Dimethyl fumarate decreases neurofilament light chain in CSF and blood of treatment naïve relapsing MS patients

Abstract

ObjectivesIn a prospective phase IV trial of the first-line oral treatment dimethyl fumarate (DMF), we examined dynamics of neurofilament light (NFL) chain in serum, plasma and cerebrospinal fluid (CSF) samples collected over 12 months from relapsing-remitting multiple sclerosis (RRMS) patients. NFL changes were related to disease activity.MethodsWe examined NFL levels by single-molecule array in 88 CSF, 348 plasma and 131 sera from treatment-naïve RRMS patients (n=52), healthy controls (n=23) and a placebo group matched by age, sex and NFL (n=52). Plasma/sera were collected at baseline, and 1, 3, 6 and 12 months after DMF. CSF samples were collected at baseline and 12 months after DMF.ResultsNFL concentration in CSF, plasma and serum correlated highly (p<0.0001 for all), but plasma levels were only 76.9% of paired serum concentration. After 12 months of DMF treatment, NFL concentration decreased by 73%, 69% and 55% in the CSF, serum and plasma (p<0.0001, respectively). Significant reduction in blood was observed after 6 and 12 months treatment compared with baseline (p<0.01 and p<0.0001, respectively) and to placebo (p<0.0001). Patients with NFL above the 807.5 pg/mL cut-off in CSF had 5.0-times relative risk of disease activity (p<0.001).ConclusionsThis study provides Class II evidence that first-line DMF reduces NFL in both blood and CSF after 6 months and normalises CSF levels in 73% of patients. High NFL concentration in CSF after a year reflected disease activity. NFL levels were higher in serum than in plasma, which should be considered when NFL is used as a biomarker.

Neurofilaments: The C-Reactive Protein of Neurology

“…Ideally, large populations of healthy individuals are required to generate normative data for reference use. While most studies compare diseased patients with normal healthy controls, many samples are collected from patients referred to hospital due to a complaint that is later resolved or not caused by neurological disease [97]. Such symptomatic controls may not represent the true levels of NF in the general population.…”

“…While CSF has some obvious advantages in CNS disease, its use is often limited by the invasive nature of the procedure that precludes its use as a frequent longitudinal marker. In general, there are strong correlations between NF-L levels in CSF, serum, and plasma [97,101,166,167], but while specificity and sensitivity are high in CSF due to the higher levels of NF-L, sensitivity is often lower in plasma [101,164,166,168] and even lower in serum [97]. Finally, the test methods also affect the results.…”

“…ECL-based assays are sensitive and require only a small sample volume to produce a large range of results [2]. These methods have largely been replaced by the Simoa technology, however, as digital immunoassays can significantly improve sensitivity and deliver reliable and robust data on both CSF, serum, and plasma NF-L, even between different laboratories [97,141].…”

“…In the past decade, however, the emergence of other biomarkers in CSF, like NF-L, has provided further insight into MS diagnosis and disease progression [93][94][95][96]. Several studies have shown that NF-L is elevated in the blood and CSF of newly diagnosed MS patients and that this is correlated with disease severity and prognosis [21,[97][98][99]. NF-L is also elevated during disease activity such as a clinical relapse of new lesions on MRI [100,101].…”

“…Repeated NF-L measures in the blood might be an attractive marker of treatment response since treatment with disease-modifying drugs such as dimethyl fumerate, interferon-beta, natalizumab, fingolimod, cladribine, and alemtuzumab resulted in significant reductions in NF-L in the CSF and blood [21,97,[104][105][106][107].…”