PROJECT SUMMARY Mechanical thrombectomy (MT) has revolutionized the treatment of stroke due to large vessel occlusion (LVO) in patients with moderate or severe stroke symptoms. However, clinical management remains controversial in LVO patients with relatively minor deficits because these patients were not well represented in the MT clinical trials. Up to one third of patients with LVO and minor deficits will experience early neurologic deterioration (END) which portends significant long-term disability. Observational studies, though conflicting and limited by selection bias, suggest that some of these patients may benefit from early MT, but it remains challenging to predict END and waiting for END to pursue MT has been associated with poor functional outcome. The development of predictive biomarkers for END represents a critical need for the optimization of MT therapy in patients with LVO and relatively mild clinical deficits. In moderate or severe stroke with LVO, contrast based perfusion imaging indicates the presence of an ischemic penumbra based on prolonged transit time, and has been crucial in optimizing patient selection and extending the time window for MT. However, the role of contrast based perfusion imaging is less clear in LVO patients with minor clinical deficits because prolonged transit time in this patient population does not reliably predict eventual infarction. Further, current imaging strategies are limited to a snapshot in time and thus fail to account for the dynamic nature of tissue physiology and function. END is a consequence of progressive loss of collateral blood flow supplying the ischemic penumbra, but the paucity of data on the early temporal evolution of the ischemic penumbra remains a key knowledge gap for predicting clinical outcomes such as END. This project will leverage the availability of research MRI within a new stroke and neurointensive care unit to characterize the temporal evolution of penumbral blood flow and oxygen metabolism in LVO patients with NIH stroke scale (NIHSS) < 6, within the first 24 hours of symptom onset. A unique aspect of this study will be the use of serial MRI scanning to quantify short-term changes in penumbral physiology. The scanning protocol will also leverage innovative MRI methodologies for noninvasively mapping cerebral blood flow and tissue oxygen extraction. We hypothesize that serial MRI will identify flow and metabolic deterioration in advance of clinical deterioration and with greater sensitivity than standard clinical single time point imaging. This exploratory R21 project will validate a novel imaging strategy, provide new insights into the evolution of the ischemic penumbra during the hyperacute phase of ischemic stroke, and provide critical data needed to design future studies using this approach to personalize clinical care of stroke patients with LVO and minor deficits.