Multiple sclerosis (MS) is a chronic autoimmune disease that affects the central nervous system (CNS). It is characterized by inflammation, demyelination, and neurodegeneration, leading to a wide range of symptoms and disability progression. Monitoring disease activity and predicting disability worsening in MS is crucial for optimizing treatment strategies and improving patient outcomes. Recent studies have highlighted the potential of neurofilament light (NfL) as an early biomarker of disability worsening in MS. In this article, we will explore the findings of two observational cohorts that investigated the temporal dynamics of NfL levels in association with different patterns of confirmed disability worsening (CDW) in MS.
The Study
The study, published in JAMA Neurology, was led by Dr. Ahmed Abdelhak and involved two observational cohorts: the Expression, Proteomics, Imaging, Clinical (EPIC) study and the Swiss Multiple Sclerosis Cohort (SMSC). The EPIC study included 609 participants, while the SMSC had 1290 participants. The researchers aimed to determine whether and when NfL levels are elevated in the context of CDW, which was defined as worsening of the Expanded Disability Status Scale (EDSS) that was confirmed after 6 or more months.
Neurofilament Light as a Biomarker
Neurofilament light (NfL) is a protein that is predominantly expressed in neurons. It is released into the cerebrospinal fluid (CSF) and blood when neurons are damaged or undergo degeneration. Elevated levels of NfL have been observed in various neurological conditions, including MS. In recent years, NfL has emerged as a promising biomarker for disease activity and disability progression in MS.
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The Temporal Dynamics of NfL Levels
The study found that increased NfL levels were detected approximately 1 year preceding relapse-associated worsening events (CDW-R) and approximately 12-24 months prior to worsening independent of clinical relapses (CDW-NR). This suggests that NfL levels may serve as an early indicator of impending disability worsening in MS.
In the EPIC cohort, serum NfL values were measured using a Simoa assay, while in the SMSC, NfL concentrations were measured by the NF-light Advantage kit. Both cohorts showed elevated NfL levels at various time points preceding the confirmed disability worsening events.
Association with Relapse Onset
Interestingly, the study also found that relapse onset was closer to the CDW-R event in the SMSC compared to the EPIC cohort. This suggests that the timing of NfL elevation may be influenced by the underlying disease activity and relapse occurrence.
Different Patterns of CDW
The study identified two distinct patterns of disability worsening events: CDW-R and CDW-NR. CDW-R refers to disability worsening that is associated with relapses, while CDW-NR represents disability worsening independent of clinical relapses. The findings showed that NfL levels were elevated at different time points preceding these events.
In the EPIC cohort, NfL elevation was seen at both visits preceding the CDW-NR event. In the SMSC, higher NfL levels were observed at CDW-NR(–2) with a trend for higher levels at CDW-NR(–1). These findings suggest that NfL levels may reflect ongoing pathological processes leading to disability worsening, even in the absence of clinical relapses.
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Predictive Value of NfL Levels
After compiling long-term data, the study found that higher NfL levels in both cohorts were associated with a higher risk of future disability worsening. A NfL z score greater than 1.0 was linked with a 70% higher risk over the subsequent 11.0 months in the SMSC and a trend for a 91% higher risk at 12.6 months in the EPIC cohort. This suggests that NfL levels may have predictive value in identifying individuals at risk of disability worsening in the near future.
Implications for Treatment
The findings of this study have important implications for the treatment of MS. By assessing NfL levels, clinicians may be able to identify individuals who are at a higher risk of disability worsening and intervene earlier with appropriate treatment strategies. Monitoring NfL levels could also serve as a tool for evaluating treatment success in preventing disability worsening.
Conclusion
The temporal dynamics of NfL levels in association with disability worsening events provide valuable insights into the pathophysiology of MS. Elevated NfL levels precede relapse-associated worsening events and disability worsening independent of clinical relapses. These findings suggest that NfL may serve as an early biomarker of impending disability worsening in MS. Further research is needed to fully understand the role of NfL in MS and its potential for personalized treatment approaches.
References
- Abdelhak A, Benkert P, Schaedelin S, et al. Neurofilament light chain elevation and disability progression in multiple sclerosis. JAMA Neurol. Published online November 6, 2023. doi:10.1001/jamaneurol.2023.3997