Vascular Permeability in Cerebral Cavernous Malformations

• Published in: Journal of cerebral blood flow and metabolism Vol. 35; no. 10; pp. 1632 - 1639
• Main Authors: Mikati, Abdul G, Khanna, Omaditya, Zhang, Lingjiao, Girard, Romuald, Shenkar, Robert, Guo, Xiaodong, Shah, Akash, Larsson, Henrik BW, Tan, Huan, Li, Luying, Wishnoff, Matthew S, Shi, Changbin, Christoforidis, Gregory A, Awad, Issam A
• Format: Journal Article
• Language: English
• Published: London, England SAGE Publications 01.10.2015; Sage Publications Ltd; Nature Publishing Group
• Subjects: Adolescent; Adult; Aged; Aging - physiology; Biomarkers; Brain Ischemia - physiopathology; Capillary Permeability - drug effects; Cerebrovascular Circulation - drug effects; Child; Child, Preschool; Female; Genotype; Hemangioma, Cavernous, Central Nervous System - genetics; Hemangioma, Cavernous, Central Nervous System - physiopathology; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors - therapeutic use; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Male; Middle Aged; Observer Variation; Original; Pilot Projects; Young Adult; neuroradiology; cerebrovascular disease; intracranial hemorrhage; neurosurgery; MRI
• DOI: 10.1038/jcbfm.2015.98
• ISSN: 0271-678X; 1559-7016

Patients with the familial form of cerebral cavernous malformations (CCMs) are haploinsufficient for the CCM1, CCM2, or CCM3 gene. Loss of corresponding CCM proteins increases RhoA kinase-mediated endothelial permeability in vitro, and in mouse brains in vivo. A prospective case-controlled observational study investigated whether the brains of human subjects with familial CCM show vascular hyperpermeability by dynamic contrast-enhanced quantitative perfusion magnetic resonance imaging, in comparison with CCM cases without familial disease, and whether lesional or brain vascular permeability correlates with CCM disease activity. Permeability in white matter far (WMF) from lesions was significantly greater in familial than in sporadic cases, but was similar in CCM lesions. Permeability in WMF increased with age in sporadic patients, but not in familial cases. Patients with more aggressive familial CCM disease had greater WMF permeability compared to those with milder disease phenotype, but similar lesion permeability. Subjects receiving statin medications for routine cardiovascular indications had a trend of lower WMF, but not lesion, permeability. This is the first demonstration of brain vascular hyperpermeability in humans with an autosomal dominant disease, as predicted mechanistically. Brain permeability, more than lesion permeability, may serve as a biomarker of CCM disease activity, and help calibrate potential drug therapy.