Multiple sclerosis is a highly heterogeneous disease, and the detection of neuroaxonal damage as well as its quantification is a critical step for patients. Blood-based serum neurofilament light chain (sNfL) is currently under close investigation as an easily accessible biomarker of prognosis and treatment response in patients with multiple sclerosis. There is abundant evidence that sNfL levels reflect ongoing inflammatory-driven neuroaxonal damage (e.g. relapses or MRI disease activity) and that sNfL levels predict disease activity over the next few years. In contrast, the association of sNfL with long-term clinical outcomes or its ability to reflect slow, diffuse neurodegenerative damage in multiple sclerosis is less clear. However, early results from real-world cohorts and clinical trials using sNfL as a marker of treatment response in multiple sclerosis are encouraging. Importantly, clinical algorithms should now be developed that incorporate the routine use of sNfL to guide individualized clinical decision-making in people with multiple sclerosis, together with additional fluid biomarkers and clinical and MRI measures. Here, we propose specific clinical scenarios where implementing sNfL measures may be of utility, including, among others: initial diagnosis, first treatment choice, surveillance of subclinical disease activity and guidance of therapy selection.

Department of Neurology and Center of Clinical Neuroscience 1st Faculty of Medicine Charles University and General University Hospital Prague 116 36 Czech Republic

Department of Neurology Focus Program Translational Neuroscience University Medical Center of the Johannes Gutenberg University Mainz Mainz 55131 Germany

Department of Neurology Hospital General Universitari Vall D'Hebron Cemcat Barcelona 08035 Spain

Division of Neurology Department of Medicine St Michael's Hospital University of Toronto Toronto Ontario M5S 3H2 Canada

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Reich DS, Lucchinetti CF, Calabresi PA.. Multiple sclerosis. N Engl J Med. 2018;378(2):169–180. PubMed PMC

Suthiphosuwan S, Kim D, Bharatha A, Oh J.. Imaging markers for monitoring disease activity in multiple sclerosis. Curr Treat Options Neurol. 2017;19(5):18. PubMed

Khalil M, Teunissen CE, Otto M, et al.Neurofilaments as biomarkers in neurological disorders. Nat Rev Neurol. 2018;14(10):577–589. PubMed

Uphaus T, Bittner S, Groschel S, et al.NfL (neurofilament light chain) levels as a predictive marker for long-term outcome after ischemic stroke. Stroke. 2019;50(11):3077–3084. PubMed

Moseby-Knappe M, Mattsson N, Nielsen N, et al.Serum neurofilament light chain for prognosis of outcome after cardiac arrest. JAMA Neurol. 2019;76(1):64–71. PubMed PMC

Bridel C, van Wieringen WN, Zetterberg H, et al.; the NFL Group. Diagnostic value of cerebrospinal fluid neurofilament light protein in neurology: A systematic review and meta-analysis. JAMA Neurol. 2019;76(9):1035. PubMed PMC

Aktas O, Renner A, Huss A, et al.Serum neurofilament light chain: No clear relation to cognition and neuropsychiatric symptoms in stable MS. Neurol Neuroimmunol Neuroinflamm. 2020;7(6):e885. PubMed PMC

Disanto G, Barro C, Benkert P, et al.; the Swiss Multiple Sclerosis Cohort Study Group. Serum neurofilament light: A biomarker of neuronal damage in multiple sclerosis. Ann Neurol. 2017;81(6):857–870. PubMed PMC

Varhaug KN, Barro C, Bjornevik K, et al.Neurofilament light chain predicts disease activity in relapsing-remitting MS. Neurol Neuroimmunol Neuroinflamm. 2018;5(1):e422. PubMed PMC

Rosengren LE, Karlsson JE, Karlsson JO, Persson LI, Wikkelso C.. Patients with amyotrophic lateral sclerosis and other neurodegenerative diseases have increased levels of neurofilament protein in CSF. J Neurochem. 1996;67(5):2013–2018. PubMed

Lycke JN, Karlsson JE, Andersen O, Rosengren LE.. Neurofilament protein in cerebrospinal fluid: potential marker of activity in multiple sclerosis. J Neurol Neurosurg Psychiatry. 1998;64(3):402–404. PubMed PMC

Rissin DM, Kan CW, Campbell TG, et al.Single-molecule enzyme-linked immunosorbent assay detects serum proteins at subfemtomolar concentrations. Nat Biotechnol. 2010;28(6):595–599. PubMed PMC

Kuhle J, Barro C, Andreasson U, et al.Comparison of three analytical platforms for quantification of the neurofilament light chain in blood samples: ELISA, electrochemiluminescence immunoassay and Simoa. Clin Chem Lab Med. 2016;54(10):1655–1661. PubMed

Kuhle J, Barro C, Disanto G, et al.Serum neurofilament light chain in early relapsing remitting MS is increased and correlates with CSF levels and with MRI measures of disease severity. Mult Scler. 2016;22(12):1550–1559. PubMed

Novakova L, Zetterberg H, Sundstrom P, et al.Monitoring disease activity in multiple sclerosis using serum neurofilament light protein. Neurology. 2017;89(22):2230–2237. PubMed PMC

Myhr KM, Torkildsen O.. Serum NFL levels should be used to monitor multiple sclerosis evolution-No. Mult Scler. 2020;26(1):19–21. PubMed

Altmann P, Leutmezer F, Zach H, et al.Serum neurofilament light chain withstands delayed freezing and repeated thawing. Sci Rep. 2020;10(1):19982. PubMed PMC

Keshavan A, Heslegrave A, Zetterberg H, Schott JM.. Stability of blood-based biomarkers of Alzheimer’s disease over multiple freeze-thaw cycles. Alzheimers Dement (Amst). 2018;10:448–451. PubMed PMC

Comabella M, Montalban X.. Body fluid biomarkers in multiple sclerosis. Lancet Neurol. 2014;13(1):113–126. PubMed

Housley WJ, Pitt D, Hafler DA.. Biomarkers in multiple sclerosis. Clin Immunol. 2015;161(1):51–58. PubMed

Bittner S, Steffen F, Uphaus T, et al.; KKNMS Consortium. Clinical implications of serum neurofilament in newly diagnosed MS patients: A longitudinal multicentre cohort study. EBioMedicine. 2020;56:102807. PubMed PMC

Bsteh G, Berek K, Hegen H, et al.Serum neurofilament levels correlate with retinal nerve fiber layer thinning in multiple sclerosis. Mult Scler. 2019;26(13):1682–1690. PubMed

Barro C, Benkert P, Disanto G, et al.Serum neurofilament as a predictor of disease worsening and brain and spinal cord atrophy in multiple sclerosis. Brain. 2018;141(8):2382–2391. PubMed

Canto E, Barro C, Zhao C, et al.Association between serum neurofilament light chain levels and long-term disease course among patients with multiple sclerosis followed up for 12 years. JAMA Neurol. 2019;76(11):1359. PubMed PMC

Barro C, Chitnis T, Weiner HL.. Blood neurofilament light: a critical review of its application to neurologic disease. Ann Clin Transl Neurol. 2020;7(12):2508–2523. PubMed PMC

Thebault S, Booth RA, Rush CA, MacLean H, Freedman MS.. Serum neurofilament light chain measurement in MS: hurdles to clinical translation. Front Neurosci. 2021;15:654942. PubMed PMC

Kapoor R, Smith KE, Allegretta M, et al.Serum neurofilament light as a biomarker in progressive multiple sclerosis. Neurology. 2020;95(10):436–444. PubMed PMC

Kuhle J, Barro C, Hrusovsky K, Chang L, Jeromin A.. International multi-site analytical validation of the Simoa NF-light assay in human serum samples from multiple sclerosis patients. Mult Scler. 2018;24:249–251.

Sharma A, Petrillo M, Zhao G, Unkown A, Unkown A.. Strategic platform selection and validation of biomarker assays to measure serum neurofilament light and heavy chain in multiple sclerosis. Mult Scler. 2018;24:660–661.

Gauthier A, Viel S, Perret M, et al.; OFSEP Investigators. Comparison of Simoa(TM) and Ella(TM) to assess serum neurofilament-light chain in multiple sclerosis. Ann Clin Transl Neurol. 2021;8(5):1141–1150. PubMed PMC

Freedman M, Gnanapavan S.. Letter to the Editor: Consensus statement on neurofilament proteins in multiple sclerosis under development by Consortium of Multiple Sclerosis Centers (CMSC) expert panel. Int J MS Care. 2020;22(6):294. PubMed PMC

Chitnis T. Serum NFL levels should be used to monitor multiple sclerosis evolution-Commentary. Mult Scler. 2020;26(1):21–22. PubMed

Kim H, Lee EJ, Kim S, et al.Serum biomarkers in myelin oligodendrocyte glycoprotein antibody-associated disease. Neurol Neuroimmunol Neuroinflamm. 2020;7(3):e708. PubMed PMC

Peng L, Bi C, Xia D, Mao L, Qian H.. Increased cerebrospinal fluid neurofilament light chain in central nervous system inflammatory demyelinating disease. Mult Scler Relat Disord. 2019;30:123–128. PubMed

Watanabe M, Nakamura Y, Michalak Z, et al.Serum GFAP and neurofilament light as biomarkers of disease activity and disability in NMOSD. Neurology. 2019;93(13):e1299–e1311. PubMed

Dalla Costa G, Martinelli V, Moiola L, et al.Serum neurofilaments increase at progressive multifocal leukoencephalopathy onset in natalizumab-treated multiple sclerosis patients. Ann Neurol. 2019;85(4):606–610. PubMed

Bjornevik K, Munger KL, Cortese M, et al.Serum neurofilament light chain levels in patients with presymptomatic multiple sclerosis. JAMA Neurol. 2019;77(1):58. PubMed PMC

Matute-Blanch C, Villar LM, Alvarez-Cermeno JC, et al.Neurofilament light chain and oligoclonal bands are prognostic biomarkers in radiologically isolated syndrome. Brain. 2018;141(4):1085–1093. PubMed

Miller DH, Chard DT, Ciccarelli O.. Clinically isolated syndromes. Lancet Neurol. 2012;11(2):157–169. PubMed

Arrambide G, Espejo C, Eixarch H, et al.Neurofilament light chain level is a weak risk factor for the development of MS. Neurology. 2016;87(11):1076–1084. PubMed PMC

van der Vuurst de Vries RM, Wong YYM, Mescheriakova JY, et al.High neurofilament levels are associated with clinically definite multiple sclerosis in children and adults with clinically isolated syndrome. Mult Scler. 2019;25(7):958–967. PubMed PMC

Teunissen CE, Iacobaeus E, Khademi M, et al.Combination of CSF N-acetylaspartate and neurofilaments in multiple sclerosis. Neurology. 2009;72(15):1322–1329. PubMed

Dalla Costa G, Martinelli V, Sangalli F, et al.Prognostic value of serum neurofilaments in patients with clinically isolated syndromes. Neurology. 2019;92(7):e733–e741. PubMed PMC

Siller N, Kuhle J, Muthuraman M, et al.Serum neurofilament light chain is a biomarker of acute and chronic neuronal damage in early multiple sclerosis. Mult Scler. 2019;25(5):678–686. PubMed

Zipp F, Oh J, Fragoso YD, Waubant E.. Implementing the 2017 McDonald criteria for the diagnosis of multiple sclerosis. Nat Rev Neurol. 2019;15(8):441–445. PubMed

Srpova B, Uher T, Hrnciarova T, et al.Serum neurofilament light chain reflects inflammation-driven neurodegeneration and predicts delayed brain volume loss in early stage of multiple sclerosis. Mult Scler. 2021;27(1):52–60. PubMed

Uher T, McComb M, Galkin S, et al.Neurofilament levels are associated with blood-brain barrier integrity, lymphocyte extravasation, and risk factors following the first demyelinating event in multiple sclerosis. Mult Scler. 2020;27(2):220–231. PubMed

Sellebjerg F, Royen L, Soelberg Sorensen P, Oturai AB, Jensen PEH.. Prognostic value of cerebrospinal fluid neurofilament light chain and chitinase-3-like-1 in newly diagnosed patients with multiple sclerosis. Mult Scler. 2019;25(11):1444–1451. PubMed

Kuhle J, Nourbakhsh B, Grant D, et al.Serum neurofilament is associated with progression of brain atrophy and disability in early MS. Neurology. 2017;88(9):826–831. PubMed PMC

Disanto G, Adiutori R, Dobson R, et al.; International Clinically Isolated Syndrome Study Group. Serum neurofilament light chain levels are increased in patients with a clinically isolated syndrome. J Neurol Neurosurg Psychiatry. 2016;87(2):126–129. PubMed

Jakimovski D, Kuhle J, Ramanathan M, et al.Serum neurofilament light chain levels associations with gray matter pathology: a 5-year longitudinal study. Ann Clin Transl Neurol. 2019;6(9):1757–1770. PubMed PMC

Chitnis T, Gonzalez C, Healy BC, et al.Neurofilament light chain serum levels correlate with 10-year MRI outcomes in multiple sclerosis. Ann Clin Transl Neur. 2018;5(12):1478–1491. PubMed PMC

Bhan A, Jacobsen C, Myhr KM, Dalen I, Lode K, Farbu E.. Neurofilaments and 10-year follow-up in multiple sclerosis. Mult Scler. 2018;24(10):1301–1307. PubMed

Manouchehrinia A, Stridh P, Khademi M, et al.Plasma neurofilament light levels are associated with risk of disability in multiple sclerosis. Neurology. 2020;94(23):e2457–e2467. PubMed PMC

Thebault S, Abdoli M, Fereshtehnejad SM, Tessier D, Tabard-Cossa V, Freedman MS.. Serum neurofilament light chain predicts long term clinical outcomes in multiple sclerosis. Sci Rep. 2020;10(1):10381. PubMed PMC

Leppert D, Kuhle J.. Blood neurofilament light chain at the doorstep of clinical application. Neurol Neuroimmunol Neuroinflamm. 2019;6(5):e599. PubMed PMC

Magliozzi R, Howell OW, Nicholas R, et al.Inflammatory intrathecal profiles and cortical damage in multiple sclerosis. Ann Neurol. 2018;83(4):739–755. PubMed

Rosso M, Gonzalez CT, Healy BC, et al.Temporal association of sNfL and gad-enhancing lesions in multiple sclerosis. Ann Clin Transl Neurol. 2020;7(6):945–955 PubMed PMC

Dutta R, Trapp BD.. Mechanisms of neuronal dysfunction and degeneration in multiple sclerosis. Prog Neurobiol. 2011;93(1):1–12. PubMed PMC

Jakimovski D, Zivadinov R, Ramanthan M, et al.Serum neurofilament light chain level associations with clinical and cognitive performance in multiple sclerosis: A longitudinal retrospective 5-year study. Mult Scler. 2019;26(13):1670–1681. PubMed

Kappos L, Wolinsky JS, Giovannoni G, et al.Contribution of relapse-independent progression vs relapse-associated worsening to overall confirmed disability accumulation in typical relapsing multiple sclerosis in a pooled analysis of 2 randomized clinical trials. JAMA Neurol. 2020;77(9):1132–1140. PubMed PMC

Quintana E, Coll C, Salavedra-Pont J, et al.Cognitive impairment in early stages of multiple sclerosis is associated with high cerebrospinal fluid levels of chitinase 3-like 1 and neurofilament light chain. Eur J Neurol. 2018;25(9):1189–1191. PubMed

Delcoigne B, Manouchehrinia A, Barro C, et al.Blood neurofilament light levels segregate treatment effects in multiple sclerosis. Neurology. 2020;94(11):e1201–e1212. PubMed PMC

Gaetani L, Salvadori N, Lisetti V, et al.Cerebrospinal fluid neurofilament light chain tracks cognitive impairment in multiple sclerosis. J Neurol. 2019;266(9):2157–2163. PubMed

Kuhle J, Kropshofer H, Barro C, Unkown A, Unkown A.. The predictive value of neurofilament light chain levels in blood for cognitive impairment in patients with secondary progressive multiple sclerosis (S12.009). Neurology. 2019;92:S12.009

Fleischer V, Muthuraman M, Anwar AR, et al.Continuous reorganization of cortical information flow in multiple sclerosis: A longitudinal fMRI effective connectivity study. Sci Rep. 2020;10(1):806. PubMed PMC

Geurts JJ, Calabrese M, Fisher E, Rudick RA.. Measurement and clinical effect of grey matter pathology in multiple sclerosis. Lancet Neurol. 2012;11(12):1082–1092. PubMed

Abdelhak A, Huss A, Kassubek J, Tumani H, Otto M.. Serum GFAP as a biomarker for disease severity in multiple sclerosis. Sci Rep. 2018;8(1):14798. PubMed PMC

Hogel H, Rissanen E, Barro C, et al.Serum glial fibrillary acidic protein correlates with multiple sclerosis disease severity. Mult Scler. 2020;26(2):210–219. PubMed

Norgren N, Sundstrom P, Svenningsson A, Rosengren L, Stigbrand T, Gunnarsson M.. Neurofilament and glial fibrillary acidic protein in multiple sclerosis. Neurology. 2004;63(9):1586–1590. PubMed

Saraste M, Bezukladova S, Matilainen M, et al.High serum neurofilament associates with diffuse white matter damage in MS. Neurol Neuroimmunol Neuroinflamm. 2021;8(1):e926. PubMed PMC

Huss A, Otto M, Senel M, Ludolph AC, Abdelhak A, Tumani H.. A score based on NfL and glial markers may differentiate between relapsing-remitting and progressive MS course. Front Neurol. 2020;11:608. PubMed PMC

Bittner S, Ruck T, Wiendl H, Grauer OM, Meuth SG.. Targeting B cells in relapsing-remitting multiple sclerosis: from pathophysiology to optimal clinical management. Ther Adv Neurol Disord. 2017;10(1):51–66. PubMed PMC

Engel S, Steffen F, Uphaus T, et al.Association of intrathecal pleocytosis and IgG synthesis with axonal damage in early MS. Neurol Neuroimmunol Neuroinflamm. 2020;7(3):e679. PubMed PMC

Farina G, Magliozzi R, Pitteri M, et al.Increased cortical lesion load and intrathecal inflammation is associated with oligoclonal bands in multiple sclerosis patients: a combined CSF and MRI study. J Neuroinflammation. 2017;14(1):40. PubMed PMC

Engel S, Friedrich M, Muthuraman M, et al.Intrathecal B-cell accumulation and axonal damage distinguish MRI-based benign from aggressive onset in MS. Neurol Neuroimmunol Neuroinflamm. 2019;6(5):e595. PubMed PMC

Magliozzi R, Howell OW, Durrenberger P, et al.Meningeal inflammation changes the balance of TNF signalling in cortical grey matter in multiple sclerosis. J Neuroinflammation. 2019;16(1):259. PubMed PMC

Magliozzi R, Pitteri M, Ziccardi S, et al.CSF parvalbumin levels reflect interneuron loss linked with cortical pathology in multiple sclerosis. Ann Clin Transl Neurol. 2021;8(3):534–547. PubMed PMC

Khalil M, Pirpamer L, Hofer E, et al.Serum neurofilament light levels in normal aging and their association with morphologic brain changes. Nat Commun. 2020;11(1):812. PubMed PMC

Vagberg M, Norgren N, Dring A, et al.Levels and age dependency of neurofilament light and glial fibrillary acidic protein in healthy individuals and their relation to the brain parenchymal fraction. PLoS One. 2015;10(8):e0135886. PubMed PMC

Gunnarsson M, Malmestrom C, Axelsson M, et al.Axonal damage in relapsing multiple sclerosis is markedly reduced by natalizumab. Ann Neurol. 2011;69(1):83–89. PubMed

Sejbaek T, Nielsen HH, Penner N, et al.Dimethyl fumarate decreases neurofilament light chain in CSF and blood of treatment naive relapsing MS patients. J Neurol Neurosurg Psychiatry. 2019;90(12):1324–1330. PubMed PMC

Preziosa P, Rocca MA, Filippi M.. Current state-of-art of the application of serum neurofilaments in multiple sclerosis diagnosis and monitoring. Expert Rev Neurother. 2020;20(8):747–769. PubMed

Kuhle J, Kropshofer H, Haering DA, et al.Blood neurofilament light chain as a biomarker of MS disease activity and treatment response. Neurology. 2019;92(10):e1007–e1015. PubMed PMC

Sormani MP, Haering DA, Kropshofer H, et al.Blood neurofilament light as a potential endpoint in phase 2 studies in MS. Ann Clin Transl Neurol. 2019;6(6):1081–1089. PubMed PMC

Fyfe I. Trials take MS treatment forward. Nat Rev Neurol. 2019;15(11):620. PubMed

Bittner S, Zipp F.. AAN unveils new guidelines for MS disease-modifying therapy. Nat Rev Neurol. 2018;14(7):384–386. PubMed

Piehl F, Kockum I, Khademi M, et al.Plasma neurofilament light chain levels in patients with MS switching from injectable therapies to fingolimod. Mult Scler. 2018;24(8):1046–1054. PubMed

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