{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T17:50:19Z","timestamp":1791309019747,"version":"4.3.1"},"reference-count":46,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T00:00:00Z","timestamp":1791244800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Serum neurofilament light chain (sNfL) is a well-established biomarker of neuroaxonal injury in multiple sclerosis (MS), associated with inflammatory disease activity, treatment response, and future clinical outcomes. As a downstream marker of tissue injury rather than a direct readout of a specific immune pathway, its increasing availability raises a more demanding question: when does sNfL provide enough additional information to improve management of an individual patient? This review examines sNfL from the perspective of clinical actionability and personalized decision support rather than biomarker validity alone. Reliable patient-level use requires analytical comparability, consideration of biological and clinical confounders, individualized normalization, temporal context, and longitudinal interpretation. Even when these conditions are met, clinical value depends on whether sNfL adds meaningful information beyond established clinical and magnetic resonance imaging monitoring. Current evidence best supports its role as a decision-support biomarker: unexpected or persistent abnormalities may justify verification, closer surveillance, or targeted reassessment, whereas normal values cannot reliably exclude clinically relevant MS biology, including relapse-independent disability accumulation. This asymmetry, together with the limited disease specificity of sNfL, argues against universal treatment thresholds and supports complementary biomarker and multimodal approaches. Evidence that sNfL predicts outcomes or influences intended management does not establish that acting on this information improves patient outcomes. Prospective studies are beginning to address this translational gap by evaluating sNfL-informed management strategies. The key remaining step is to demonstrate that acting on sNfL information\u2014not merely measuring or interpreting it\u2014improves clinically meaningful outcomes. Until then, sNfL is best positioned for biomarker-informed personalized monitoring rather than fully biomarker-guided care.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1979820","type":"journal-article","created":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T16:51:15Z","timestamp":1791305475000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Beyond biomarker validation: defining when serum neurofilament light chain should influence management in multiple sclerosis"],"prefix":"10.3389","volume":"17","author":[{"given":"Ana Bel\u00e9n","family":"Caminero","sequence":"first","affiliation":[{"name":"Department of Neurology, Complejo Asistencial de \u00c1vila","place":["\u00c1vila, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,10,6]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(22)00009-6","article-title":"Serum neurofilament light chain for individual prognostication of disease activity in people with multiple sclerosis: a retrospective modelling and validation study","volume":"21","author":"Benkert","year":"2022","journal-title":"Lancet Neurol"},{"key":"B2","doi-asserted-by":"publisher","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","year":"2024","journal-title":"EBioMedicine"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1038\/s41582-024-00955-x","article-title":"Neurofilaments as biomarkers in neurological disorders\u2014towards clinical application","volume":"20","author":"Khalil","year":"2024","journal-title":"Nat Rev Neurol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1097\/EDE.0b013e3181c30fb2","article-title":"Assessing the performance of prediction models: a framework for traditional and novel measures","volume":"21","author":"Steyerberg","year":"2010","journal-title":"Epidemiology"},{"key":"B5","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1186\/s41512-018-0037-2","article-title":"Quantifying the added value of new biomarkers: how and how not","volume":"2","author":"Cook","year":"2018","journal-title":"Diagn Progn Res"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1177\/13524585241277044","article-title":"Impact of serum neurofilament light on clinical decisions in a tertiary multiple sclerosis clinic","volume":"30","author":"van Lierop","year":"2024","journal-title":"Mult Scler"},{"key":"B7","doi-asserted-by":"publisher","first-page":"607","DOI":"10.1186\/s13063-024-08454-6","article-title":"MultiSCRIPT-Cycle 1\u2014a pragmatic trial embedded within the Swiss Multiple Sclerosis Cohort (SMSC) on neurofilament light chain monitoring to inform personalized treatment decisions in multiple sclerosis: a study protocol for a randomized clinical trial","volume":"25","author":"Janiaud","year":"2024","journal-title":"Trials"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1136\/bmjopen-2025-110058","article-title":"Application of serum neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP) as biomarkers in the clinical management of multiple sclerosis (NeuroFilMS): a protocol for an observational cohort study","volume":"16","author":"Rust","year":"2026","journal-title":"BMJ Open"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2026.1815022","article-title":"Serum neurofilament light chain in multiple sclerosis: from biological signal to clinically informed decision-making","volume":"17","author":"Caminero","year":"2026","journal-title":"Front Neurol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1177\/0272989X06295361","article-title":"Decision curve analysis: a novel method for evaluating prediction models","volume":"26","author":"Vickers","year":"2006","journal-title":"Med Decis Making"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2362.2011.02562.x","article-title":"Assessing the incremental value of diagnostic and prognostic markers: a review and illustration","volume":"42","author":"Steyerberg","year":"2012","journal-title":"Eur J Clin Invest"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.i6","article-title":"Net benefit approaches to the evaluation of prediction models, molecular markers, and diagnostic tests","volume":"352","author":"Vickers","year":"2016","journal-title":"BMJ"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1017\/S026646231800048X","article-title":"Evidence required by health technology assessment and reimbursement bodies evaluating diagnostic or prognostic algorithms that include omics data","volume":"34","author":"Barna","year":"2018","journal-title":"Int J Technol Assess Health Care"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/j.msard.2026.107330","article-title":"Is serum neurofilament light chain accurate enough to guide multiple sclerosis care? Diagnostic performance and optimal cutoff in a systematic review and meta-analysis","volume":"112","author":"Santana","year":"2026","journal-title":"Mult Scler Relat Disord"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1111\/ene.70505","article-title":"Neurofilament light chain concentration in the prediction of treatment response in multiple sclerosis","volume":"33","author":"Moradi","year":"2026","journal-title":"Eur J Neurol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1016\/j.msard.2024.105838","article-title":"Does serum neurofilament light chain measurement influence therapeutic decisions in multiple sclerosis","volume":"90","author":"Saposnik","year":"2024","journal-title":"Mult Scler Relat Disord"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1177\/13524585261423032","article-title":"Are neurofilament light chain levels ready for routine clinical use?\u2014Yes","volume":"32","author":"Sandgren","year":"2026","journal-title":"Mult Scler"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1177\/13524585261423029","article-title":"Are neurofilament light chain levels ready for routine clinical use?\u2014No","volume":"32","author":"Sotirchos","year":"2026","journal-title":"Mult Scler"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1515\/cclm-2026-0944","article-title":"Serum neurofilament light chain as a biomarker of inflammatory activity in relapsing-remitting multiple sclerosis: a real-world longitudinal cohort study","author":"de Las Heras Fl\u00f3rez","year":"2026","journal-title":"Clin Chem Lab Med"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/j.cca.2025.120447","article-title":"Validation and generation of age-specific reference intervals for a new blood neurofilament light chain assay","volume":"577","author":"Booth","year":"2025","journal-title":"Clin Chim Acta"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/j.msard.2025.106637","article-title":"Serum neurofilament light chain as a biomarker in multiple sclerosis: a cross-sectional observation in real-world clinical practice","volume":"103","author":"Sahoo","year":"2025","journal-title":"Mult Scler Relat Disord"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1002\/acn3.50972","article-title":"Confounding effect of blood volume and body mass index on blood neurofilament light chain levels","volume":"7","author":"Manouchehrinia","year":"2020","journal-title":"Ann Clin Transl Neurol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(23)00210-7","article-title":"Serum neurofilament light chain reference database for individual application in paediatric care: a retrospective modelling and validation study","volume":"22","author":"Abdelhak","year":"2023","journal-title":"Lancet Neurol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1002\/acn3.70149","article-title":"Serum neurofilament light chain in multiple sclerosis: superiority of age- and BMI-corrected Z scores\/percentiles over absolute cutoff values for prediction of treatment response","volume":"12","author":"Einsiedler","year":"2025","journal-title":"Ann Clin Transl Neurol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000007032","article-title":"Blood neurofilament light chain as a biomarker of MS disease activity and treatment response","volume":"92","author":"Kuhle","year":"2019","journal-title":"Neurology"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000209357","article-title":"Temporal relationship between serum neurofilament light chain and radiologic disease activity in patients with multiple sclerosis","volume":"102","author":"Fox","year":"2024","journal-title":"Neurology"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000218451","article-title":"Refining treatment monitoring in patients with relapsing multiple sclerosis based on changes on neurofilament light chain Z-scores","volume":"107","author":"Fern\u00e1ndez","year":"2026","journal-title":"Neurology"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1212\/NXI.0000000000000555","article-title":"Profiling individual clinical responses by high-frequency serum neurofilament assessment in MS","volume":"6","author":"Akg\u00fcn","year":"2019","journal-title":"Neurol Neuroimmunol Neuroinflamm"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1007\/s00415-024-12701-w","article-title":"In multiple sclerosis patients a single serum neurofilament light chain (sNfL) dosage is strongly associated with 12 months outcome: data from a real-life clinical setting","volume":"271","author":"Malucchi","year":"2024","journal-title":"J Neurol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1016\/j.msard.2023.104695","article-title":"Early neurofilament light and glial fibrillary acidic protein levels improve predictive models of multiple sclerosis outcomes","volume":"74","author":"Bose","year":"2023","journal-title":"Mult Scler Relat Disord"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1177\/17562864251374903","article-title":"Prognostic value of blood-based biomarkers in multiple sclerosis patients in the absence of clinical relapses or new MRI lesions","volume":"18","author":"Brummer","year":"2025","journal-title":"Ther Adv Neurol Disord"},{"key":"B32","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1002\/acn3.51704","article-title":"Associations of sNfL with clinico-radiological measures in a large MS population","volume":"10","author":"Sotirchos","year":"2023","journal-title":"Ann Clin Transl Neurol"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneuroim.2026.578928","article-title":"Tracking the invisible: impact of disease-modifying therapies on serum neurofilament light chain and clinical outcomes in treatment-na\u00efve multiple sclerosis","volume":"417","author":"Khedr","year":"2026","journal-title":"J Neuroimmunol"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1177\/13524585251407973","article-title":"Neurofilament light chain as a surrogate candidate for disease activity in multiple sclerosis (LUMINOUS)\u2014a meta-regression of randomized controlled trials","volume":"32","author":"Pretzsch","year":"2026","journal-title":"Mult Scler"},{"key":"B35","doi-asserted-by":"publisher","first-page":"670","DOI":"10.1007\/s10072-026-09284-x","article-title":"Comorbidities in multiple sclerosis: acquired hepatocerebral degeneration mimicking disease progression","volume":"47","author":"Einsiedler","year":"2026","journal-title":"Neurol Sci"},{"key":"B36","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1186\/s12974-018-1249-7","article-title":"Neurofilament levels, disease activity and brain volume during follow-up in multiple sclerosis","volume":"15","author":"H\u00e5kansson","year":"2018","journal-title":"J Neuroinflamm"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2023.3997","article-title":"Neurofilament light chain elevation and disability progression in multiple sclerosis","volume":"80","author":"Abdelhak","year":"2023","journal-title":"JAMA Neurol"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2022.5250","article-title":"Serum glial fibrillary acidic protein compared with neurofilament light chain as a biomarker for disease progression in multiple sclerosis","volume":"80","author":"Meier","year":"2023","journal-title":"JAMA Neurol"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1002\/acn3.51969","article-title":"Serum glial fibrillary acidic protein and disability progression in progressive multiple sclerosis","volume":"11","author":"Abdelhak","year":"2024","journal-title":"Ann Clin Transl Neurol"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awaf433","article-title":"GFAP and NfL as predictors of disease progression and relapse activity in fingolimod-treated multiple sclerosis","volume":"149","author":"Maleska Maceski","year":"2026","journal-title":"Brain"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1016\/j.msard.2026.107439","article-title":"Prognostic effect of serum glial fibrillary acidic protein and neurofilament light chain for predicting progression independent of relapse activity in multiple sclerosis: a systematic review","volume":"114","author":"Maazi","year":"2026","journal-title":"Mult Scler Relat Disord"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1212\/NXI.0000000000200167","article-title":"Increasing neurofilament and glial fibrillary acidic protein after treatment discontinuation predicts multiple sclerosis disease activity","volume":"10","author":"Bose","year":"2023","journal-title":"Neurol Neuroimmunol Neuroinflamm"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1016\/j.msard.2026.107343","article-title":"Discontinuation of disease-modifying therapies in patients with multiple sclerosis: a retrospective case-control study","volume":"112","author":"Caba\u00f1as Engenios","year":"2026","journal-title":"Mult Scler Relat Disord"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awae260","article-title":"Serum biomarkers at disease onset for personalized therapy in multiple sclerosis","volume":"147","author":"Monreal","year":"2024","journal-title":"Brain"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp-2025-335831","article-title":"Blood biomarkers for predicting disability worsening in progressive multiple sclerosis: a multinational, individual participant-level analysis","volume":"96","author":"Abdelhak","year":"2025","journal-title":"J Neurol Neurosurg Psychiatry"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1177\/13524585251335466","article-title":"Personalized treatment decision algorithms for the clinical application of serum neurofilament light chain in multiple sclerosis: a modified Delphi study","volume":"31","author":"Yaldizli","year":"2025","journal-title":"Mult Scler"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1979820\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T16:51:16Z","timestamp":1791305476000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1979820\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,6]]},"references-count":46,"alternative-id":["10.3389\/fimmu.2026.1979820"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1979820","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,6]]},"article-number":"1979820"}}