The predictive value of serum neurofilament light chain levels beyond MRI measures for clinical and radiological disease progression in the earliest stages of multiple sclerosis

Abstract Objective This study investigated the predictive value of neurofilament light chain (NfL) levels beyond MRI measures of disease activity in multiple sclerosis (MS). Methods This study is a retrospective post hoc analysis of the early interferon treatment group of the combined 5-year REFLEX/REFLEXION studies in clinically isolated syndrome. Baseline z-scored NfL (zNfL) and changes in zNfL during the first two years were related to brain atrophy, lesion activity, and clinical progression. Results This study included 262 patients (61.83% female, mean age 31.68 ± 8.43, median Expanded Disability Status Scale 1.5). Mean zNfL levels were highest at baseline and higher in patients with gadolinium-enhancing lesions or high T2 lesion counts ( p < 0.001). Baseline zNfL correlated with higher volumes of T2 lesions at baseline and new/enlarging/shrinking/disappearing lesions in years 1 and 2 ( r s = 0.20–0.68, p = 0.002– <0.001), faster subsequent central atrophy ( r = 0.16, p = 0.035), and an increased risk of and faster conversion to clinically definite MS (OR = 1.18, p = 0.035; HR = 1.16, p = 0.021). Baseline zNfL was no longer predictive when including baseline MRI variables and demographics. Longitudinal zNfL changes correlated especially with shrinking lesions during year 1 ( r s = − 0.42, p < 0.001) and new/enlarging lesions during year 2 ( r s = 0.26 and 0.23, p < 0.001). Subsequent global and central atrophy ( r = −0.18, p = 0.025; r = 0.20, p = 0.015) were only related to zNfL changes during year 2, even after including baseline MRI variables and demographics. Discussion Cross-sectional zNfL was related to active disease and predictive of disease progression, but not after taking MRI measures into account. The longitudinal zNfL changes were related to lesion activity and subsequent atrophy, even after including MRI measures.