PROJECT SUMMARY This work proposes a multi-site study between Vanderbilt University Medical Center (VUMC) and Johns Hopkins University (JHU) that will apply novel neuroimaging and angiographic tools to test fundamental hypotheses regarding how biomarkers of stroke risk, vascular steno-occlusion, and cerebrospinal fluid (CSF) motion inform treatment candidacy and pathogenesis in North American patients with idiopathic moyamoya disease (MMD). MMD has unknown etiology and is characterized by steno-occlusion of the supraclinoid internal carotid arteries and proximal branches, subsequent development of collateral vessels, and more than a seven-fold risk increase of stroke. Importantly, once thought to be a rare condition affecting primarily females of Asian ethnicity, or more common as a syndromic complication of other disorders, MMD is being reported with increasing frequency in North America. While much work has increased our understanding of cerebrovascular disease treatments generally, MMD etiology remains unknown, animal disease models do not exist, biomarkers that may place patients at highest risk for stroke have not been conclusively established, and randomized treatment trials have not been performed. As randomized clinical trials of surgical revascularization vs. medical management are unethical owing to the benefits that revascularization surgery is believed to confer for many patients, there is now a need to accurately identify factors that underlie the North American phenotype and develop personalized signatures of tissue physiology that inform neurological impairment and treatment response in these patients. To address this need, Radiology, Neurology, and Neurosurgery faculty at VUMC and JHU have developed and applied magnetic resonance imaging (MRI) and angiographic tools, on similar MRI and digital subtraction angiography equipment, to help characterize the spectrum and hemodynamic origins of impairment in North American MMD patients undergoing these indirect surgical revascularizations. Here, we propose to extend these promising single center studies to evaluate generalizable and pre-surgical biomarkers of ischemic symptomatology, surgical response, and cerebral ischemia by leveraging overlapping imaging equipment, established investigators with ongoing collaborations, and two of the largest North American MMD treatment centers. Additionally, we will explore new directions in this field, whereby we will evaluate whether neuroimaging markers of aberrant neurofluid flow provide indicators of impaired cortical hemodynamics. Successful completion should provide new technologies that can expand the diagnostic and surveillance imaging infrastructure for the growing number of patients with idiopathic moyamoya disease.