Introduction: The clinical course cerebral of cavernous malformations (CCMs) is highly variable, with a limited number of recent studies querying factors associated with disease severity. We hereby explore a panel of peripheral plasma biomarkers implied with inflammation and angiogenesis in relation to CCM clinical activity.
Methods: Blood samples of 85 CCM patients (49 with solitary/sporadic lesions and 36 with multifocal/familial CCMs) were collected at the time of the clinical visit, concurrently with advanced MRI sequences. Twenty a priori chosen plasma biomarkers were quantified and analyzed in relation to established parameters of disease categorization and severity, including genotype, lesion burden, age at symptomatic presentation, CCM-related seizures and the number and timing of prior symptomatic hemorrhages. We first tested classic univariate correlations of each biomarker with disease features, including an FDR correction, and we then applied a multivariate hierarchical clustering approach. We further correlated the peripheral plasma biomarkers with measures of lesional permeability and iron deposition using previously validated MRI protocols.
Results: MMP2 and ICAM1 levels were significantly higher (p=0.02 and p=0.04 respectively) in patients with seizure activity while MMP9 was lower (p=0.04). VEGF and endoglin/CD105 (p=0.04 for both) plasma levels were both lower in patients who had suffered a symptomatic bleed in the prior 3 months. The hierarchical clustering analysis revealed a cluster of 4 plasma inflammatory cytokines (TNFα, IL1β, IL2 and IFNγ) separating patients into high and low inflammatory states. The high inflammatory state was associated with more CCM hemorrhagic events during a patient’s lifetime (p=0.04) but not recent bleeding. CCM lesion iron concentrations were inversely correlated with IL-10 (r=-0.61, p=0.02), CCL2/MCP1 (r=-0.60, p=0.02) and ROBO4 (r=-0.53, p=0.05) in CCM lesions that recently bled.
Conclusion: Peripheral plasma biomarkers reflect seizure and recent hemorrhagic activity from CCM. And clusters of pro-inflammatory biomarkers correlate with cumulative chronic disease aggressiveness. Other biomarkers may reflect the clearance of lesional iron after recent hemorrhage.