Enhancing the clinical value of serum neurofilament light chain measurement
Peter Kosa, Ruturaj Masvekar, Mika Komori, Jonathan Phillips, Vighnesh Ramesh, Mihael Varosanec, Mary Sandford, Bibiana Bielekova
Peter Kosa, Ruturaj Masvekar, Mika Komori, Jonathan Phillips, Vighnesh Ramesh, Mihael Varosanec, Mary Sandford, Bibiana Bielekova
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Clinical Research and Public Health Neuroscience

Enhancing the clinical value of serum neurofilament light chain measurement

Abstract

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 R2 = 0.57 to 0.67). Covariate adjustment significantly improved the correlation of sNFL with the number of contrast-enhancing lesions (from R2 = 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 sNFL 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.TRIAL REGISTRATION ClinicalTrials.gov NCT00794352.FUNDING Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH (AI001242 and AI001243).

Authors

Peter Kosa, Ruturaj Masvekar, Mika Komori, Jonathan Phillips, Vighnesh Ramesh, Mihael Varosanec, Mary Sandford, Bibiana Bielekova

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Figure 3

sNFL correlates better with MS disease severity outcomes than cNFL.

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sNFL correlates better with MS disease severity outcomes than cNFL. (A) ...
(A) Disease severity in MS is a measure of how fast patients accumulate disability. Slow accumulation of disability over time results in low MS severity (green); fast accumulation of disability results in high MS severity (red). Because it is difficult to measure rates of disability progression prospectively and longitudinally, MS severity outcomes are collected cross-sectionally, measuring past rates of disability progression by normalizing disability to the patient’s age (Age-Related Multiple Sclerosis Severity Score [ARMSS] and Multiple Sclerosis Disease Severity Scale [MS-DSS]) or disease duration (MSSS). Correlation analysis of 3 MS severity outcomes, MS-DSS, MSSS, and ARMSS, with 3 NFL values, measured cNFL, measured sNFL, and sNFL-predicted cNFL, in 2 independent cohorts: training cohort (B) and validation cohort (C). Purple line represents linear regression model with gray shading corresponding to 95% confidence interval. Difference in number of patients/samples used for these analyses is because of exclusion of samples due to missing respective MS severity data.