{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T16:44:55Z","timestamp":1793724295016,"version":"4.6.1"},"reference-count":34,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T00:00:00Z","timestamp":1788912000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T00:00:00Z","timestamp":1788912000000},"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":["Ann Clin Transl Neurol"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Neurofilament light chain (NfL) is a biomarker of neuroaxonal injury in multiple sclerosis (MS), yet associations with functional outcomes remain unclear. Longitudinal associations between serum NfL (sNfL) and daily step count (STEPS) from wearable devices were assessed in a large international progressive MS cohort.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A post hoc analysis of the Phase III randomized controlled trial SPI2 (high\u2010dose biotin vs. placebo RCT) pooled treatment arms due to no observed therapeutic benefit. Participants with sNfL and step count data were included. STEPS were calculated within \u00b115\u2010days of baseline, 6, 12, 15, and 27\u2010month visits. Mixed\u2010effects models with 1000 bootstrap iterations assessed contemporaneous associations with each measure alternately specified as the outcome, adjusting for age and sex. Lagged models evaluated whether 0\u20136\u2010month sNFL changes predicted subsequent 6\u201312\u2010month STEPS changes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Among 506 participants (53.8% female; mean age 52.7 [SD: 7.7] years; median EDSS 6.0 [4.5\u20136.0]), mean sNfL\n                      <jats:italic>z<\/jats:italic>\n                      \u2010score was 1.00 (SD: 0.95), and median STEPS were 3029 [1708\u20135210]. Higher sNfL was associated with lower STEPS (IRR\u2009=\u20090.97,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.014), consistent across sex, treatment, disability, and disease\u2010modifying treatment status. Conversely, higher STEPS were associated with lower sNfL\n                      <jats:italic>z<\/jats:italic>\n                      \u2010scores; a 10% increase in STEPS corresponded to a 0.015 decrease in sNfL\n                      <jats:italic>z<\/jats:italic>\n                      \u2010score (95% CI \u22120.022 to \u22120.008;\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001). Greater prior 6\u2010month increases in sNfL were associated with a lower subsequent STEPS (\n                      <jats:italic>\u03b2<\/jats:italic>\n                      \u2009=\u2009\u2212141; 95% CI \u2212302 to 21;\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.088; trend), corresponding to 141 fewer steps per 1\u2010SD sNfL increase.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Interpretation<\/jats:title>\n                    <jats:p>Higher sNfL was associated with reduced daily ambulatory activity in progressive MS, and vice versa. Rising sNfL may precede mobility decline, highlighting sNfL as a potential indicator of functional worsening.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial Registration<\/jats:title>\n                    <jats:p>\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/clinicaltrials.gov\">ClinicalTrials.gov<\/jats:ext-link>\n                      NCT02936037; EudraCT database 2016\u2010000700\u201029\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/acn3.70527","type":"journal-article","created":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T07:54:11Z","timestamp":1788940451000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Association Between Neurofilament Light Chain and Real\u2010World Ambulatory Function in Progressive\n                    <scp>MS<\/scp>"],"prefix":"10.1002","author":[{"given":"Gabby B.","family":"Joseph","sequence":"first","affiliation":[{"name":"Department of Radiology and Biomedical Imaging University of California, San Francisco  San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2906-0421","authenticated-orcid":false,"given":"Megan","family":"McCune","sequence":"additional","affiliation":[{"name":"Department of Neurology, UCSF Weill Institute for Neurosciences University of California, San Francisco  San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riley","family":"Bove","sequence":"additional","affiliation":[{"name":"Department of Neurology, UCSF Weill Institute for Neurosciences University of California, San Francisco  San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9731-4169","authenticated-orcid":false,"given":"Ahmed","family":"Abdelhak","sequence":"additional","affiliation":[{"name":"Department of Neurology, UCSF Weill Institute for Neurosciences University of California, San Francisco  San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7689-2533","authenticated-orcid":false,"given":"Bruce A. C.","family":"Cree","sequence":"additional","affiliation":[{"name":"Department of Neurology, UCSF Weill Institute for Neurosciences University of California, San Francisco  San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6199-5484","authenticated-orcid":false,"given":"Valerie J.","family":"Block","sequence":"additional","affiliation":[{"name":"Department of Neurology, UCSF Weill Institute for Neurosciences University of California, San Francisco  San Francisco California USA"},{"name":"Department of Physical Therapy and Rehabilitation Science University of California, San Francisco  San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,9]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"crossref","first-page":"988","DOI":"10.1212\/CON.0000000000001136","article-title":"Epidemiology and Pathophysiology of Multiple Sclerosis","volume":"28","author":"Ward M.","year":"2022","journal-title":"Continuum (Minneapolis, MN)"},{"key":"e_1_2_11_3_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.jneuroim.2023.578268","article-title":"Biomarkers of Disability Worsening in Inactive Primary Progressive Multiple Sclerosis","volume":"387","author":"Baeva M. E.","year":"2024","journal-title":"Journal of Neuroimmunology"},{"key":"e_1_2_11_4_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.ebiom.2024.104970","article-title":"Guidance for Use of Neurofilament Light Chain as a Cerebrospinal Fluid and Blood Biomarker in Multiple Sclerosis Management","volume":"101","author":"Freedman M. S.","year":"2024","journal-title":"eBioMedicine"},{"key":"e_1_2_11_5_1","doi-asserted-by":"crossref","DOI":"10.1212\/NXI.0000000000200052","article-title":"Serum GFAP and NfL Levels Differentiate Subsequent Progression and Disease Activity in Patients With Progressive Multiple Sclerosis","volume":"10","author":"Barro C.","year":"2023","journal-title":"Neurology(R) Neuroimmunology & Neuroinflammation"},{"key":"e_1_2_11_6_1","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1038\/s41582-024-00955-x","article-title":"Neurofilaments as Biomarkers in Neurological Disorders \u2010 Towards Clinical Application","volume":"20","author":"Khalil M.","year":"2024","journal-title":"Nature Reviews Neurology"},{"key":"e_1_2_11_7_1","doi-asserted-by":"crossref","first-page":"3011","DOI":"10.1093\/brain\/awaf144","article-title":"Markers of Axonal Injury in Blood and Tissue Triggered by Acute and Chronic Demyelination","volume":"148","author":"Abdelhak A.","year":"2025","journal-title":"Brain: A Journal of Neurology"},{"key":"e_1_2_11_8_1","doi-asserted-by":"crossref","DOI":"10.3390\/neurolint17040056","article-title":"Neurofilament Light Chain and Multiple Sclerosis: Building a Neurofoundational Model of Biomarkers and Diagnosis","volume":"17","author":"Aburashed R.","year":"2025","journal-title":"Neurology International"},{"key":"e_1_2_11_9_1","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.1001\/jamaneurol.2023.3997","article-title":"Neurofilament Light Chain Elevation and Disability Progression in Multiple Sclerosis","volume":"80","author":"Abdelhak A.","year":"2023","journal-title":"JAMA Neurology"},{"key":"e_1_2_11_10_1","doi-asserted-by":"crossref","first-page":"1359","DOI":"10.1001\/jamaneurol.2019.2137","article-title":"Association Between Serum Neurofilament Light Chain Levels and Long\u2010Term Disease Course Among Patients With Multiple Sclerosis Followed Up for 12\u2009Years","volume":"76","author":"Cant\u00f3 E.","year":"2019","journal-title":"JAMA Neurology"},{"key":"e_1_2_11_11_1","first-page":"1","article-title":"Continuous Daily Assessment of Multiple Sclerosis Disability Using Remote Step Count Monitoring","volume":"264","author":"Block V. J.","year":"2016","journal-title":"Journal of Neurology"},{"key":"e_1_2_11_12_1","doi-asserted-by":"crossref","DOI":"10.1001\/jamanetworkopen.2019.0570","article-title":"Association of Continuous Assessment of Step Count by Remote Monitoring With Disability Progression Among Adults With Multiple Sclerosis","volume":"2","author":"Block V. J.","year":"2019","journal-title":"JAMA Network Open"},{"key":"e_1_2_11_13_1","doi-asserted-by":"crossref","DOI":"10.3389\/fneur.2022.860008","article-title":"Making Every Step Count: Minute\u2010By\u2010Minute Characterization of Step Counts Augments Remote Activity Monitoring in People With Multiple Sclerosis","volume":"13","author":"Block V. J.","year":"2022","journal-title":"Frontiers in Neurology"},{"key":"e_1_2_11_14_1","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1177\/13524585221143726","article-title":"Association of Daily Physical Activity With Brain Volumes and Cervical Spinal Cord Areas in Multiple Sclerosis","volume":"29","author":"Block V. J.","year":"2022","journal-title":"Multiple Sclerosis (Houndmills, Basingstoke, England)"},{"key":"e_1_2_11_15_1","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1001\/jamaneurol.2022.4178","article-title":"Association of Physical Activity With Neurofilament Light Chain Trajectories in Autosomal Dominant Frontotemporal Lobar Degeneration Variant Carriers","volume":"80","author":"Casaletto K. B.","year":"2023","journal-title":"JAMA Neurology"},{"key":"e_1_2_11_16_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.msard.2022.104489","article-title":"Brain\u2010Derived Neurotrophic Factor, Neurofilament Light and Glial Fibrillary Acidic Protein Do Not Change in Response to Aerobic Training in People With MS\u2010Related Fatigue \u2010 a Secondary Analysis of a Randomized Controlled Trial","volume":"70","author":"Gravesteijn A. S.","year":"2022","journal-title":"Multiple Sclerosis and Related Disorders"},{"key":"e_1_2_11_17_1","doi-asserted-by":"crossref","first-page":"3","DOI":"10.2217\/nmt-2017-0033","article-title":"Biomarkers in the Evolution of Multiple Sclerosis","volume":"7","author":"Berger T.","year":"2017","journal-title":"Neurodegenerative Disease Management"},{"key":"e_1_2_11_18_1","doi-asserted-by":"crossref","DOI":"10.1093\/gerona\/glae043","article-title":"Associations of Neurological Biomarkers in Serum With Gait Measures: The Cardiovascular Health Study","volume":"79","author":"Nadkarni A. N.","year":"2024","journal-title":"Journals of Gerontology, Series A, Biological Sciences and Medical Sciences"},{"key":"e_1_2_11_19_1","doi-asserted-by":"crossref","first-page":"988","DOI":"10.1016\/S1474-4422(20)30347-1","article-title":"Safety and Efficacy of MD1003 (High\u2010Dose Biotin) in Patients With Progressive Multiple Sclerosis (SPI2): A Randomised, Double\u2010Blind, Placebo\u2010Controlled, Phase 3 Trial","volume":"19","author":"Cree B. A. C.","year":"2020","journal-title":"Lancet Neurology"},{"key":"e_1_2_11_20_1","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1016\/S1474-4422(17)30470-2","article-title":"Diagnosis of Multiple Sclerosis: 2017 Revisions of the McDonald Criteria","volume":"17","author":"Thompson A. 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W.","year":"2013","journal-title":"PLoS One"},{"key":"e_1_2_11_24_1","doi-asserted-by":"crossref","DOI":"10.1093\/biomtc\/ujaf099","article-title":"Negative Binomial Mixed Effects Location\u2010Scale Models for Intensive Longitudinal Count\u2010Type Physical Activity Data Provided by Wearable Devices","volume":"81","author":"Ma Q.","year":"2025","journal-title":"Biometrics"},{"key":"e_1_2_11_25_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.msard.2025.106637","article-title":"Serum Neurofilament Light Chain as a Biomarker in Multiple Sclerosis: A Cross\u2010Sectional Observation in Real\u2010World Clinical Practice","volume":"103","author":"Sahoo S.","year":"2025","journal-title":"Multiple Sclerosis and Related Disorders"},{"key":"e_1_2_11_26_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.msard.2023.104854","article-title":"NfL and GFAP in Serum Are Associated With Microstructural Brain Damage in Progressive Multiple Sclerosis","volume":"77","author":"Ammitzb\u00f8ll C.","year":"2023","journal-title":"Multiple Sclerosis and Related Disorders"},{"key":"e_1_2_11_27_1","doi-asserted-by":"crossref","DOI":"10.3389\/fneur.2025.1709389","article-title":"Validating Wearable Step Counts in Multiple Sclerosis Research: A Replication Study","volume":"16","author":"Goldman M. 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W.","year":"2022","journal-title":"Multiple Sclerosis and Related Disorders"},{"key":"e_1_2_11_32_1","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1212\/WNL.0000000000010346","article-title":"Serum Neurofilament Light as a Biomarker in Progressive Multiple Sclerosis","volume":"95","author":"Kapoor R.","year":"2020","journal-title":"Neurology"},{"key":"e_1_2_11_33_1","doi-asserted-by":"crossref","first-page":"e203","DOI":"10.1212\/WNL.0000000000011241","article-title":"Efficacy of High\u2010Intensity Aerobic Exercise on Brain MRI Measures in Multiple Sclerosis","volume":"96","author":"Langeskov\u2010Christensen M.","year":"2021","journal-title":"Neurology"},{"key":"e_1_2_11_34_1","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1002\/ana.24954","article-title":"Serum Neurofilament Light: A Biomarker of Neuronal Damage in Multiple Sclerosis","volume":"81","author":"Disanto G.","year":"2017","journal-title":"Annals of Neurology"},{"key":"e_1_2_11_35_1","doi-asserted-by":"crossref","first-page":"2382","DOI":"10.1093\/brain\/awy154","article-title":"Serum Neurofilament as a Predictor of Disease Worsening and Brain and Spinal Cord Atrophy in Multiple Sclerosis","volume":"141","author":"Barro C.","year":"2018","journal-title":"Brain: A Journal of Neurology"}],"container-title":["Annals of Clinical and Translational Neurology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/acn3.70527","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/acn3.70527","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/acn3.70527","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T07:54:16Z","timestamp":1788940456000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/acn3.70527"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,9]]},"references-count":34,"alternative-id":["10.1002\/acn3.70527"],"URL":"https:\/\/doi.org\/10.1002\/acn3.70527","archive":["Portico"],"relation":{},"ISSN":["2328-9503","2328-9503"],"issn-type":[{"value":"2328-9503","type":"print"},{"value":"2328-9503","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,9]]},"assertion":[{"value":"2026-06-05","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-24","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-09","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"acn3.70527"}}