Objective:

To identify features of active lesions associated with elevated sNfL in pwMS. 

Background:

Serum neurofilament light chain (sNfL) is a proposed biomarker in people with multiple sclerosis (pwMS), but elevation with active lesions varies. 

Design/Methods:

We retrospectively identified pwMS ≥20 years meeting 2024 criteria with sNfL measured by Simoa assay. Among 1292 cases reviewed, 299 had ≥1 gadolinium-enhancing lesion on MRI within 90 days of sNfL. All cases were assessed for sNfL elevation (defined by age-adjusted reference data). A stratified cohort (n=83), randomly selected and divided by sNfL status (elevated vs normal), underwent detailed clinical and radiographic review. Wilcoxon rank-sum and Fisher’s exact tests were used. 

Results:

Among 299 pwMS with enhancing lesions, the frequency of sNfL elevation within 3 months was 44% (133/299). In the stratified cohort (35/83 sNfL elevated, 42%), sex (70% female vs. 57%, p=0.25) and timing between MRI and serum (median 4 vs 4.5 days, p=0.99) did not differ between elevated and normal NfL. PwMS with elevated sNfL were younger (median 35 vs 44.5 years, p=0.002). Relapsing-remitting MS was most common (91%). Frequency of enhancing brain (29/34 [83%] vs 36/48 [75%]; p=0.25), and optic nerve (1/35 [3%] vs. 5/48 [10%]; p=0.5) lesions were similar between groups. Enhancing spinal cord lesions were more frequent with elevated sNfL (16/35 [46%] vs 11/48 [23%], p=0.03), as were tumefactive brain lesions (8/35 [23%] vs 2/48 [4%], p=0.04) and diffusion restriction (14/35 [40%] vs 4/48 [8%], p=0.0008). Elevated sNfL was associated with more enhancing brain lesions (median 1 [range 1-33] vs. 1 [1-5], p=0.04) and larger lesion diameter (median 10.4 mm vs 7.1, p=0.04). 

Conclusions:

SNfL elevation occurred in fewer than half of pwMS with enhancing lesions and was more frequent with spinal cord involvement and large diffusion-restricting brain lesions, suggesting regional axonal vulnerability may influence biomarker response.