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 4

Two hypotheses explaining superiority of sNFL in predicting MS severity.

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Two hypotheses explaining superiority of sNFL in predicting MS severity....
(A) Hypothesis 1: Dilution of cNFL due to brain atrophy while sNFL concentration remains unaffected. Brain atrophy was evaluated by brain parenchymal fraction (BPFr) and by semiquantitative measure of brain atrophy (none, mild, moderate, and severe). (B) NFL residuals that fall within IQR (gray) were removed, resulting in a subset of samples with proportionally higher (above the third quartile [teal]) and lower cNFL (below the first quartile [salmon]), with comparable sNFL levels. (C) Paired Wilcoxon rank sum test showed marginally significant difference in BPFr (top left) and total brain atrophy (bottom left) between samples with different cNFL levels in the training cohort. These observations were not confirmed in the validation cohort (top and bottom right). (D) Hypothesis 2: Increase of sNFL due to spinal cord (SC) damage. NFL from damaged peripheral nerves and SC roots is released directly into blood, increasing sNFL concentration while cNFL remains unchanged. SC damage was evaluated using a semiquantitative MRI outcome (a sum of lesion load and atrophy at the level of medulla and cervical spine) and by clinical outcome capturing damage of lower motor neurons (sum of muscle atrophy scores) and damage to peripheral/autonomous nervous system (score for bowel, bladder, sexual, and autonomic dysfunctions) generated from neurological exams digitalized using the NeurEx app. (E) NFL residuals that fall within IQR (gray) were removed, resulting in a subset of samples with proportionally higher sNFL (above the third quartile [teal]) and lower sNFL (below the first quartile [salmon]), with comparable cNFL levels. (F) Paired Wilcoxon rank sum test showed a statistically significant difference in MRI (top left) and clinical (bottom left) outcomes between samples with different sNFL levels in the training cohort; the observed differences were confirmed in the validation cohort (top and bottom right). The box plots depict the minimum and maximum values (whiskers), the upper and lower quartiles, and the median. The length of the box represents the IQR.