A woman standing with elbow crutches on a bridge as she looks into the distance


Emerging evidence suggests neurofilament light chain (NfL) might be important in predicting progression of multiple sclerosis (MS). A study in Neurology reported that MS patients with elevated levels of this nerve protein biomarker were 40% to 70% more likely than those with low levels of NfL to have worsening symptoms within 1 year.

“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,” said study author Ali Manouchehrinia, PhD, an assistant professor at the Karolinska Institutet’s Department of Clinical Neuroscience in Stockholm, Sweden, in a statement.

NfL appears in the cerebrospinal fluid (CSF) following axonal brain injury in certain neurologic disorders. According to senior author Ingrid Skelton Kockum, PhD, professor at the Karolinska Institutet’s Department of Clinical Neuroscience, NfL levels in CSF have correlated with long-term outcomes in MS. “NfL levels in CSF have also been shown to be correlated with NfL in blood,” however, no study has ever shown that blood NfL levels associate with future disability for MS patients, Kockum told CLN Stat.

Researchers sought to investigate this association, enrolling 4,385 individuals with MS and randomly selecting 1,026 people matched for age and sex who did not have MS. They measured plasma NfL concentrations with the high sensitivity Single Molecule Array (Simoa) NF-Light Advantage Kit and used the Expanded Disability Status Scale (EDSS) to categorize the MS participants via age-stratified NfL levels above the 80th, 95th, and 99th percentiles of the control group.

EDSS is a scale used to measure disability of MS patients and monitor change over time, Kockum said. “It has been used extensively in clinical trials for different novel medications for MS and many research studies,” she added. Values in the scale range from 0 (normal neurological exam well) to 10 (death due to MS). Some other important values include: 3 (moderate disability or mild disability; no impairment to walking); 4 (able to walk without aid or rest for 500 meters), and 6 (requires a walking aid to walk about 100 meters with or without resting).

Participants were followed for a total of 5 years to see if they developed increased levels of disability. Investigators also looked to see if individuals with high NfL levels developed secondary progressive multiple sclerosis (SPMS). MS patients had an average NfL level of 11.4 pg/ml compared to 7.5 pg/ml in the non-MS patients. Overall, investigators determined that high plasma NfL correlated with sustained EDSS scores 3.0 and 4.0. MS patients were 40% to 70% more likely to have worsening disability during the following year, and 50% more likely to reach a level of moderate disability that affected daily activities. The results reflect other variables that could affect the risk of poorer outcomes in the MS patients, such as rate of relapse and longevity of disease. A total of 525 MS patients (16%) reached the moderate level of disability, and 352 patients (9%) reached significant disability. However, investigators did not find a consistent association between high protein levels and increased risk of more significant disability (EDSS 6.0) or with the risk of developing SPMS.

“In a 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,” said Manouchehrinia.

A related editorial observed that “as NfL fluctuates within individuals with relapses, a sole baseline NfL measurement might be insufficient for founding treatment decisions and prognosis. Current disease activity should be taken into account, and multiple NfL measurements over time may be needed to improve the prediction.” 

Manouchehrinia acknowledged that the level of NfL varied significantly, overlapping between the MS and non-MS cohorts. Other factors not analyzed in the study, such as other medical conditions, might influence NfL levels. While the results are encouraging, more research is needed before NfL could be used routinely in clinical practice, he added.

Since EDSS mainly measures physical disability and MS also affects patients in many other ways such as cognition, Kockum indicated that the research team “also plans to investigate if plasma NfL can predict worsening in cognitive functions estimated, using a scale called the Symbol Digit Modalities Test,” a metric that screens for organic cerebral dysfunction.