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Elevated plasma levels of neurofilament light (NfL) protein in early stages of multiple sclerosis (MS) were tied to an increased risk of disability worsening, a large case-control study suggested.

MS patients with high plasma NfL, a measure of axonal damage, were 40% to 70% more likely to have worsening disability in the next year, and were more likely to have long-term, sustained disability, reported Ali Manouchehrinia, PhD, of the Karolinska Institute in Stockholm, Sweden, and co-authors, in .

"These results suggest that elevated levels of these proteins measured early on in the course of the disease may help us to predict how the disease will develop and monitor how treatment is working," Manouchehrinia said in a statement.

More research is needed before a blood test could be used routinely in clinical settings "but our results are encouraging," he noted. "In disease like MS that is so unpredictable and varies so much from one person to the next, having a noninvasive blood test like this could be very valuable, especially since treatments are most effective in the earliest stages of the disease," he said.

Earlier small studies, including an analysis of 122 patients from the CLIMB cohort, have tied serum NfL values in the first few years after MS onset to long-term measures of brain lesion load and atrophy. A case-control study of active-duty U.S. military personnel also showed that plasma NfL levels increased 6 years before the clinical onset of MS, suggesting it may have use as a prodromal marker.

NfL can be quantified in serum reliably by single molecule array assays, noted Zoe Leonie Elise van Kempen, PhD, of Amsterdam University, the Netherlands, and co-authors, in an . "This makes NfL the ideal candidate biomarker of acute and chronic axonal damage."

In this analysis, Manouchehrinia and colleagues looked at a subset of MS cases and population-based sex- and age-matched controls from two prospective studies: the Epidemiological Investigation of Multiple Sclerosis (EIMS) and the Immunomodulation and Multiple Sclerosis Epidemiology (IMSE) cohorts. Median follow-up was 5 years.

The sample included 4,385 MS patients and 1,026 controls. Relapsing-remitting MS patients numbered 3,664, and 640 patients had progressive MS. Expanded Disability Status Scale score milestones 3.0 (indicating moderate disability), 4.0 (significant disability, but able to walk without aid or rest for 500 m), and 6.0 (requiring unilateral assistance to walk about 100 m with or without resting) were the study's endpoints.

Median plasma NfL was 11.4 pg/mL in MS patients and 7.5 pg/mL in controls. MS patients were categorized by age-stratified NfL levels above or below the 80th, 95th, and 99th percentiles of controls.

High plasma NfL was tied to increased adjusted rates of EDSS worsening in the year after sampling, with adjusted hazard ratios ranging from 1.4 (95% CI 1.1-1.8) to 1.7 (95% CI 1.4-2.3).

MS patients with plasma NfL concentrations above the 80th percentile of controls had a higher risk of reaching sustained EDSS milestones. High levels were tied to the risk of reaching a sustained EDSS score of 3.0, with adjusted hazard ratios in the neighborhood of 1.5 over all percentile cutoffs (all P<0.001).

Similar increases were seen for the risk of reaching a sustained EDSS score of 4.0. However, the risk of reaching a sustained EDSS score of 6.0 and the risk of converting to secondary progressive MS were not consistently significant.

"But before we can implement NfL as a prognostic marker on an individual level, a few things should be sorted out," van Kempen and colleagues said in their editorial.

The percentile cutoffs of NfL levels used in this study could vary across different cohorts and methods, they observed. Because NfL fluctuates in individuals with relapses, "a sole baseline NfL measurement might be insufficient for founding treatment decisions and prognosis," they added. "Current disease activity should be taken into account, and multiple NfL measurements over time may be needed to improve the prediction."

The data showed significant variability and overlap in NfL levels between controls and MS patients and within different MS phenotypes, the study investigators noted. It's also likely NfL levels were affected by other factors, like comorbidities, that were not assessed in this analysis.

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