Neurofilament Light Chain Elevation and Disability Progression in Multiple Sclerosis

Author:

Abdelhak Ahmed1,Benkert Pascal234,Schaedelin Sabine234,Boscardin W. John5,Cordano Christian167,Oechtering Johanna34,Ananth Kirtana1,Granziera Cristina348,Melie-Garcia Lester348,Montes Shivany Condor1,Beaudry-Richard Alexandra1,Achtnichts Lutz9,Oertel Frederike C.1,Lalive Patrice H.10,Leppert David34,Müller Stefanie11,Henry Roland G.1,Pot Caroline12,Matthias Amandine12,Salmen Anke13,Oksenberg Jorge R.1,Disanto Giulio1415,Zecca Chiara1415,D’Souza Marcus34,Du Pasquier Renaud12,Bridel Claire10,Gobbi Claudio1415,Kappos Ludwig34,Hauser Stephen L.1,Cree Bruce A. C.1,Kuhle Jens234,Green Ari J.116,Baranzini Sergio17,Bove Riley17,Wilson Michael17,Hollenbach Jill17,Gomez Refujia17,Santaniello Adam17,Harms Meagan17,Cooper Tiffany17,Caillier Stacy17,Lorscheider Johannes17,Cagol Alessandro17,Barakovic Muhamed17,Galbusera Riccardo 17,Yaldizli Özgür17,Subramaniam Suvitha17,Orleth Annette17,Derfuss Tobias17,Maleska Maceski Aleksandra17,Willemse Eline17,Hemkens Lars G17,Janiaud Perrine17,Demuth Lilian17,Fischer-Barnicol Bettina17,Hoepner Robert17,Chan Andrew17,Findling Oliver17,

Affiliation:

1. Weill Institute for Neurosciences, Department of Neurology, University of California at San Francisco, San Francisco

2. Department of Clinical Research, University Hospital Basel and University of Basel, Basel, Switzerland

3. Research Center for Clinical Neuroimmunology and Neuroscience (RC2NB), Departments of Biomedicine and Clinical Research, University Hospital and University of Basel, Basel, Switzerland

4. Multiple Sclerosis Center, Department of Neurology, University Hospital and University of Basel, Basel, Switzerland

5. Departments of Medicine and Epidemiology & Biostatistics, University of California at San Francisco, San Francisco

6. Department of Neurology, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genoa, Genoa, Italy

7. IRCCS Ospedale Policlinico San Martino, Genoa, Italy

8. Translational Imaging in Neurology (ThINK) Basel, Department of Biomedical Engineering, Faculty of Medicine, University Hospital Basel and University of Basel, Basel, Switzerland

9. Department of Neurology, Cantonal Hospital Aarau, Aarau, Switzerland

10. Unit of Neuroimmunology, Division of Neurology, Department of Clinical Neurosciences, University Hospital of Geneva and Faculty of Medicine, Geneva, Switzerland

11. Department of Neurology, Cantonal Hospital St Gallen, St Gallen, Switzerland

12. Department of Clinical Neurosciences, Service of Neurology, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland

13. Department of Neurology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland

14. Multiple Sclerosis Center, Department of Neurology, Neurocenter of Southern Switzerland, ECO, Lugano, Switzerland

15. Faculty of Biomedical Sciences, Università della Svizzera Italiana, Lugano, Switzerland

16. Department of Ophthalmology, University of California at San Francisco, San Francisco

17. for the UCSF, MS EPIC, and the SMSC Study Teams

Abstract

ImportanceMechanisms 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.ObjectiveTo determine whether and when NfL levels are elevated in the context of confirmed disability worsening (CDW).Design, Setting, and ParticipantsThis 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.ExposureAssociation between NfL z scores and CDW.Main Outcome MeasuresCDW 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.ResultsA 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 RelevanceThis 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.

Publisher

American Medical Association (AMA)

Subject

Neurology (clinical)

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