Association of Serum Neurofilament Light Levels With Long-term Brain Atrophy in Patients With a First Multiple Sclerosis Episode

Importance Data are needed on the potential long-term prognostic association of serum neurofilament light in multiple sclerosis (MS). Objective To evaluate serum neurofilament light as a biomarker associated with long-term disease outcomes in clinically isolated syndrome. Design, Setting, and Participants This post hoc cohort study used data from the Controlled High-Risk Avonex Multiple Sclerosis Prevention Study, a 36-month, multicenter, placebo-controlled interferon beta-1a randomized clinical trial conducted from April 1996 to March 2000, and its long-term (5- and 10-year) extension study from February 2001 to March 2009. Participants included individuals with a symptomatic initial demyelinating event and brain magnetic resonance imaging (MRI) lesions suggestive of MS. Data were analyzed from April 2017 through 2019. Exposure The variable of interest was naturally occurring serum neurofilament light concentration Main Outcomes and Measures Gadolinium-enhancing (Gd+) lesion number, T2 lesion volume, and brain parenchymal fraction, a measure of brain atrophy were measured at baseline and 5 and 10 years. Multivariate regression models evaluated whether age, sex, and baseline covariates, including serum neurofilament light, brain parenchymal fraction, Expanded Disability Status Scale, Gd+ lesion count, and T2 lesion volume, were associated with brain parenchymal fraction changes over 5 and 10 years. Results Among 308 included participants (mean [SD] age, 33.2 [7.6] years; 234 [76.0%] women), baseline serum neurofilament light concentrations were associated with Gd+ lesions (Spearman r = 0.41; P < .001) and T2 lesion volume (Spearman r = 0.42; P < .001). Among covariates for brain parenchymal fraction change, serum neurofilament light concentration had the greatest correlation with change in brain parenchymal fraction at 5 years (Spearman r = -0.38; P < .001) and was the only variable associated with brain parenchymal fraction at 10 years (Spearman r = -0.45; P < .001). Participants in the highest vs lowest baseline serum neurofilament light tertiles showed brain parenchymal fraction reduction at 5 years (-1.83% [95% CI, -1.49% to -2.18%] vs -0.95% [95% CI, -0.78% to -1.12%]; P < .001) and 10 years (-3.54% [95% CI, -2.90% to -4.17%] vs -1.90% [95% CI, -1.43% to -2.37%]; P < .001). At 5 years, 6 of 45 participants (13.3%) in the highest neurofilament tertile and 2 of 52 participants (3.8%) in the lowest neurofilament tertile achieved an Expanded Disability Status Scale score of 3.5 or greater. Conclusions and Relevance This cohort study found that higher baseline serum neurofilament light levels were associated with increased brain atrophy over 5 and 10 years. These findings suggest that serum neurofilament light could be a biomarker associated with disease severity stratification in early MS and may help to guide intervention. This cohort study examines the association of neurofilament light levels with long-term brain atrophy and disease progression in multiple sclerosis. Question Is serum neurofilament light level at the time of the first demyelinating event associated with long-term brain atrophy and disease progression? Findings In this cohort study of 308 patients with multiple sclerosis and clinically isolated syndrome in a clinical trial of intramuscular interferon beta-1a, serum neurofilament light concentrations at baseline were associated with brain atrophy progression over 5 and 10 years. Meaning These findings suggest that serum neurofilament light measured at the time of clinically isolated syndrome or early multiple sclerosis may be useful as a biomarker associated with disease severity stratification in early multiple sclerosis.