Neurofilament Light Chain Elevation and Disability Progression in Multiple Sclerosis
Authors: Abdelhak Ahmed , Benkert Pascal , Schaedelin Sabine , Boscardin W. John , Cordano Christian , Oechtering Johanna , Ananth Kirtana , Granziera Cristina , Melie-Garcia Lester , Montes Shivany Condor , Beaudry-Richard Alexandra , Achtnichts Lutz , Oertel Frederike C. , Lalive Patrice H. , Leppert David , Müller Stefanie , Henry Roland G. , Pot Caroline , Matthias Amandine , Salmen Anke , Oksenberg Jorge R. , Disanto Giulio , Zecca Chiara , D’Souza Marcus , Du Pasquier Renaud , Bridel Claire , Gobbi Claudio , Kappos Ludwig , Hauser Stephen L. , Cree Bruce A. C. , Kuhle Jens , Green Ari J. ,   UCSF, MS EPIC, and the SMSC Study Teams, Baranzini Sergio , Bove Riley , Wilson Michael , Hollenbach Jill , Gomez Refujia , Santaniello Adam , Harms Meagan , Cooper Tiffany , Caillier Stacy , Lorscheider Johannes , Cagol Alessandro , Barakovic Muhamed , Galbusera Riccardo  , Yaldizli Özgür , Subramaniam Suvitha , Orleth Annette , Derfuss Tobias , Maleska Maceski Aleksandra , Willemse Eline , Hemkens Lars G , Janiaud Perrine , Demuth Lilian , Fischer-Barnicol Bettina , Hoepner Robert , Chan Andrew , Findling Oliver 
Published: November 2023

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 &amp;lt; .001) units higher at CDW-R(−1) in EPIC and 0.32 (95% CI, 0.14-0.49; P &amp;lt; .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 &amp;lt; .001) and at CDW-NR(−1) (EPIC: 0.27; 95% CI, 0.11-0.44; P &amp;lt; .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.