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J Cereb Blood Flow Metab. 2015 Oct;35(10):1632-9. doi: 10.1038/jcbfm.2015.98. Epub 2015 May 13.

Vascular permeability in cerebral cavernous malformations.

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Neurovascular Surgery Program, Section of Neurosurgery, Department of Surgery, The University of Chicago Medicine and Biological Sciences, Chicago, Illinois, USA.
Brain Research Imaging Center, The University of Chicago Medicine and Biological Sciences, Chicago, Illinois, USA.
Section of Neuroradiology, Department of Diagnostic Radiology, The University of Chicago Medicine and Biological Sciences, Chicago, Illinois, USA.
Diagnostic Department Glostrup Hospital, University of Copenhagen, Copenhagen, Denmark.
Department of Circulation and Medical Imaging, The Norwegian University of Technology and Science, Trondheim, Norway.
Department of Neurosurgery, West China Hospital of Sichuan University, Sichuan, China.


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.

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