BACKGROUND: Increased blood brain barrier (BBB) permeability, CNS inflammation and neuroaxonal damage are pathological hallmarks in early multiple sclerosis (MS). OBJECTIVE: To investigate the associations of neurofilament light chain (NfL) levels with measures of BBB integrity and central nervous system (CNS) inflammation in MS during the first demyelinating event. METHODS: Blood and cerebrospinal fluid (CSF) were obtained from 142 MS (McDonald 2017) treatment-naive patients from the SET study (63% female; age: 29.7 ± 7.9 years) following the disease onset. NfL, albumin, immunoglobulin G (IgG), and immunoglobulin M (IgM) levels were measured in CSF and blood samples. Albumin quotient was computed as a marker of BBB integrity. Immune cell subset counts in CSF were measured using flow cytometry. MS risk factors, such as Human leukocyte antigen DRB1 locus gene (HLA DRB1)*1501, anti-Epstein-Barr virus (EBV) antibodies, and 25-hydroxy vitamin D3, were also measured. RESULTS: Higher serum NfL (sNfL) levels were associated with higher albumin quotient (p < 0.001), CSF CD80+ (p = 0.012), and CD80+ CD19+ (p = 0.015) cell frequency. sNfL levels were also associated with contrast-enhancing and T2 lesions on brain magnetic resonance imaging (MRI; all p ⩽ 0.001). Albumin quotient was not associated with any of the MS risk factors assessed. sNfL levels were associated with anti-EBV viral capsid antigen (VCA) IgG levels (p = 0.0026). CONCLUSION: sNfL levels during the first demyelinating event of MS are associated with greater impairment of BBB integrity, immune cell extravasation, and brain lesion activity on MRI.

Buffalo Neuroimaging Analysis Center Department of Neurology University at Buffalo The State University of New York Buffalo NY USA

Buffalo Neuroimaging Analysis Center Department of Neurology University at Buffalo The State University of New York Buffalo NY USA Center for Biomedical Imaging Clinical and Translational Science Institute University at Buffalo The State University of New York Buffalo NY USA

Buffalo Neuroimaging Analysis Center Department of Neurology University at Buffalo The State University of New York Buffalo NY USA IRCCS Fondazione Don Carlo Gnocchi ONLUS Milan Italy

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

Department of Pharmaceutical Sciences The State University of New York Buffalo NY USA Department of Neurology The State University of New York Buffalo NY USA

Department of Pharmaceutical Sciences University at Buffalo The State University of New York Buffalo NY USA

Department of Radiology 1st Faculty of Medicine Charles University Prague and General University Hospital Prague Czech Republic

Institute of Immunology and Microbiology 1st Faculty of Medicine Charles University Prague and General University Hospital Prague Czech Republic

Neurologic Clinic and Policlinic Departments of Medicine Biomedicine and Clinical Research University Hospital Basel University of Basel Basel Switzerland

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The potential of serum neurofilament as biomarker for multiple sclerosis