Project Summary/Abstract The long-term goal of this work is to reduce the incident of stroke by identifying the most vulnerable patients using MRI scans. Currently roughly 1 of every 8 patient who have had an initial stroke from intracranial atherosclerosis disease (ICAD) will suffer a second stroke within a year. Patients who are likely to fail medical management have loss of cerebrovascular reserve, poor collateral arterial blood supply, and/or plaque that is vulnerable to rupture from active macrophage infiltration. Our goal is to identify vulnerable patients to inform the selection for new medical management protocols, stenting or stent-less angioplasty. We will develop a suite of new MRI scans and evaluate them in the intended patient population, comparing to reference standard CO2 Challenge CVR, HMPAO SPECT or direct imaging of active macrophages. Significance: ICAD is one of the most common causes of stroke worldwide and carries an extremely a high risk of recurrent stroke. ICAD patients with severe stenosis (70 to 99%) are at particularly high risk for recurrent stroke in the vascular territory of the stenosis (~12 to 20% within 12 months) despite treatment with aspirin, Plavix and management of risk factors (hypertension, smoking etc). The use of new, preventative treatment including angioplasty, new anti-platelet medication would benefit if the most vulnerable patient can be identified. Our imaging biomarkers will improve risk stratification for the of stroke in a vulnerable, high risk population. Innovation: We have developed time resolve MRI scans that are targeted to risk factor of stroke in ICAD: (1) Cardiac Gated “Snapshot” images of transient changes in the cerebral vasculature in response to arterial pressure changes induced by the cardiac cycle. These changes are muted by a loss of cerebrovascular reserve a risk fact of stroke. (2) A new mathematical deconvolution algorithm based on linear time-invariant system theory to quantify perfusion supplied to a vascular bed through collateral arterial blood supply distal to a stenosis. (3) First ever high-resolution permeability of the intracranial arterial walls to identify macrophage infiltration. Scientific Rigor: The geometry of the human head and topology of the vasculature are unique, and we therefore perform all our studies in the intended patient population: humans with ICAD. To ensure scientific rigor, we will compare directly to reference standard values of CO2 cerebrovascular reserve, collateral arterial supply, and macrophage infiltration in plaques. Probability of Success: We have built a strong, multi-disciplinary team with a long track record of successful, collaborative neurovascular research. We believe this high probability of successful completion of the aims and high likelihood of clinical translation.