Plasma Biomarkers of Inflammation Reflect Seizures and Hemorrhagic Activity of Cerebral Cavernous Malformations

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.

Cerebral cavernous malformations form an anticoagulant vascular domain in humans and mice

“…As the number of potentially new therapeutic interventions in CCMs grows, 11,[41][42][43][44] the identification of markers to identify patients with an elevated risk for hemorrhage becomes imperative. Indeed, recent studies 45,46 showed that levels of inflammatory and angiogenic molecules in peripheral blood plasma could predict CCM clinical Figure 4. KLF2 and KLF4 regulate expression of endothelial TM.…”

Biomarkers of cavernous angioma with symptomatic hemorrhage

“…Proinflammatory gene variants have been associated with higher lesion counts in Hispanic American patients with a common CCM1 (Q455X) mutation, but not with the risk of bleeding from individual lesions (7,8). A "proinflammatory cluster" of plasma cytokines, vitamin D, and non-HDL cholesterol plasma levels has been correlated with chronic CA disease severity, but not recent bleeding (9,10). A systematic literature review of biologic mechanisms implicated in brain hemorrhage and CA identified a set of plasma molecules potentially playing a role in this disease (10,11).…”

Novel hemorrhage models of cerebral cavernous malformations

“…Inhibition of vascular endothelial growth factor (VEGF) signaling with SU5416, a VEGFR2 specific antibody, in an inducible CCM1 mouse model reduced CCM formation and hemorrhage [40]. By contrast, an exploratory biomarker study found plasma levels of VEGF to be lower in CCM patients who had a hemorrhage in the past 3 months when compared to CCM patients without hemorrhage [68]. Thus, the role of angiogenesis in CCM formation and hemorrhage in the human disease, as well as how it contributes to the phenotype of inducible mouse models remains unclear.…”