Plasma Vitamin D and Non-HDL Cholesterol Reflect the Disease Severity of Cerebral Cavernous Malformation

Introduction and Hypothesis: Cerebral cavernous malformations (CCMs) are common cerebrovascular anomalies with highly variable but potentially disabling disease behavior disease behavior. Factors portending an aggressive clinical course are not known. An association of disease severity with vitamin D has been suggested in preclinical studies, and other evidence supports a role of inflammation in the pathobiology of CCM. Methods: A prospective case-controlled study enrolled 43 consecutive patients with CCM disease (20 sporadic/solitary and 23 multifocal/familial). Non-fasting peripheral venous blood samples were analyzed for plasma levels of 25-(OH) vitamin D, high-density lipoprotein (HDL) and non-HDL cholesterol, C-reactive protein (CRP), and for leukocyte Rho-kinase (ROCK) activity. We correlated these biomarkers with prospectively defined parameters of chronic (a history of multiple adjudicated clinically overt hemorrhages, early age of clinical onset or high lesion burden in familial cases) and recent (lesional growth or hemorrhage in the preceding year, or new lesion formation in familial cases) disease aggressiveness. Results: Patients with historically aggressive CCM disease had significantly lower 25-(OH) vitamin D and non-HDL cholesterol levels. Neither was predictive of recent disease activity. HDL cholesterol, CRP levels and ROCK activity did not correlate with historical or recent disease severity. Receiver operating characteristic curves for 25-(OH) vitamin D or non-HDL cholesterol showed ‘fair’ accuracy: Area under curve (AUC)= 0.73 (p=0.01) and 0.74 (p=0.007), respectively. Combination of the two parameters improved the accuracy to AUC=0.80 (p Conclusions: This is the first evidence of correlation of peripheral blood biomarkers with the severity of human CCM disease. Validation of these biomarkers and their potential modification may influence the clinical care of CCM.