1.  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.  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. Yr1Yr2Yr3Yr4Yr5 Aim 1: Database and clinical factors XXXXX Aim 2: GWAS and fine mapping XXXX Aim 3: Change in lesion burden XX 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.  The cerebral cavernous malformation signaling pathway promotes vascular integrity via Rho GTPases. 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. Saeid Taheri, PhD Blaine L. Hart, M.D. Anatomy and transfer rate in CCM: left to right, FLAIR image showing 3 CCMs; Ki (transfer rate) map; and VP (intravascular volume) map. 1)Use dynamic contrast-enhanced MRI (DCEMRI) to detect abnormalities in brain permeability in CCM patients and correlate with anatomic lesion information. 2)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.