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Neurofilament Light Chain Elevation and Disability Progression in Multiple Sclerosis.
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.
Affiliation
  • Abdelhak A; Weill Institute for Neurosciences, Department of Neurology, University of California at San Francisco, San Francisco.
  • Benkert P; Department of Clinical Research, University Hospital Basel and University of Basel, Basel, Switzerland.
  • Schaedelin S; Research Center for Clinical Neuroimmunology and Neuroscience (RC2NB), Departments of Biomedicine and Clinical Research, University Hospital and University of Basel, Basel, Switzerland.
  • Boscardin WJ; Multiple Sclerosis Center, Department of Neurology, University Hospital and University of Basel, Basel, Switzerland.
  • Cordano C; Department of Clinical Research, University Hospital Basel and University of Basel, Basel, Switzerland.
  • Oechtering J; Research Center for Clinical Neuroimmunology and Neuroscience (RC2NB), Departments of Biomedicine and Clinical Research, University Hospital and University of Basel, Basel, Switzerland.
  • Ananth K; Multiple Sclerosis Center, Department of Neurology, University Hospital and University of Basel, Basel, Switzerland.
  • Granziera C; Departments of Medicine and Epidemiology & Biostatistics, University of California at San Francisco, San Francisco.
  • Melie-Garcia L; Weill Institute for Neurosciences, Department of Neurology, University of California at San Francisco, San Francisco.
  • Montes SC; Department of Neurology, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genoa, Genoa, Italy.
  • Beaudry-Richard A; IRCCS Ospedale Policlinico San Martino, Genoa, Italy.
  • Achtnichts L; Research Center for Clinical Neuroimmunology and Neuroscience (RC2NB), Departments of Biomedicine and Clinical Research, University Hospital and University of Basel, Basel, Switzerland.
  • Oertel FC; Multiple Sclerosis Center, Department of Neurology, University Hospital and University of Basel, Basel, Switzerland.
  • Lalive PH; Weill Institute for Neurosciences, Department of Neurology, University of California at San Francisco, San Francisco.
  • Leppert D; Research Center for Clinical Neuroimmunology and Neuroscience (RC2NB), Departments of Biomedicine and Clinical Research, University Hospital and University of Basel, Basel, Switzerland.
  • Müller S; Multiple Sclerosis Center, Department of Neurology, University Hospital and University of Basel, Basel, Switzerland.
  • Henry RG; Translational Imaging in Neurology (ThINK) Basel, Department of Biomedical Engineering, Faculty of Medicine, University Hospital Basel and University of Basel, Basel, Switzerland.
  • Pot C; Research Center for Clinical Neuroimmunology and Neuroscience (RC2NB), Departments of Biomedicine and Clinical Research, University Hospital and University of Basel, Basel, Switzerland.
  • Matthias A; Multiple Sclerosis Center, Department of Neurology, University Hospital and University of Basel, Basel, Switzerland.
  • Salmen A; Translational Imaging in Neurology (ThINK) Basel, Department of Biomedical Engineering, Faculty of Medicine, University Hospital Basel and University of Basel, Basel, Switzerland.
  • Oksenberg JR; Weill Institute for Neurosciences, Department of Neurology, University of California at San Francisco, San Francisco.
  • Disanto G; Weill Institute for Neurosciences, Department of Neurology, University of California at San Francisco, San Francisco.
  • Zecca C; Department of Neurology, Cantonal Hospital Aarau, Aarau, Switzerland.
  • D'Souza M; Weill Institute for Neurosciences, Department of Neurology, University of California at San Francisco, San Francisco.
  • Du Pasquier R; Unit of Neuroimmunology, Division of Neurology, Department of Clinical Neurosciences, University Hospital of Geneva and Faculty of Medicine, Geneva, Switzerland.
  • Bridel C; Research Center for Clinical Neuroimmunology and Neuroscience (RC2NB), Departments of Biomedicine and Clinical Research, University Hospital and University of Basel, Basel, Switzerland.
  • Gobbi C; Multiple Sclerosis Center, Department of Neurology, University Hospital and University of Basel, Basel, Switzerland.
  • Kappos L; Department of Neurology, Cantonal Hospital St Gallen, St Gallen, Switzerland.
  • Hauser SL; Weill Institute for Neurosciences, Department of Neurology, University of California at San Francisco, San Francisco.
  • Cree BAC; Department of Clinical Neurosciences, Service of Neurology, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland.
  • Kuhle J; Department of Clinical Neurosciences, Service of Neurology, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland.
  • Green AJ; Department of Neurology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
JAMA Neurol ; 80(12): 1317-1325, 2023 Dec 01.
Article in En | MEDLINE | ID: mdl-37930670
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Neurofilament Proteins / Disability Evaluation / Multiple Sclerosis Limits: Adult / Female / Humans Language: En Journal: JAMA Neurol Year: 2023 Document type: Article Country of publication:
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Neurofilament Proteins / Disability Evaluation / Multiple Sclerosis Limits: Adult / Female / Humans Language: En Journal: JAMA Neurol Year: 2023 Document type: Article Country of publication: