Association Between Neurofilament Light Chain and Real‐World Ambulatory Function in Progressive MS

OBJECTIVE: Neurofilament light chain (NfL) is a biomarker of neuroaxonal injury in multiple sclerosis (MS), yet associations with functional outcomes remain unclear. Longitudinal associations between serum NfL (sNfL) and daily step count (STEPS) from wearable devices were assessed in a large international progressive MS cohort. METHODS: A post hoc analysis of the Phase III randomized controlled trial SPI2 (high-dose biotin vs. placebo RCT) pooled treatment arms due to no observed therapeutic benefit. Participants with sNfL and step count data were included. STEPS were calculated within ±15-days of baseline, 6, 12, 15, and 27-month visits. Mixed-effects models with 1000 bootstrap iterations assessed contemporaneous associations with each measure alternately specified as the outcome, adjusting for age and sex. Lagged models evaluated whether 0-6-month sNFL changes predicted subsequent 6-12-month STEPS changes. RESULTS: Among 506 participants (53.8% female; mean age 52.7 [SD: 7.7] years; median EDSS 6.0 [4.5-6.0]), mean sNfL z-score was 1.00 (SD: 0.95), and median STEPS were 3029 [1708-5210]. Higher sNfL was associated with lower STEPS (IRR = 0.97, p = 0.014), consistent across sex, treatment, disability, and disease-modifying treatment status. Conversely, higher STEPS were associated with lower sNfL z-scores; a 10% increase in STEPS corresponded to a 0.015 decrease in sNfL z-score (95% CI -0.022 to -0.008; p < 0.001). Greater prior 6-month increases in sNfL were associated with a lower subsequent STEPS (β = -141; 95% CI -302 to 21; p = 0.088; trend), corresponding to 141 fewer steps per 1-SD sNfL increase. INTERPRETATION: Higher sNfL was associated with reduced daily ambulatory activity in progressive MS, and vice versa. Rising sNfL may precede mobility decline, highlighting sNfL as a potential indicator of functional worsening. TRIAL REGISTRATION: ClinicalTrials.gov NCT02936037; EudraCT database 2016-000700-29.