Temporal profile of serum neurofilament light in multiple sclerosis: Implications for patient monitoring.

OBJECTIVE: To understand how longitudinal serum neurofilament light chain (sNfL) patterns can inform its use as a prognostic biomarker in multiple sclerosis (MS) and evaluate whether sNfL reflects MS disease activity and disease-modifying therapy usage. METHODS: This was a post hoc analysis of longitudinal data and samples from the ADVANCE trial (NCT00906399) of patients with relapsing-remitting MS (RRMS). sNfL was measured every 3 months for 2 years, then every 6 months for 4 years. Regression models explored how sNfL data predicted 4-year values of brain volume, expanded disability status scale score, and T2 lesions. sNfL levels were assessed in those receiving placebo, peginterferon beta-1a, and those with disease activity. RESULTS: Baseline sNfL was a predictor of 4-year brain atrophy and development of new T2 lesions. Clinical (p = 0.02) and magnetic resonance imaging (MRI) (p < 0.01) outcomes improved in those receiving peginterferon beta-1a whose sNfL decreased to <16 pg/mL after 12 months versus those whose sNfL remained ⩾16 pg/mL. Mean sNfL levels decreased in peginterferon beta-1a-treated patients and increased in placebo-treated patients (-9.5% vs. 6.8%; p < 0.01). sNfL was higher and more variable in patients with evidence of active MS. CONCLUSION: These data support sNfL as a prognostic and disease-monitoring biomarker for RRMS.

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 ß-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.

Neurofilament light levels are associated with long-term outcomes in multiple sclerosis.

BACKGROUND: Neurofilament light chain (NfL) is a promising marker of disease activity/treatment response in multiple sclerosis (MS), although its predictive value for long-term clinical outcomes remains unclear. OBJECTIVE: We measured NfL from a phase 3 trial in relapsing-remitting MS and investigated its association with outcomes after 8 and 15 years. METHODS: NfL concentrations were measured by single molecule array assay in cerebrospinal fluid (CSF) from MS patients (n = 235) in a 2-year randomized clinical trial (RCT) of intramuscular interferon ß-1a, and in serum (n = 164) from the extension study. RESULTS: Year 2 CSF and Year 3 serum NfL were associated with brain parenchymal fraction (BPF) change over 8 years (p < 0.0001, r = -0.46; p < 0.05. r = -0.36, respectively) and were predictive of reaching Expanded Disability Status Scale (EDSS) ⩾ 6.0 at Year 8 (odds ratio (OR) (upper vs lower tertile) = 3.4; 95% confidence interval (CI) = 1.2-9.9, p < 0.05; OR = 11.0, 95% CI = 2.0-114.6; p < 0.01, respectively). Serum NfL concentration (Year 4) was predictive of reaching EDSS score ⩾6.0 at 15 years (OR (upper vs lower tertile) = 4.9; 95% CI = 1.4-20.4; p < 0.05). NfL concentrations were complementary to 2-year BPF change in predicting long-term outcomes. CONCLUSION: Serum and CSF NfL concentrations were associated with long-term clinical outcomes in MS patients and are promising biomarkers for disease severity stratification supporting treatment decisions.