ObjectiveTo assess the value of annual serum neurofilament light (NfL) measures in predicting 10‐year clinical and MRI outcomes in multiple sclerosis (MS).MethodsWe identified patients in our center's Comprehensive Longitudinal Investigations in MS at Brigham and Women's Hospital (CLIMB) study enrolled within 5 years of disease onset, and with annual blood samples up to 10 years (n = 122). Serum NfL was measured using a single molecule array (SIMOA) assay. An automated pipeline quantified brain T2 hyperintense lesion volume (T2LV) and brain parenchymal fraction (BPF) from year 10 high‐resolution 3T MRI scans. Correlations between averaged annual NfL and 10‐year clinical/MRI outcomes were assessed using Spearman's correlation, univariate, and multivariate linear regression models.ResultsAveraged annual NfL values were negatively associated with year 10 BPF, which included averaged year 1–5 NfL values (unadjusted P < 0.01; adjusted analysis P < 0.01), and averaged values through year 10. Linear regression analyses of averaged annual NfL values showed multiple associations with T2LV, specifically averaged year 1–5 NfL (unadjusted P < 0.01; adjusted analysis P < 0.01). Approximately 15–20% of the BPF variance and T2LV could be predicted from early averaged annual NfL levels. Also, averaged annual NfL levels with fatigue score worsening between years 1 and 10 showed statistically significant associations. However, averaged NfL measurements were not associated with year 10 EDSS, SDMT or T25FW in this cohort.InterpretationSerum NfL measured during the first few years after the clinical onset of MS contributed to the prediction of 10‐year MRI brain lesion load and atrophy.

ObjectiveMultiple sclerosis (MS) is an autoimmune demyelinating disorder, which is characterized by relapses and remissions. Serum neurofilament light chain (sNfL) is an emerging biomarker of disease activity but its clinical use is still limited. In this study, we aim to characterize the temporal association between sNfL and new clinical relapses and new gadolinium‐enhancing (Gd+) lesions.MethodsAnnual sNfL levels were measured with a single‐molecule array (SIMOA) assay in 94 patients with MS enrolled in the Comprehensive Longitudinal Investigation of Multiple Sclerosis at the Brigham and Women’s Hospital (CLIMB) study. We used a multivariable linear mixed‐effects model to test the temporal association of sNfL with clinical relapses and/or new Gd+ lesions. We adjusted this model for age, disease duration, sex, and disease‐modifying therapies (DMTs) use.ResultsIn the 3 months after a Gd+ lesion, we observed an average 35% elevation in sNfL (P < 0.0001) compared to remission samples. We also observed an average 32.3% elevation in sNfL at the time of or prior to a Gd+ lesion (P = 0.002) compared to remission. We observed a significant elevation in sNfL after a clinical relapse only when associated with a Gd+ lesion.InterpretationOur findings support sNfL as a marker of clinical relapses and Gd+ lesions. sNfL peaks in a 3‐month window around Gd+ lesions. sNfL shows promise as a biomarker of neurological inflammation and possibly of simultaneous Gd+ lesions during a clinical relapse.

Background and ObjectivesNeurodegeneration and astrocytic activation are pathologic hallmarks of progressive multiple sclerosis (MS) and can be quantified by serum neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP). We investigated sNfL and sGFAP as tools for stratifying patients with progressive MS based on progression and disease activity status.MethodsWe leveraged our Comprehensive Longitudinal Investigation of MS at the Brigham and Women's Hospital (CLIMB) natural history study, which includes clinical, MRI data and serum samples collected over more than 20 years. We included patients with MS with a confirmed Expanded Disability Status Scale (EDSS) score ≥3 that corresponds with our classifier for patients at high risk of underlying progressive pathology. We analyzed sNfL and sGFAP within 6 months from the confirmed EDSS score ≥3 corresponding with our baseline visit. Patients who further developed 6-month confirmed disability progression (6mCDP) were classified as progressors. We further stratified our patients into active/nonactive based on new brain/spinal cord lesions or relapses in the 2 years before baseline or during follow-up. Statistical analysis on log-transformed sGFAP/sNfL assessed the baseline association with demographic, clinical, and MRI features and associations with future disability.ResultsWe included 257 patients with MS who had an average EDSS score of 4.0 and a median follow-up after baseline of 7.6 years. sNfL was higher in patients with disease activity in the 2 years before baseline (adjusted β = 1.21; 95% CI 1.04–1.42;p= 0.016), during the first 2 years of follow-up (adjusted β = 1.17; 95% CI = 1.01–1.36;p= 0.042). sGFAP was not increased in the presence of disease activity. Higher sGFAP levels, but not sNfL levels, were associated with higher risk of 6mCDP (adjusted hazard ratio [HR] = 1.71; 95% CI = 1.19–2.45;p= 0.004). The association was stronger in patients with low sNfL (adjusted HR = 2.44; 95% CI 1.32–4.52;p= 0.005) and patients who were nonactive in the 2 years prior or after the sample.DiscussionHigher levels of sGFAP correlated with subsequent progression, particularly in nonactive patients, whereas sNfL reflected acute disease activity in patients with MS at high risk of underlying progressive pathology. Thus, sGFAP and sNfL levels may be used to stratify patients with progressive MS for clinical research studies and clinical trials and may inform clinical care.