miller School of Medicine  Miami FL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Cooley","sequence":"additional","affiliation":[{"name":"Department of Neurology and ALS Center University of Miami Miller School of Medicine  Miami FL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruchika","family":"Sachdev","sequence":"additional","affiliation":[{"name":"Biomarker Development Novartis Biomedical Research  Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lili","family":"Yu","sequence":"additional","affiliation":[{"name":"Biomarker Development Novartis Biomedical Research  Cambridge MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Bidinosti","sequence":"additional","affiliation":[{"name":"Diseases of Aging and Regenerative Medicine Novartis Biomedical Research  Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ludivine","family":"Flotte","sequence":"additional","affiliation":[{"name":"Diseases of Aging and Regenerative Medicine Novartis Biomedical Research  Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3985-3989","authenticated-orcid":false,"given":"Mark","family":"Nash","sequence":"additional","affiliation":[{"name":"Diseases of Aging and Regenerative Medicine Novartis Biomedical Research  Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lori L.","family":"Jennings","sequence":"additional","affiliation":[{"name":"Disease Area X, Novartis Biomedical Research  Cambridge MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0898-6081","authenticated-orcid":false,"given":"James D.","family":"Berry","sequence":"additional","affiliation":[{"name":"Sean M. 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