Blood levels of key protein may help predict MS progression

Blood levels of neurofilament light chain (NfL), a marker of nerve damage, may help predict the risk of future disease activity and progression in people with multiple sclerosis (MS) who are starting treatment, a study found.

However, NfL levels at treatment initiation did not independently predict long-term disease progression after accounting for MRI findings and other factors.

Changes in NfL levels over time were not associated with measures of disease progression, but increases in NfL during the second year of treatment were associated with faster brain atrophy over the following three years, even after accounting for baseline MRI findings and demographic factors.

“In subjects with early MS starting interferon treatment, [blood NfL] levels at baseline were predictive of disease progression,” the researchers wrote. “However, this predictive value was lost when taking MRI measures into account,” so “baseline [NfL level] reflects inflammatory disease activity and seems especially useful in the absence of MRI.” Both measures, they said, “have a unique role in the prediction and monitoring of progression in MS.”

The study, “The predictive value of serum neurofilament light chain levels beyond MRI measures for clinical and radiological disease progression in the earliest stages of multiple sclerosis,” was published in the Journal of Neurology.

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Beyond MRI

MS is marked by inflammation that damages healthy cells in the brain and spinal cord. The disease course varies considerably, and predicting its progression remains challenging, particularly in its earliest stages.

Predictions about how MS is likely to evolve are made based largely on MRI scans that look at lesions (areas of inflammatory damage in the brain). But researchers continue to investigate whether blood biomarkers can provide additional information about a person’s likely disease course.

NfL is a structural protein found in nerve fibers that is released when nerve cells are damaged. A growing body of evidence suggests that higher blood levels of NfL are associated with inflammatory activity and nerve damage in MS. However, it remains unclear whether NfL assessments can improve predictions of long-term MS activity based on MRI scans.

To find out, researchers analyzed data from the REFLEX study (NCT00404352) and its long-term extension REFLEXION (NCT00813709). These studies, which ran from 2006 to 2013, tracked people with clinically isolated syndrome, a first episode of neurological symptoms suggestive of MS, who were considered at high risk of developing the disease.

This analysis involved 262 participants who started the approved MS therapy Rebif (interferon beta-1a) and were followed for five years in the trials. Over the course of follow-up, about 40% of patients converted to clinically definite MS.

Researchers measured serum NfL levels at the beginning of the study and after six, 12, and 24 months. Because NfL levels are known to vary with age and body composition, the researchers used z-scored NfL (zNfL), which indicates how a person’s NfL levels compare with what’s expected in healthy people of a similar age and body mass index.

The team examined two types of NfL measurements: levels at individual time points, which provide a snapshot of nerve damage at a given time, and changes in levels over time. They assessed how both measures related to MRI findings, clinical outcomes, and subsequent brain volume loss (brain atrophy).

At the start of the study, higher zNfL levels were associated with a greater lesion burden on MRI scans, greater brain atrophy over time, and a greater likelihood of converting to clinically definite MS over the five-year study period. However, when the analyses were adjusted for initial MRI measures and demographic factors, including age and sex, the associations between zNfL and conversion to MS and brain atrophy were no longer statistically significant.

“Once baseline MRI measures and demographics were taken into account, baseline zNfL levels lost their predictive value,” the researchers wrote.

The findings suggest that baseline NfL levels largely reflect disease activity already captured by MRI measures, rather than providing clearly independent information about long-term outcomes in this group.

The researchers also examined whether changes in zNfL levels over the first and second years of treatment were associated with clinical outcomes. Only increases in zNfL during the second year were associated with faster brain atrophy during the final three years of follow-up. No other associations were observed.

“Baseline zNfL levels reflected lesion burden and were predictive of disease progression but only if MRI measures were not taken into account,” the researchers concluded. “We also observed that initial zNfL decreases over time were associated with the resolution of inflammation, while later zNfL increases were associated with a more neurodegenerative profile.”