The individual course of MS is notoriously unpredictable, and a person may have to wait many months to know whether a disease-modifying therapy (DMT) is effective against short and longer-term disease activity. The search for a biomarker to predict disease activity, disease progression and to monitor response to therapy remains a challenge.

Neurofilament light chain (NfL) is a component of nerve cells that is released into the spinal fluid and then later into the blood after nerve damage. Higher levels of NfL may reflect ongoing disease activity. Recent advances have made it possible to measure NfL in the blood, giving it added potential in a clinical setting as an MS biomarker. However, essential information about what are normal levels in the blood and how the changing levels of NfL should be interpreted by doctors and people with MS has been missing.

The research study and what it showed

The research team is from the Swiss MS Cohort Study Group at the MS Center in University Hospital Basel and is led by Professor Jens Kuhle. The team first aimed to establish normal reference blood levels of NfL in the general population. This could then be used as a reference with which to compare to people with MS. Even in people with no known health issues, blood levels of NfL gradually increase with age. Accounting for these factors is an important first step towards understanding what NfL levels mean in the context of MS.

The team had access to over 10,000 blood samples from biobanks in Europe and the USA, which allowed them to establish what are considered normal NfL levels in different age groups. They found that in the general population, NfL levels generally increase by about 2% per year, and begin to climb at a faster rate after around age 50. They also found that higher body weight was associated with lower NfL levels.

Based on these findings, the team then developed a statistical model that adjusts NfL levels for differences in age and body weight, and allows deriving NfL Z-scores, or percentiles. NfL Z-scores reflect deviation from what would be considered normal in the general population for a given weight and age.

The team then tested the score’s predictive value in blood samples from 1,313 participants of the Swiss MS Cohort, a study group of people with MS who have been followed over several years and contributed blood samples to be stored in a biobank. They found that higher Z-scores served as a red flag that could warn of increased disease activity in the following year, such as an increased risk of an MS relapse, more disability, or MRI-detected active inflammation.

The researchers also investigated whether NfL Z-scores could indicate how well MS therapies were working. Looking across groups, those on the more highly effective therapies, such as monoclonal antibodies (alemtuzumab, natalizumab, ocrelizumab, rituximab), tended to have near-normal NfL Z-scores. Those on less powerful first-generation therapies (interferons, glatiramer acetate) tended to have higher Z-scores, closer to scores of those who were not on therapy.

The team was able to confirm these findings in blood samples from 4341 participants followed in the Swedish MS registry.

Dr. Robert Fox, Chair of the International Progressive MS Alliance’s Scientific Steering Committee says:

‘This study brings us a significant step closer to having a blood test that can predict an individual’s risk for upcoming MS disease activity and detect how well their disease-modifying therapy is working. Moreover, this represents important progress toward the critical unmet need for biomarkers that give early reflections of treatment response which in turn may both improve clinical care and speed clinical trials testing new therapies.’

Additional research is ongoing to further understand how blood NfL levels may be impacted by other medical conditions, whether NfL levels are substantially different in diverse populations, and how this biomarker may be used as a measure of effectiveness in clinical trials.

To further this important work and to facilitate the use of Z-scores (or percentiles) in clinical practice, Dr. Kuhle’s team has developed an online platform that enables the calculation of individuals’ Z-scores to interpret NfL measurements of individuals with MS, adjusted for age and body weight, as a potential way to evaluate current or future disease activity.

You can read more about the study and its findings in The Lancet Neurology: