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.

Background: Serum neurofilament light chain (sNfL) is a marker of neuroaxonal injury. There is a lack of studies investigating the dynamics of relationships between sNfL levels and radiological disease activity over long-term follow-up in multiple sclerosis (MS). Objectives: To investigate the relationship among repeated measures of sNfL, lesion burden accumulation, brain volume loss and clinical measures. Methods: We investigated 172 patients in the early stages of MS (McDonald 2017 criteria). Clinical exams were performed every 3 months and brain magnetic resonance imaging (MRI) scans were collected annually over 48 months. sNfL levels were measured in serum by Simoa assay at the time of treatment initiation and then annually over 36 months. Results: In repeated-measures analysis, considering all time points, we found a strong relationship between percentage changes of sNfL and lesion burden accumulation assessed by T1 lesion volume ( p < 0.001) and T2 lesion number ( p < 0.001). There was no relationship between percentage changes of sNfL and brain volume loss over 36 months ( p > 0.1). Early sNfL levels were associated with delayed brain volume loss after 48 months ( p < 0.001). Patients with No Evidence of Disease Activity (NEDA-3) status showed lower sNfL levels compared with active MS patients. Conclusions: sNfL is associated with ongoing neuroinflammation and predictive of future neurodegeneration in early MS.

ObjectiveTo determine whether serum neurofilament light chain (sNfL) levels are associated with recent MRI activity in patients with relapsing-remitting MS (RRMS).MethodsThis observational study included 163 patients (405 samples) with early RRMS from the Study of Early interferon-beta1a (IFN-β1a) Treatment (SET) cohort and 179 patients (664 samples) with more advanced RRMS from the Genome-Wide Association Study of Multiple Sclerosis (GeneMSA) cohort. Based on annual brain MRI, we assessed the ability of sNfL cutoffs to reflect the presence of combined unique active lesions, defined as new/enlarging lesion compared with MRI in the preceding year or contrast-enhancing lesion. The probability of active MRI lesions among patients with different sNfL levels was estimated with generalized estimating equations models.ResultsFrom the sNfL samples ≥90th percentile, 81.6% of the SET (OR = 3.4, 95% CI = 1.8-6.4) and 48.9% of the GeneMSA cohort samples (OR = 2.6, 95% CI = 1.7-3.9) was associated with radiological disease activity on MRI. The sNfL level between the 10th and 30th percentile was reflective of negligible MRI activity: 1.4% (SET) and 6.5% (GeneMSA) of patients developed ≥3 active lesions, 5.8% (SET) and 6.5% (GeneMSA) developed ≥2 active lesions, and 34.8% (SET) and 11.8% (GeneMSA) showed ≥1 active lesion on brain MRI. The sNfL level <10th percentile was associated with even lower MRI activity. Similar results were found in a subgroup of clinically stable patients.ConclusionsLow sNfL levels (≤30th percentile) help identify patients with MS with very low probability of recent radiologic disease activity during the preceding year. This result suggests that in future, sNfL assessment may substitute the need for annual brain MRI monitoring in considerable number (23.1%–36.4%) of visits in clinically stable patients.