Abstract
The clinical course of cerebral cavernous malformations (CCMs) is highly variable. Based on recent discoveries implicating angiogenic and inflammatory mechanisms, we hypothesized that serum biomarkers might reflect chronic or acute disease activity. This single-site prospective observational cohort study included 85 CCM patients, in whom 24 a priori chosen plasma biomarkers were quantified and analyzed in relation to established clinical and imaging parameters of disease categorization and severity. We subsequently validated the positive correlations in longitudinal follow-up of 49 subjects. Plasma levels of matrix metalloproteinase-2 and intercellular adhesion molecule 1 were significantly higher (P = 0.02 and P = 0.04, respectively, FDR corrected), and matrix metalloproteinase-9 was lower (P = 0.04, FDR corrected) in patients with seizure activity at any time in the past. Vascular endothelial growth factor and endoglin (both P = 0.04, FDR corrected) plasma levels were lower in patients who had suffered a symptomatic bleed in the prior 3 months. The hierarchical clustering analysis revealed a cluster of four plasma inflammatory cytokines (interleukin 2, interferon gamma, tumor necrosis factor alpha, and interleukin 1 beta) separating patients into what we designated “high” and “low” inflammatory states. The “high” inflammatory state was associated with seizure activity (P = 0.02) and more than one hemorrhagic event during a patient’s lifetime (P = 0.04) and with a higher rate of new hemorrhage, lesion growth, or new lesion formation (P < 0.05) during prospective follow-up. Peripheral plasma biomarkers reflect seizure and recent hemorrhagic activity in CCM patients. In addition, four clustered inflammatory biomarkers correlate with cumulative disease aggressiveness and predict future clinical activity.
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Acknowledgments
We would like to thank Mark H. Ginsberg from The University of California San Diego for helpful discussions.
Sources of Funding
This work was partially supported by a grant from the NIH (R21NS087328) to IAA, by the William and Judith Davis Fund in Neurovascular Surgery Research, and by the Safadi Translational Fellowship to RG. Funding sources played no role in the formulation of research questions nor the interpretation of results.
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All procedures performed in this study involving human participants were in accordance to the Declaration of Helsinki and approved by The University of Chicago Institutional Review Board (IRB). The ethical principles guiding the IRB are consistent with The Belmont Report and comply with the rules and regulations of The Federal Policy for the Protection of Human Subjects (56 FR 28003).
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Girard, R., Zeineddine, H.A., Fam, M.D. et al. Plasma Biomarkers of Inflammation Reflect Seizures and Hemorrhagic Activity of Cerebral Cavernous Malformations. Transl. Stroke Res. 9, 34–43 (2018). https://doi.org/10.1007/s12975-017-0561-3
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DOI: https://doi.org/10.1007/s12975-017-0561-3