Proteomic Insights into Aging and Pathophysiology in Multiple Sclerosis

The evolving demographics of Multiple Sclerosis (MS) challenge the traditional notion of it being a young adult's disease. The study by Wilson and Abdelhak highlights that the prevalence of MS peaks between ages 55 and 64 in the United States, emphasizing the urgent need for research focused on aging populations. This demographic shift underscores how aging influences MS pathophysiology, disability progression, and the efficacy of disease-modifying treatments (DMTs).

Biomarkers in MS: Beyond the Basics
Advanced biomarker profiling is critical to understanding the interplay between immune-mediated damage and age-related tissue vulnerability. Conventional markers such as Neurofilament Light Chain (NfL) and Glial Fibrillary Acidic Protein (GFAP), though widely used, predominantly indicate downstream CNS injury. A deeper exploration of mechanistic biomarkers is needed to reveal the processes driving tissue damage in MS.

Proteomic Analysis: A Game-Changer
In a recent breakthrough study, Held et al. (2025) employed advanced antibody-based proteomics to examine thousands of proteins in cerebrospinal fluid (CSF), unveiling critical age-related shifts in MS-associated immune profiles:
Age-Associated Changes: Older MS patients showed reduced adaptive immune inflammation markers in the CSF compared to younger individuals. In contrast, proteins like Growth Differentiation Factor 15 (GDF15), associated with aging, were elevated.

Common Pathways in MS: Elevated markers of axonal injury (e.g., NfL), glial activation (e.g., CHI3L1), and immune activity (notably B-cell pathways) were consistent across MS cases. These findings align with recent proteomic studies using blood and CSF samples.

Clinical Phenotypes: One Disease Spectrum?
Interestingly, the proteomic profile revealed minimal differences between Primary Progressive MS (PPMS) and Relapsing-Remitting MS (RRMS). These results support the hypothesis that RRMS and PPMS represent phenotypic variations within a single pathologic spectrum. For example:
Shared biomarkers like CXCL-13, sBCMA, and sTACI were linked to B-cell activation in both phenotypes.
The findings echo other studies demonstrating the efficacy of B-cell depleting therapies in both RRMS and PPMS.

Implications for Aging and Therapy
Proteomic findings illuminate why DMTs are less effective in older MS populations. Aging is accompanied by reduced inflammatory activity in the CSF, potentially limiting the therapeutic impact of immune-targeting treatments. These observations advocate for age-specific strategies in MS management.

Challenges and Future Directions
While the Held et al. study offers valuable insights, limitations exist:
Sample Size: A small cohort may limit statistical power, particularly in subgroup analyses.
CSF-Centric Focus: While informative for CNS inflammation, CSF proteomics does not capture systemic immune changes associated with aging.

Despite these limitations, high-throughput proteomics is poised to transform MS research, enabling pathway-level analyses that transcend traditional single-protein studies.

Conclusion
This study represents a milestone in understanding the proteomic landscape of MS across different age groups. It underscores the importance of tailoring MS research and treatment strategies to address age-related pathophysiological shifts. Future collaborative efforts integrating diverse data platforms will be key to unraveling the complexities of MS progression and phenotypic variations.

References:
Wilson, M. R., & Abdelhak, A. (2024). Proteomic Profiling and Pathophysiological Implications in Multiple Sclerosis. Neurology: Neuroimmunology & Neuroinflammation, 12(1), e200341.