Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Observational Study
. 2023 Dec 1;80(12):1317-1325.
doi: 10.1001/jamaneurol.2023.3997.

Neurofilament Light Chain Elevation and Disability Progression in Multiple Sclerosis

Ahmed Abdelhak  1 , Pascal Benkert  2   3   4 , Sabine Schaedelin  2   3   4 , W John Boscardin  5 , Christian Cordano  1   6   7 , Johanna Oechtering  3   4 , Kirtana Ananth  1 , Cristina Granziera  3   4   8 , Lester Melie-Garcia  3   4   8 , Shivany Condor Montes  1 , Alexandra Beaudry-Richard  1 , Lutz Achtnichts  9 , Frederike C Oertel  1 , Patrice H Lalive  10 , David Leppert  3   4 , Stefanie Müller  11 , Roland G Henry  1 , Caroline Pot  12 , Amandine Matthias  12 , Anke Salmen  13 , Jorge R Oksenberg  1 , Giulio Disanto  14   15 , Chiara Zecca  14   15 , Marcus D'Souza  3   4 , Renaud Du Pasquier  12 , Claire Bridel  10 , Claudio Gobbi  14   15 , Ludwig Kappos  3   4 , Stephen L Hauser  1 , Bruce A C Cree  1 , Jens Kuhle  2   3   4 , Ari J Green  1   16 ; UCSF, MS EPIC, and the SMSC Study Teams
Collaborators, Affiliations
Observational Study

Neurofilament Light Chain Elevation and Disability Progression in Multiple Sclerosis

Ahmed Abdelhak et al. JAMA Neurol. .

Abstract

Importance: Mechanisms contributing to disability accumulation in multiple sclerosis (MS) are poorly understood. Blood neurofilament light chain (NfL) level, a marker of neuroaxonal injury, correlates robustly with disease activity in people with MS (MS); however, data on the association between NfL level and disability accumulation have been conflicting.

Objective: To determine whether and when NfL levels are elevated in the context of confirmed disability worsening (CDW).

Design, setting, and participants: This study included 2 observational cohorts: results from the Expression, Proteomics, Imaging, Clinical (EPIC) study at the University of California San Francisco (since 2004) were confirmed in the Swiss Multiple Sclerosis Cohort (SMSC), a multicenter study in 8 centers since 2012. Data were extracted from EPIC in April 2022 (sampling July 1, 2004, to December 20, 2016) and SMSC in December 2022 (sampling June 6, 2012, to September 2, 2021). The study included 2 observational cohorts in tertiary MS centers. All participants of both cohorts with available NfL results were included in the study, and no eligible participants were excluded or declined to participate.

Exposure: Association between NfL z scores and CDW.

Main outcome measures: CDW was defined as Expanded Disability Status Scale (EDSS) worsening that was confirmed after 6 or more months and classified into CDW associated with clinical relapses (CDW-R) or independent of clinical relapses (CDW-NR). Visits were classified in relation to the disability worsening events into CDW(-2) for 2 visits preceding event, CDW(-1) for directly preceding event, CDW(event) for first diagnosis of EDSS increase, and the confirmation visit. Mixed linear and Cox regression models were used to evaluate NfL dynamics and to assess the association of NfL with future CDW, respectively.

Results: A total of 3906 EPIC visits (609 participants; median [IQR] age, 42.0 [35.0-50.0] years; 424 female [69.6%]) and 8901 SMSC visits (1290 participants; median [IQR] age, 41.2 [32.5-49.9] years; 850 female [65.9%]) were included. In CDW-R (EPIC, 36 events; SMSC, 93 events), NfL z scores were 0.71 (95% CI, 0.35-1.07; P < .001) units higher at CDW-R(-1) in EPIC and 0.32 (95% CI, 0.14-0.49; P < .001) in SMSC compared with stable MS samples. NfL elevation could be detected preceding CDW-NR (EPIC, 191 events; SMSC, 342 events) at CDW-NR(-2) (EPIC: 0.23; 95% CI, 0.01-0.45; P = .04; SMSC: 0.28; 95% CI, 0.18-0.37; P < .001) and at CDW-NR(-1) (EPIC: 0.27; 95% CI, 0.11-0.44; P < .001; SMSC: 0.09; 95% CI, 0-0.18; P = .06). Those findings were replicated in the subgroup with relapsing-remitting MS. Time-to-event analysis confirmed the association between NfL levels and future CDW-R within approximately 1 year and CDW-NR (in approximately 1-2 years).

Conclusions and relevance: This cohort study documents the occurrence of NfL elevation in advance of clinical worsening and may hint to a potential window of ongoing dynamic central nervous system pathology that precedes the diagnosis of CDW.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest Disclosures: Dr Abdelhak reported receiving grants from German Multiple Sclerosis Society and Weill Institute for Neurosciences outside the submitted work. Dr Cordano reported receiving grants from Italian Multiple Sclerosis Foundation and nonfinancial support from Merck Serono outside the submitted work. Dr Oechtering reported receiving grants from Swiss MS Society and consulting fees from Merck and Roche outside the submitted work. Dr Oertel reported receiving grants from National Multiple Sclerosis Society, American Academy of Neurology, Hertie Network of Excellence in Clinical Neurosciences, Deutsche Gesellschaft für Neurologie Research, ECTRIMS, and ACTRIMS outside the submitted work. Dr Leppert reported being chief medical officer of GeNeuro. Dr Henry reported receiving grants from Philanthropy, Medday, Roche/Genentech, and Atara and personal fees from Boston Pharma, Roche/Genentech, Novartis, and QIA outside the submitted work. Dr Pot reported receiving consulting fees and/or travel compensation for activities with Biogen, Merck, Novartis, Roche, and Sanofi Genzyme outside the submitted work. Dr Salmen reported receiving speaker honoraria from Bristol Myers Squibb, CSL Behring, Novartis, and Roche and grants from Baasch Medicus Foundation, the Medical Faculty of the University of Bern, and the Swiss MS Society to institution outside the submitted work. Dr Zecca reported receiving grants from Biogen, Bristol, Merck, Novartis, Teva, Lundbeck, Almirall, Sanofi, and Roche outside the submitted work. Dr Kappos reported receiving consultant fees from Bayer AG, Bristol Myers Squibb, Celltrion Inc, df-mp Molnia & Pohlman, Eli Lilly (Suisse) SA, EMD Serono, GlaxoSmithKline, Janssen, Japan Tobacco Inc, Merck (Schweiz) AG, Novartis, Roche, Shionogi BV, Wellmera AG, and Zai Lab; advisory board fees from Biogen, Clene Nanomedicine Inc, Genentech, Janssen, Merck (Schweiz) AG, Minoryx Therapeutics, Novartis, and Santhera Pharmaceuticals; grants from European Union, Innosuisse, Novartis, Roche, and SNF; speaker fees from F&U, Janssen, Merck (Schweiz) AG, Novartis, and Roche; and license fees from Neurostatus outside the submitted work. Dr Hauser reported receiving grants from the National Institutes of Health/National Institute of Neurological Disorders and Stroke and the Valhalla Foundation; advisory board fees and stock options from Neurona, Accure, Alector, and Annexon; consulting fees from BD, Moderna, and NGM Bio; and travel reimbursement from Roche and Novartis outside the submitted work. Dr Cree reported receiving grants from Genentech and consulting fees from Alexion, Atara, Autobahn, Avotres, Biogen, Boston Pharma, EMD Serono, Gossamer Bio, Hexal/Sandoz, Horizon, Immunic AG, Neuron23, Novartis, Sanofi, and TG Therapeutics outside the submitted work. Dr Kuhle reported receiving grants from Swiss MS Society, Swiss National Research Foundation, Progressive MS Alliance, Biogen, Merck, Celgene, Bristol Myers Squibb, Novartis, Octave Bioscience, Roche, Sanofi, Alnylam, Bayer, Immunic, Quanterix, Neurogenesis, Stata DX, and University Basel outside the submitted work. Dr Green reported receiving grants from F. Hoffmann La Roche, Fishman Family, and Westridge Foundation and advisory board fees from Pipeline Therapeutics outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Neurofilament Light Chain (NfL) Dynamics in Relation to Future Disability Worsening
The y-axis showing the marginal means of NfL z scores and P values from mixed linear models correcting for age, sex, disease course (relapsing vs progressive multiple sclerosis [MS]), disease-modifying treatment (DMT) categories (high-efficacy monoclonal antibodies, oral DMT, platform DMT, and untreated), and recent relapse (within 90 days) for confirmed disability worsening associated with clinical relapses (CDW-R) and CDW independent of clinical relapses (CDW-NR), respectively. EPIC indicates Expression, Proteomics, Imaging, Clinical study; SMSC, Swiss Multiple Sclerosis Cohort; stMS, participants with stable MS without evidence of disease activity or CDW. aP < .001. bP < .01. cP < .05.
Figure 2.
Figure 2.. Future Risk of Confirmed Disability Worsening With Clinical Relapses (CDW-R) Based on Neurofilament Light Chain (NfL) z Score
In the Expression, Proteomics, Imaging, Clinical (EPIC) study (A) and Swiss Multiple Sclerosis Cohort (SMSC) (B), NfL z score less than or equal to 1 or greater than 1 was used as a time-varying covariate, correcting for age, sex, disease course (relapsing vs progressive multiple sclerosis [MS]), disease-modifying treatment (DMT) category (monoclonal antibodies, oral DMT, platform DMT, and untreated), recent relapse (within 90 days) at measurement visit, and Expanded Disability Status Scale at baseline. aHR indicates adjusted hazard ratio.
Figure 3.
Figure 3.. Future Risk of Confirmed Disability Worsening Independent of Clinical Relapses (CDW-NR) based on Neurofilament Light Chain (NfL) z Score
NfL z score less than or equal to 1 or greater than 1 was used as a time-varying covariate, either at CDW-NR(−1) or CDW-NR(−2), correcting for age, sex, disease course (relapsing vs progressive multiple sclerosis [MS]), disease-modifying treatment (DMT) category (high-efficacy monoclonal antibodies, oral DMT, platform DMT, and untreated), recent relapse (within 90 days) at measurement visit, and Expanded Disability Status Scale (EDSS) at baseline. NfL z score was associated with higher risk for future CDW-NR at visits CDW-NR(−1) in the Expression, Proteomics, Imaging, Clinical (EPIC) study (B) and CDW-NR(−2) in Swiss Multiple Sclerosis Cohort (SMSC) (C). NfL z scores at visits closest to the event, CDW-NR(−1) in SMSC (A), or too distant from the event, CDW-NR(−2) in EPIC (D), were not significantly associated with CDW-NR. aHR indicates adjusted hazard ratio.
See this image and copyright information in PMC

References

    1. 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. doi:10.1038/s41467-020-14612-6 - DOI - PMC - PubMed
    1. Benkert P, Meier S, Schaedelin S, et al. ; NfL Reference Database in the Swiss Multiple Sclerosis Cohort Study Group . Serum neurofilament light chain for individual prognostication of disease activity in people with multiple sclerosis: a retrospective modelling and validation study. Lancet Neurol. 2022;21(3):246-257. doi:10.1016/S1474-4422(22)00009-6 - DOI - PubMed
    1. 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. doi:10.1212/WNL.0000000000007032 - DOI - PMC - PubMed
    1. Abdelhak A, Cordano C, Boscardin WJ, et al. . Plasma neurofilament light chain levels suggest neuroaxonal stability following therapeutic remyelination in people with multiple sclerosis. J Neurol Neurosurg Psychiatry. 2022;jnnp-2022-329221. doi:10.1136/jnnp-2022-329221 - DOI - PMC - PubMed
    1. Shaw G, Madorsky I, Li Y, et al. . Uman-type neurofilament light antibodies are effective reagents for the imaging of neurodegeneration. Brain Commun. 2023;5(2):fcad067. doi:10.1093/braincomms/fcad067 - DOI - PMC - PubMed

Publication types