Objective: To investigate the association between plasma NfL (pNfL) levels and risk of developing sustained disability worsening.

Methods: Concentrations of pNfL were determined in 4,385 persons with MS and 1,026 randomly selected population-based sex- and age-matched controls using the highly sensitive Single Molecule Array (SimoaTM) NF-light® Advantage kit. We assessed the impact of age-stratified pNfL levels above 80th, 95th and 99th of controls' percentiles on the risk of Expanded Disability Status Scale (EDSS) worsening within the following year and reaching sustained EDSS scores of 3.0, 4.0 and 6.0 and conversion to secondary progressive (SP) MS.

Results: The median (interquartile range) pNfL was 7.5 (4.1) pg/ml in controls and 11.4 (9.6) pg/ml in MS (P <0.001). The median (interquartile range) duration of follow-up was 5 years (5.1). High pNfL was associated with increased adjusted rates of EDSS worsening ranging between 1.4 (95% confidence intervals (CI): 1.1-1.8) and 1.7 (95%CI: 1.4-2.3). High pNfL was also associated with the risk of reaching a sustained EDSS score of 3.0 with adjusted rates ranging between 1.5 (95%CI: 1.2-1.8) and 1.55 (95%CI: 1.3-1.8) over all percentile cut-offs (all P<0.001). Similar increases were observed for risk of sustained EDSS score 4.0. In contrast, the risk for reaching sustained EDSS score 6.0 and conversion to SP MS was not consistently significant.

Conclusions: Elevated pNfL levels at early stages of MS are associated with increased risk of reaching sustained disability worsening. Hence, pNfL may serve as a prognostic tool to assess the risk of developing permanent disability in MS.