High blood NfL levels predict greater MS disability in year or two: Study

Elevated blood levels of neurofilament light chain (NfL), an established biomarker of nerve damage, are associated with a higher risk of near-term disability worsening in people with multiple sclerosis (MS), according to a large study.

Findings imply that there’s usually a window of time — about a year or two — between elevated NfL levels being detected and patients starting to experience greater disability. More aggressive treatment given during this period may help in avoiding disease progression, the researchers suggested.

“This rising of NfL up to two years before signs of disability worsening, represents the window when interventions may prevent worsening,” Ahmed Abdelhak, MD, a neurologist and clinical instructor at the University of California San Francisco (UCSF) and study co-author, said in a UCSF press release.

The study, “Neurofilament Light Chain Elevation and Disability Progression in Multiple Sclerosis,” was published in JAMA Neurology. The work was supported in part by Roche, the Swiss National Research Foundation, the National Institutes of Health, and the National MS Society.

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Abdelhak presented these biomarker and disability findings last month at the ECTRIMS conference.

The NfL protein helps to provide structure to nerve fibers, but it can be released into blood and other body fluids when nerve cells are damaged. Emerging data suggest that elevated NfL blood levels may be a useful marker of disease activity in MS.

A global team of researchers assessed blood NfL levels in 1,899 MS patients being followed in two observational studies: the EPIC study being conducted at USCF (609 patients) and the SMSC study in Switzerland (1,209 patients).

Study participants undergo annual assessments, including measures of blood NfL levels, for up to 10 years. The researchers compared trends in NfL levels against the timing of confirmed disability worsening, defined as a meaningful increase in Expanded Disability Status Scale (EDSS) scores that’s confirmed in a follow-up visit at least six months later.

Results indicated that NfL levels tended to rise notably about one year before confirmed disability worsening associated with an incomplete recovery from an MS relapse (a sudden attack of new or worsening symptoms). When disability worsening was independent of relapse activity, NfL levels tended to rise more gradually about one to two years before disability worsening was confirmed.

High NfL levels precede MS disability worsening by 11 to 21 months

“The reported NfL elevation preceding CDW [confirmed disability worsening] events highlights the value of NfL as an early biomarker of disability worsening and points to the existence of different windows of dynamic central nervous system pathology preceding” progression that follows a relapse and progression that doesn’t, the scientists wrote.

Data also suggest that NfL levels begin rising earlier when disability worsening is not tied to a relapse, a pattern indicating a “more prolonged process” and one whose NfL elevations show a “decrease in intensity in advance of increased impairment,” said Ari Green, MD, a study co-author and medical director of the UCSF Multiple Sclerosis and Neuroinflammation Center.

“This aligns with recognition that death of nerve cells is a slow process that builds toward permanent disability and means that interventions to protect nerve cells might have time to also stop disability,” Green added.

Researchers also looked at whether elevated NfL levels might be used to predict the risk of future disability worsening. For these analyses, they specifically defined high NfL levels as a z score greater than 1 — which is basically a statistical way to define patients with levels markedly higher than average levels for healthy people of the same age.

An analysis of data from the SMSC study showed that patients with high NfL levels were at a significantly increased risk — by approximately 70% — of relapse-associated disability worsening at the following visit, about 11 months later.

The risk of relapse-associated worsening also increased about 12.6 months after high NfL levels were detected in the EPIC study, though this analysis’ results did not quite achieve statistical significance.

Elevated NfL levels also associated with a significantly higher risk of disability worsening independent of relapse activity in both studies: by about 40% after one year in the U.S. study, and about 49% after 21 months (nearly two years) in the Swiss study.

Time-linked relationship between rising NfL levels and disability progression

In contrast, a finding of elevated NfL levels closer to confirmed disability worsening being detected — about 10.8 months earlier in the SMSC study — or further away from the event (26.2 months earlier in EPIC), did not significantly associate with an increased risk of disability progression independent of relapse activity.

“A strength of this study is that almost all findings could be replicated in both cohorts [study groups] despite their different designs, which lends credence to the results,” the scientists noted.

“In addition to the groundbreaking findings on the temporal relationship between NfL increases and gradual disease progression in MS, the study supports the important role of NfL as an early marker of nerve damage,” said Jens Kuhle, MD, PhD, a study co-author and head of the Multiple Sclerosis Center at University Hospital Basel in Switzerland.

“Monitoring NfL levels might be able to detect disease activity with higher sensitivity than clinical exam or conventional imaging,” Kuhle added.

Future studies could test whether more aggressive treatments given when high NfL levels are detected might help to reduce the risk of long-term disability, the scientists added.