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Is Lesion Permeability the Culprit in Cerebral Cavernous Malformations?

Is Lesion Permeability the Culprit in Cerebral Cavernous Malformations?. Cavernous Malformation Thin walled, single layer of endothelium, cluster of bubble-like structures filled with stagnant blood Congenital or de novo Single or multiple Sporadic CCM 80% Familial CCM 20%.

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Is Lesion Permeability the Culprit in Cerebral Cavernous Malformations?

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  1. Is Lesion Permeability the Culprit in Cerebral Cavernous Malformations? • Cavernous Malformation • Thin walled, single layer of endothelium, cluster of bubble-like structures filled with stagnant blood • Congenital or de novo • Single or multiple • Sporadic CCM 80% • Familial CCM 20%

  2. Importance in the Southwestern US • NM has highest density of inherited CM worldwide • Autosomal dominant disorder • Common Hispanic founder mutation • Hundreds of families • Large families • Multiple lesions • All ages • Geographic and cultural isolation • Limited availability of neurological and neurosurgical care in NM

  3. Aim 1 • Establish Registry @ University of New Mexico • 500 CCM1-CHM patients • In collaboration with Angioma Alliance • Aim 2 • Modifier genes: clinical variability • Lesion burden: primary outcome • Potential surrogate for adverse outcomes • Aim 3 • longitudinal component • natural history data with detailed imaging

  4. Whitehead KJ, Chan AC, Navankasattusas S, Koh W, London NR, Ling J, Mayo AH, Drakos SG, Jones CA, Zhu W, Marchuk DA, Davis GE, Li DY • The cerebral cavernous malformation signaling pathway promotes vascular integrity via Rho GTPases. • Nat Med. 2009 Feb;15(2):177-84. Epub 2009 Jan 18 • CCM2 mouse model, no CCM’s but increased permeability of skin • Decreased permeability of skin with simvastatin

  5. Anatomy and transfer rate in CCM: left to right, FLAIR image showing 3 CCMs; Ki (transfer rate) map; and VP (intravascular volume) map. • Use dynamic contrast-enhanced MRI (DCEMRI) to detect abnormalities in brain permeability in CCM patients and correlate with anatomic lesion information. • Compare change in permeability from baseline to three months in a group of CCM patients placed on statin medication with change in permeability for a control group of CCM patients not on statin medication, which could lay the basis for drug treatment trials for the larger CCM community. • 3) Develop plans for a large blinded prospective clinical statin trial comparing outcome (number of hemorrhages, worsening of epilepsy) using permeability as a biomarker. Saeid Taheri, PhD Blaine L. Hart, M.D.

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