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CHARLOTTE, N.C. — Plasma neurofilament light chain (NfL) levels tracked closely with cognitive function in patients with relapsing multiple sclerosis (RMS), a new analysis showed, adding more evidence that the protein may hold promise as a routine biomarker for this outcome.

The data come from the ENLIGHTEN phase 3b trial, a single-arm study that evaluated the effect of the S(1)P inhibitor ozanimod on cognitive loss in patients with RMS. The primary results, presented earlier this year, showed a preservation or slight increase in cognitive function in most patients taking the drug over a 3-year period.

In the new analysis, the change in NfL — a marker of axonal damage and neuronal degeneration — was evaluated in relationship to cognitive function over the course of the study.

NfL “has been proposed by others as a biomarker of disease activity as well as treatment response, but this adds evidence for a potential role in tracking cognitive function,” said investigator John DeLuca, PhD, a professor in the Department of Neurology at Rutgers New Jersey Medical School, Newark, New Jersey.

The findings were presented on May 28 at the Consortium of Multiple Sclerosis Centers (CMSC) 2026 Annual Meeting.

Closer Look at NfL and Cognition

Cognitive decline is common in relapsing MS, affecting roughly half of the patients. But in the ENLIGHTEN trial, 60% of the patients treated with ozanimod saw their cognitive scores improve over 3 years. Cognitive function remained stable in 28% and only 12% reported a decline.

For the new analysis, researchers wanted to assess the link between NfL levels and cognitive outcomes in that multicenter trial. They included 164 patients (mean age, 39.5 years; 86% women; 68% treatment-naive) with early RMS from the original trial who received a daily dose of 0.92 mg of ozanimod and had data on cognitive function and NfL levels.

Cognition was evaluated at baseline and at 1, 2, and 3 years of follow-up with the Symbol Digit Modalities Test (SDMT), the second edition of the California Verbal Learning Test (CVLT-II), and the revised Brief Visuospatial Memory Test (BVMT-R). Cognitive loss was defined as a 1.5 SD below normative values.

At baseline, the mean plasma NfL value was already elevated significantly relative to values normal for healthy control individuals (3.5 vs < 3.0 mean log2; P < .0001). At 1-year follow-up, the mean NfL level was comparable (< 3.0 mean log2) to the normative values. The mean levels remained at normal levels at year 2 and 3.

Higher NfL Linked to Impairment

Overall, NfL levels decreased over time, regardless of cognitive impairment. And mean higher plasma NfL levels were significantly associated with impairment across all cognitive tests at baseline and over the course of treatment, DeLuca reported.

For SDMT specifically, the median NfL levels were significantly higher in patients with cognitive impairment at baseline relative to those with normal function. Over the next 3 years, a mean reduction in NfL was observed for all patients regardless of baseline cognitive function (P < .05), with similar reductions in SDMT-impaired and -unimpaired groups.

Greater cognitive impairment was also correlated with higher median NfL levels at baseline on CVLT-II. In this case, a significantly greater reduction in scores was observed during follow-up for those with impaired vs unimpaired cognition at baseline.

The pattern was similar for BVMT-R scores. Median NfL levels were significantly higher at baseline among those impaired vs unimpaired. Over time, there was a greater mean reduction in NfL among those impaired vs unimpaired at baseline, although the numerical difference did not reach significance.

“Reductions in NfL observed with ozanimod treatment may reflect reductions in neuroaxonal injury, consistent with better overall cognitive performance in early RMS,” researchers reported.

NfL Elevations Not Specific to MS

As a cytoskeleton protein that is shed into the central spinal food (and reaching the plasma) following neuronal damage, NfL is nonspecific and observed in other neurodegenerative disorders, including Alzheimer’s disease. In MS, several forms of disability have been correlated with higher NfL levels in a number of studies, including one published in 2025.

This has led some investigators to evaluate NfL as a practical surrogate biomarker for MS-related cognitive loss. Among examples, a linear trend was seen between rising NfL levels and cognitive loss in 450 patients with MS who were part of a National Health and Nutrition Examination Survey. That study was also published last year.

In recent papers, such experts as Amit Bar-Or, MD, a neurologist at the University of Pennsylvania in Philadelphia, and Mark S. Freedman, MD, who is affiliated with the University of Ottawa in Ottawa, Ontario, Canada, have suggested NfL remains promising but not yet proven to be useful for guiding MS management overall or for cognitive impairment specifically.

Yet based on the available evidence, some clinicians, at least at academic centers, have begun monitoring this protein as an added tool for understanding the disease course.

“Currently in my clinical practice, I utilize serum NfL, which can indicate axonal damage, to establish a baseline and track any changes over time,” Krupa Pandey, MD, an associate professor of neurology and director of the Center for Multiple Sclerosis and Related Conditions at the Hackensack University Medical Center in Hackensack, New Jersey, told Medscape Medical News.

However, she acknowledged that its role for evaluating cognition — whether as a snapshot in time or over follow-up — is not yet established.

“Studies such as ENLIGHTEN offer an optimistic outlook on how a biomarker may correlate with clinical symptoms such as cognition, but larger studies utilizing other modalities such as fMRI [in the context of] detailed outcomes would even be more helpful,” she said.

The study received financial support from Bristol Myers Squibb. DeLuca reported having financial relationships with Biogen, Bristol Myers Squibb, EMD Serono, Genentech, Janssen and Novartis. Bar-Or reported having financial relationships with Abata, Accure, Atara, Biogen, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Gossamer, Horizon, Immunic, Janssen, Medimmune, Merck/DMD Serono, Novartis, Roche/Genentech, Sangamo, Sanofi-Genzyme, and Viracta. Freedman reported having financial relationships with Alexion, AstraZeneca, Biogen Idec, EMD Serono, Find Therapeutics, Hoffman-La Roche, Horizon, Novartis, Quanterix, Sanofi-Genzyme, and Teva Canada Innovation. Pandey reported having financial relationships with Alexion, Biogen, Bristol Myers Squibb, Genentech, and Sanofi.