PROJECT SUMMARY/ABSTRACT ABSTRACT Intracranial atherosclerotic stenosis (ICAS) is the most common cause of ischemic stroke in the world and continues to have the highest rate of stroke recurrence (>15% of patients in the first year). In comparison, carotid stenosis has a first-year stroke recurrence rate of <5% of patients, but the medical and surgical treatments that work for carotid stenosis are not as successful for ICAS. We propose that the failure to prevent ICAS stroke recurrence reflects that percentage stenosis alone is not the optimal approach to risk stratification, and that focusing on functional blood flow and the ICAS plaque itself will add critical information. Using MRI, we have shown that hemodynamic impairment and disruption caused by ICAS, measured with phase-contrast quantitative MRA and computational fluid dynamic wall shear stress, is correlated with the risk of recurrent stroke. We have also found an association between ICAS plaque enhancement on vessel wall MRI and recurrent ischemic stroke. To further explore our paradigm shifting approach of advanced MRI measurement of ICAS hemodynamic and plaque biomarkers, we will conduct an ancillary imaging study to CAPTIVA, a 3-arm trial of patients with symptomatic ICAS causing 70-99% stenosis randomly assigned to aspirin plus ticagrelor, rivaroxaban, or clopidogrel. Our ancillary study, CAPTIVA-MRI, will establish if there are MRI biomarkers that can identify ICAS patients who fail best medical management and could identify precision medicine treatment approaches for ICAS patients. We will perform multimodal MRI imaging in a subgroup of 300 CAPTIVA patients at the baseline and the 1-year follow-up visit. After decades of focusing on stenosis, the proposed approach could change ICAS research, based on mechanistic understanding of how ICAS causes stroke. We have assembled a team with the required expertise for a prospective multicenter MRI study, including primary investigators of the VERiTAS and MyRIAD prospective multicenter MRI studies of ICAS. The parent trial, CAPTIVA, does not include standardized brain or vascular imaging, presenting a clear opportunity. The proposed study will provide vital and actionable data for future research and will answer critical questions about ICAS progression and provide valuable MRI data for a wide variety of important analyses in the CAPTIVA trial dataset.