Enhancing the clinical value of serum neurofilament light chain measurement

BACKGROUND. Serum neurofilament light chain (sNFL) is becoming an important biomarker of neuro-axonal injury. Though sNFL correlates with CSF NFL (cNFL), 40% to 60% of variance remains unexplained. We aimed to mathematically adjust sNFL to strengthen its clinical value. METHODS. We measured NFL in a blinded fashion in 1138 matched CSF and serum samples from 571 patients. Multiple linear regression (MLR) models constructed in the training cohort were validated in an independent cohort. RESULTS. An MLR model that included age, blood urea nitrogen, alkaline phosphatase, creatinine, and weight improved correlations of cNFL with sNFL (from R-2 = 0.57 to 0.67). Covariate adjustment significantly improved the correlation of sNFL with the number of contrast-enhancing lesions (from R-2 = 0.18 to 0.28; 36% improvement) in the validation cohort of patients with multiple sclerosis (MS). Unexpectedly, only sNFL, but not cNFL, weakly but significantly correlated with cross-sectional MS severity outcomes. Investigating 2 nonoverlapping hypotheses, we showed that patients with proportionally higher s NFL to cNFL had higher clinical and radiological evidence of spinal cord (SC) injury and probably released NFL from peripheral axons into blood, bypassing the CSF. CONCLUSION. sNFL captures 2 sources of axonal injury, central and peripheral, the latter reflecting SC damage, which primarily drives disability progression in MS.

Automated summary

This study aimed to enhance the clinical value of serum neurofilament light chain (sNFL) through mathematical adjustment. The results showed that adjustment including age, blood urea nitrogen, alkaline phosphatase, creatinine, and weight significantly improved the correlations between sNFL and cerebrospinal fluid NFL (cNFL), as well as the correlations with the number of lesions in multiple sclerosis patients. In addition, there was a weak but significant correlation between sNFL and cross-sectional severity outcomes in multiple sclerosis.