A cohort study found glial fibrillary acid protein may be a reliable cerebrospinal fluid biomarker for differentiating progressive multiple sclerosis from relapsing disease.
Multiple sclerosis (MS) presents a complex challenge in clinical management due to its varied progression patterns and the absence of precise biological markers to predict disease course. Two MS types, relapsing and progressive, are driven by distinct underlying mechanisms. Relapsing MS involves acute inflammatory episodes mediated by peripheral immune cell migration into the central nervous system (CNS), leading to perivascular inflammatory lesions observable on MRI scans. Conversely, progressive MS is marked by chronic CNS inflammation and neurodegeneration, often without clear relapse episodes.
This cohort study, published in JAMA Neurology, aimed to identify CSF biomarkers associated with progressive MS.
Certain CSF Biomarkers Seem to be Unique to Progressive MS
This study aimed to distinguish biological markers indicative of progressive MS from those associated with acute inflammatory relapses. The research focused on cerebrospinal fluid (CSF), which is considered the most accessible compartment reflecting CNS tissue status. Leveraging data from the Ocrelizumab Biomarker Outcome Evaluation (OBOE) study, which examined patients undergoing anti-CD20 treatment, the researchers analyzed CSF samples, clinical assessments, and brain MRI scans.
The test cohort included patients with relapsing MS (RMS) or primary progressive MS (PPMS) who received ocrelizumab. Various CSF markers measured included proteins related to immune cells, glial cells, cytokines, and neuroaxonal injury. Comparisons between RMS and PPMS cohorts revealed elevated levels of specific markers in PPMS, suggesting ongoing CNS inflammation independent of acute disease activity.
Researchers assessed correlations between CSF biomarkers and clinical or MRI metrics. Notably, markers reflecting astroglial activity (e.g., glial fibrillary acid protein (GFAP)) and neuroaxonal injury (e.g., NfH) showed associations with MS lesion burden and disease severity, particularly in PPMS. These findings suggest a role for glial cells in progressive MS pathology. Further analyses, including single-nucleus RNA sequencing (snRNA-seq) of MS brain tissue and proteomic analysis of CSF samples, provided additional support for the involvement of astrocytes in progressive MS. The data highlighted GFAP as a potential biomarker for progressive disease, as its levels remained elevated despite anti-CD20 treatment, which predominantly affects acute inflammatory processes.
In a separate confirmation cohort, elevated CSF GFAP levels were associated with future disability progression, validating its prognostic value across MS phenotypes. Interestingly, serum GFAP levels did not correlate strongly with CSF levels or disease outcomes, suggesting the importance of CSF-specific markers in reflecting CNS pathology.
The Bottom Line
The study underlines the role of glial cells, particularly astrocytes, in driving progressive disease processes. Identifying GFAP and NfH as potential biomarkers for progressive MS provides valuable insights for future clinical trials and treatment strategies to target underlying disease mechanisms. Further research is warranted to validate these findings and explore their clinical implications in MS management.
Source:
Cross, A. H., Gelfand, J. M., Thebault, S., Bennett, J. L., Von Büdingen, H., Cameron, B., Carruthers, R., Edwards, K. R., Fallis, R. J., Gerstein, R. M., Giacomini, P. S., Greenberg, B., Hafler, D. A., Ionete, C., Kaunzner, U., Kodama, L., Lock, C., Longbrake, E. E., Musch, B., . . . Bar‐Or, A. (2024). Emerging cerebrospinal fluid biomarkers of disease activity and progression in multiple sclerosis. JAMA Neurology. https://doi.org/10.1001/jamaneurol.2024.0017
