Serum neurofilament light chain levels associations with gray matter pathology: a 5-year longitudinal study

Gray matter (GM) pathology is closely associated with physical and cognitive impairment in persons with multiple sclerosis (PwMS). Similarly, serum neurofilament light chain (sNfL) levels are related to MS disease activity and progression.

To assess the cross-sectional and longitudinal associations between sNfL and MRI-derived lesion and brain volume outcomes in PwMS and age-matched healthy controls (HCs).

Forty-seven HCs and 120 PwMS were followed over 5 years. All subjects underwent baseline and follow-up 3T MRI and sNfL examinations. Lesion volumes (LV) and global, tissue-specific and regional brain volumes were assessed. sNfL levels were analyzed using single molecule array (Simoa) assay and quantified in pg/mL. The associations between sNfL levels and MRI outcomes were investigated using regression analyses adjusted for age, sex, baseline disease modifying treatment (DMT) use and change in DMT over the follow-up. False discovery rate (FDR)-adjusted q-values <0.05 were considered significant.

In PwMS, baseline sNfL was associated with baseline T₁ -, T₂ - and gadolinium-LV (q = 0.002, q = 0.001 and q < 0.001, respectively), but not with their longitudinal changes. Higher baseline sNfL levels were associated with lower baseline deep GM (β = -0.257, q = 0.017), thalamus (β = -0.216, q = 0.0017), caudate (β = -0.263, q = 0.014) and hippocampus (β = -0.267, q = 0.015) volumes. Baseline sNfL was associated with longitudinal decline of deep GM (β = -0.386, q < 0.001), putamen (β = -0.395, q < 0.001), whole brain (β = -0.356, q = 0.002), thalamus (β = -0.272, q = 0.049), globus pallidus (β = -0.284, q = 0.017), and GM (β = -0.264, q = 0.042) volumes. No associations between sNfL and MRI-derived measures were seen in the HCs.

Higher sNfL levels were associated with baseline LVs and greater development of GM atrophy in PwMS.