{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T08:07:40Z","timestamp":1788941260569,"version":"build-2803163510"},"reference-count":44,"publisher":"Springer Science and Business Media LLC","issue":"10","license":[{"start":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T00:00:00Z","timestamp":1788912000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T00:00:00Z","timestamp":1788912000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Merck"}],"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>Objective<\/jats:title>\n                    <jats:p>This study investigated the predictive value of neurofilament light chain (NfL) levels beyond MRI measures of disease activity in multiple sclerosis (MS).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This study is a retrospective post hoc analysis of the early interferon treatment group of the combined 5-year REFLEX\/REFLEXION studies in clinically isolated syndrome. Baseline z-scored NfL (zNfL) and changes in zNfL during the first two years were related to brain atrophy, lesion activity, and clinical progression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      This study included 262 patients (61.83% female, mean age 31.68 \u00b1 8.43, median Expanded Disability Status Scale 1.5). Mean zNfL levels were highest at baseline and higher in patients with gadolinium-enhancing lesions or high T2 lesion counts (\n                      <jats:italic>p<\/jats:italic>\n                      &lt; 0.001). Baseline zNfL correlated with higher volumes of T2 lesions at baseline and new\/enlarging\/shrinking\/disappearing lesions in years 1 and 2 (\n                      <jats:italic>r<\/jats:italic>\n                      <jats:sub>s<\/jats:sub>\n                      = 0.20\u20130.68,\n                      <jats:italic>p<\/jats:italic>\n                      = 0.002\u2013 &lt;0.001), faster subsequent central atrophy (\n                      <jats:italic>r<\/jats:italic>\n                      = 0.16,\n                      <jats:italic>p<\/jats:italic>\n                      = 0.035), and an increased risk of and faster conversion to clinically definite MS (OR = 1.18,\n                      <jats:italic>p<\/jats:italic>\n                      = 0.035; HR = 1.16,\n                      <jats:italic>p<\/jats:italic>\n                      = 0.021). Baseline zNfL was no longer predictive when including baseline MRI variables and demographics. Longitudinal zNfL changes correlated especially with shrinking lesions during year 1 (\n                      <jats:italic>r<\/jats:italic>\n                      <jats:sub>s<\/jats:sub>\n                      = \u2212\u20090.42,\n                      <jats:italic>p<\/jats:italic>\n                      &lt; 0.001) and new\/enlarging lesions during year 2 (\n                      <jats:italic>r<\/jats:italic>\n                      <jats:sub>s<\/jats:sub>\n                      = 0.26 and 0.23,\n                      <jats:italic>p<\/jats:italic>\n                      &lt; 0.001). Subsequent global and central atrophy (\n                      <jats:italic>r<\/jats:italic>\n                      = \u22120.18,\n                      <jats:italic>p<\/jats:italic>\n                      = 0.025;\n                      <jats:italic>r<\/jats:italic>\n                      = 0.20,\n                      <jats:italic>p<\/jats:italic>\n                      = 0.015) were only related to zNfL changes during year 2, even after including baseline MRI variables and demographics.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>Cross-sectional zNfL was related to active disease and predictive of disease progression, but not after taking MRI measures into account. The longitudinal zNfL changes were related to lesion activity and subsequent atrophy, even after including MRI measures.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00415-026-14100-9","type":"journal-article","created":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T06:32:30Z","timestamp":1788935550000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The predictive value of serum neurofilament light chain levels beyond MRI measures for clinical and radiological disease progression in the earliest stages of multiple sclerosis"],"prefix":"10.1007","volume":"273","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5876-4260","authenticated-orcid":false,"given":"Rozemarijn M.","family":"Mattiesing","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8481-2801","authenticated-orcid":false,"given":"Giordano","family":"Gentile","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9188-4408","authenticated-orcid":false,"given":"Marco","family":"Battaglini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4930-7639","authenticated-orcid":false,"given":"Nicola","family":"De Stefano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0408-0461","authenticated-orcid":false,"given":"Iman","family":"Brouwer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6705-5864","authenticated-orcid":false,"given":"Eva M. 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Brain 148:4578\u20134591","journal-title":"Brain"}],"container-title":["Journal of Neurology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00415-026-14100-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00415-026-14100-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00415-026-14100-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T08:03:23Z","timestamp":1788941003000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00415-026-14100-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,9]]},"references-count":44,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2026,10]]}},"alternative-id":["14100"],"URL":"https:\/\/doi.org\/10.1007\/s00415-026-14100-9","relation":{},"ISSN":["0340-5354","1432-1459"],"issn-type":[{"value":"0340-5354","type":"print"},{"value":"1432-1459","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,9]]},"assertion":[{"value":"30 April 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 August 2026","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 August 2026","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 September 2026","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"This work was funded by Merck (CrossRef Funder ID: https:\/\/doi.org\/10.13039\/100009945) as part of a collaborative research project. Merck reviewed this manuscript for medical accuracy only before journal submission. The authors are fully responsible for the content of this manuscript, and the views and opinions described in the publication reflect solely those of the authors. R.M. Mattiesing has received research support from Merck; G. Gentile reports no disclosures relevant to the manuscript; M. Battaglini reports no disclosures relevant to the manuscript; N. De Stefano is a consultant for Biogen, Merck, Novartis, Sanofi-Genzyme, Roche, and Teva; has grants or grants pending from FISM and Novartis, is on the speakers\u2019 bureaus of Biogen, Merck, Novartis, Roche, Sanofi-Genzyme, and Teva; and has received travel funds from Merck, Novartis, Roche, Sanofi-Genzyme, and Teva; I. Brouwer has received research support from Merck, Novartis, Teva, and the Dutch MS Research Foundation; E.M.M. Strijbis has received speaker fees from Merck and Novartis; B.M.J. Uitdehaag reports consultancy fees from Immunic Therapeutics; F. Barkhof is a steering committee or Data Safety Monitoring Board member for Biogen, Merck, Eisai, and Prothena; Advisory board member for Combinostics and Scottish Brain Sciences; Consultant for Roche, Celltrion, Rewind Therapeutics, Merck, and Bracco; Research agreements with ADDI, Merck, Biogen, GE Healthcare, and Roche; Co-founder and shareholder of Queen Square Analytics LTD; H. Vrenken has received research support from Merck, Novartis, Pfizer, and Teva, consulting fees from Merck, and speaker honoraria from Novartis; all funds were paid to his institution; M.M. Schoonheim serves on the editorial board of Neurology, Multiple Sclerosis Journal and Frontiers in Neurology, receives research support from the Dutch MS Research Foundation, Eurostars-EUREKA, ARSEP, Amsterdam Neuroscience and ZonMW (Vidi grant, project number 09150172010056) and has served as a consultant for or received research support from Atara Biotherapeutics, Biogen, Celgene\/Bristol Meyers Squibb, EIP, Sanofi, MedDay and Merck.","order":1,"name":"Ethics","label":"Conflicts of interest","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"This retrospective post hoc analysis is covered by the ethical approvals of the REFLEX\/REFLEXION studies, which were approved by the relevant institutional review board or independent ethics committee of each participating center (see Supplementary Material for a list of the participating centers that obtained ethical approval). As described previously [\n                      \n                      ,\n                      \n                      ], the REFLEX and REFLEXION studies were undertaken in compliance with the Declaration of Helsinki and standards of Good Clinical Practice according to the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use. Before initiation of the studies at each center, the relevant institutional review board or independent ethics committee reviewed and approved the study protocols, patient information leaflets, informed consent forms, and investigator brochures. All patients provided written informed consent at the screening visit of REFLEX, and before enrollment to REFLEXION.","order":2,"name":"Ethics","label":"Ethical approval","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"584"}}