A team with research support from the International Progressive MS Alliance
has published results
of a large study that measured levels of a protein in the blood that serves as a marker of nerve damage – called neurofilament light chain (NfL) – in thousands of blood samples from the general population and from people with multiple sclerosis. Based on the normal values that accounted for age and body weight, the team established a statistical model to identify increased values in individuals with MS and showed its potential for detecting clinically silent disease activity and predicting the likelihood of increased future relapses and disability worsening. Further, the team found that changes of NfL values under different therapies revealed the extent to which their MS was responding to therapy.
“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,” said Dr. Robert Fox, Chair of the Alliance’s Scientific Steering Committee. “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.”
The individual course of MS is notoriously unpredictable, and a person may have to wait many months to know whether a disease-modifying therapy is effective against short- and longer-term disease activity. The search for a biomarker to predict disease activity and progression and to monitor response to therapy in the clinic and in clinical trials 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, and higher levels 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.
- Collaborators from the Swiss Multiple Sclerosis Cohort Study Group led by Jens Kuhle, MD, PhD (MS Center at University Hospital Basel, Switzerland) sought to establish normal reference blood levels of NfL in the general population as a comparator for detecting underlying MS disease pathology. 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 toward understanding what NfL levels mean in the context of MS.
- Using vast resources of banked blood samples from 5,390 people with more than 10,000 samples from Europe and the United States, the team established what are considered normal NfL levels in different age groups. They found that in this 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 that reflect the 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 banked 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. They found that higher Z-scores served as a red flag that could warn of the risk of increased disease activity (such as MS relapse, or more disability, or MRI-detected active inflammation) in the following year. Individuals with an NfL Z-score above 1.5 (93.3 percentile) were associated with three times the risk for disease activity in the following year.
- The researchers also looked at NfL Z-scores in terms of what they might indicate about 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, while 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, which validated the predictive capacity of NfL for the course of MS, as well as being an indicator of therapy response.
- 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.
“Serum neurofilament light chain for individual prognostication of disease activity in multiple sclerosis: a retrospective modelling and validation study,”
by Pascal Benkert, Stephanie Meier, Sabine Schaedelin, Ali Manouchehrinia, Özgür Yaldizli, Aleksandra Maceski, Johanna Oechtering, Lutz Achtnichts, David Conen, Tobias Derfuss, Patrice H. Lalive, Christian Mueller, Stefanie Müller, Yvonne Naegelin, Jorge R. Oksenberg, Caroline Pot, Anke Salmen, Eline Willemse, Ingrid Kockum, Kaj Blennow, Henrik Zetterberg, Claudio Gobbi, Ludwig Kappos, Heinz Wiendl, Klaus Berger, Maria Pia Sormani, Cristina Granziera, Fredrik Piehl, David Leppert, Jens Kuhle, for the RDB in the Swiss Multiple Sclerosis Cohort Study Group, was published in The Lancet Neurology
on February 16, 2022.