Prior research has shown that levels of serum neurofilament light (sNfL), a promising biomarker of disease activity in multiple sclerosis (MS), increase with age, according to Tanuja Chitnis, MD, FAAN.  “In patients with MS, sNfL levels are acutely elevated after new MRI lesions and disease relapses and have been used to predict longer-term brain atrophy rates,” she explains. “However, previous studies did not considered whether patients with MS were experiencing an acute attack or new gadolinium enhancing (Gad+) lesions at the time of their blood draw. We know that younger patients experience a more inflammatory form of disease with more frequent relapses and new Gad+ lesions and, thus, hypothesized that sNfL will be increased in younger patients at the time of acute new attacks/Gad+ lesions.”

For a paper published in the Journal of Neuroimaging, Dr. Chitnis and colleagues conducted a comprehensive longitudinal study including 94 patients with MS who underwent annual sNfL measurements performed with a single-molecule array assay. The study team’s object was to explore the relationship of sNfL and age at different MS disease stages. They used multivariable linear mixed-effects models with random intercept to test the association between age and sNfL during remission and after a Gad+ lesion. The model was adjusted for medication and sex.

Younger Patients With MS Have More Inflammatory Form

“Our findings support existing research showing that, when compared with older patients, younger patients with MS have a more inflammatory form of the disease with higher relapse rates,” Dr. Chitnis notes. “They also have more frequent Gad+ lesions and larger, acute new lesion volumes than older patients with MS. The sNfL levels appear to reflect this more inflammatory form of disease in younger patients.”

Although sNfL increases with age at a remission timepoint, it shows the opposite relationship with age at a Gad+ timepoint, explains Dr. Chitnis (Table 1). Further evaluation illustrates the interaction of age and Gad+ status (Table 2). “We used an ‘interaction’ statistical model, which found that older age at a Gad+ lesion was associated with a decrease in sNfL levels,” she says.

Previous research conducted by the study team showed that Gad+ lesions represent the strongest drivers to sNfL elevation, even after adjustment for age. “Nevertheless, our current study shows that the underlying implication of age being linearly associated with sNfL levels may be a misleading assumption,” write Dr. Chitnis and colleagues. “As a matter of fact, Gad+ lesions resulted in a greater elevation in sNfL in younger patients compared [with] older patients.”

sNfL: Potential Informative Biomarker of Disease Severity

Contributing factors to higher levels of sNfL in younger patients may include more pronounced neuroinflammation due to more active adaptive immunity, which was demonstrated by elevated Th17 activity and a more active inflammatory profile in younger patients compared with older patients. “Older patients had higher sNfL levels than younger patients during remission, the same trend shown in healthy controls, which may be explained by age-related neurodegeneration and axonal loss,” write the study authors. Dr. Chitnis adds that the more inflammatory form of the disease form among younger patients with MS may warrant more highly effective treatments that typically used with older patients.  “sNfL may eventually be considered an informative biomarker of disease activity severity,” she says.

Dr. Chitnis and colleagues plan to examine the correlation between sNfL levels and MRI Gad+ lesion volumes in both older and young patients with MS to understand whether the inverse age association is due to larger or more frequent lesions. “Future research should take into account Gad+ lesion status when interpreting sNfL levels and their relationship to age,” she says.