Biomarker sNfL Falls Short for MS Diagnosis, Experts Say

PHOENIX — Despite its growing role in monitoring treatment response and disease activity in multiple sclerosis (MS), serum neurofilament light chain (sNfL) lacks the specificity needed for diagnosis and will not be included in upcoming revisions to the McDonald criteria, experts say.

In addition to monitoring treatment response, sNfL has the potential to eventually play a part in predicting disease course, “but diagnosis? Not so much,” said Tanuja Chitnis, MD, senior neurologist, Brigham M ultiple S clerosis Center, Harvard Medical School, Boston, at the Consortium of Multiple Sclerosis Centers (CMSC) 2025 Annual Meeting.

This not only applies to sNfL but other fluid biomarkers, including glial fibrillary acidic protein (GFAP), which has enormous promise for tracking and understanding the course of MS but also needs context and has important limitations.

“We do not yet know for sure what the updated McDonald criteria will recommend specifically, but sNfL is not very helpful for diagnosis,” said Mark Freedman, MD, director of the Multiple Sclerosis Research Unit at the University of Ottawa, Ottawa, Ontario, Canada. He, like Chitnis, does not see sNfL as a diagnostic tool either as an isolated value or in the context of other currently available signs of disease.

Most, if not all, patients with a diagnosis of MS who are eventually confirmed typically have elevated levels of sNfL, but Freedman, who led the symposium on fluid biomarkers said this information is not helpful. And sNfL, he noted climbs with neurodegeneration, but this is not unique to MS.

Many other diseases associated with neuronal damage, including amyotrophic lateral sclerosis, are linked to much higher sNfL levels at diagnosis, underscoring its poor specificity, said Freedman, who has led consensus papers on its use. The most recent was published in 2024 on behalf of the CMSC.

An Indicator of Response

Chitnis said sNfL may eventually play a role in MS diagnosis when combined with other variables, including fluid biomarkers, but for now, its primary value lies in disease management, where it serves as a sensitive tool for monitoring treatment response.

A sensitive indicator of disease activity sNfL provides information beyond MRI, said Chitnis, who tracks levels every 3-6 months after initiating or switching therapy. A lack of decline may signal inadequate disease control. Freedman echoed this view, noting that if levels don’t drop within a few months of starting treatment, he begins to question its effectiveness — even before other signs of treatment failure appear.

“If I do not see sNfL fall within a few months of starting therapy, I start questioning the therapy,” he said.

The clinical value of sNfL was highlighted in a 2023 CSMC consensus paper, which endorsed its use for tracking recovery after relapse, guiding therapy decisions, and clarifying discrepancies between MRI and clinical findings. Since then, evidence supporting its use has only strengthened, Freedman said.

“The tests are now accessible everywhere,” he said. He also noted that there is growing confidence that sNfL is a substitute for MRI in many specific scenarios, such as when access to MRI is limited by cost or distance to an imaging device.

Multiple sNfL assays are available, but they are not interchangeable. They vary in sensitivity, turnaround time, methodology, and cutoff values — so any changes in sNfL levels must be tracked using the same assay throughout.

“We have to be careful about using apps to interpret the results,” Chitnis cautioned, noting that such tools are now commercially available. She added that interpretation also depends on the reference population and can be influenced by factors like body mass index, renal function, and age.

‘A Novel Window Into the Brain’

The value of sNfL in monitoring treatment response — and in tasks such as assessing disease activity in patients with MS who have discontinued DMT — may be just the beginning for this biomarker, which is under active investigation for a range of additional uses, said Chitnis.

She noted that the clinical utility of fluid biomarkers like sNfL is likely to expand significantly as researchers learn how to interpret them in combination. In several studies, pairing sNfL with GFAP has offered new insights into progressive MS, particularly when the two markers trend in opposite directions.

Despite an imperfect correlation, patients with high GFAP but low sNfL, relative to the other way around, “probably represent our nonactive secondary progressive MS disease cohort,” Chitnis said.

“This is getting at our understanding of who might be more progressive in regard to the loss of the glial structure in the brain,” she added.

Meanwhile, other potential biomarkers associated with increased clinical and radiological MS activity are showing promise. In a recent study led by Chitnis, a panel of 20 such proteins correlated more precisely with gadolinium lesion activity, clinical relapse, and annualized relapse rate than sNfL alone.

Ultimately, fluid biomarkers like sNfL are providing “a novel window into the brain” relevant not just to monitoring disease but potentially revealing the sequence of underlying pathophysiology of MS, said Chitnis.

These appear to differentiate relatively benign disease from events leading to the irreversible damage of late stages progression.

Chitnis reported financial relationships with more than 15 pharmaceutical or device companies, including those that produce assays for sNfL. Freedman reported financial relationships with more than 20 pharmaceutical or device companies, including those that produce assays for sNfL.