Current clinical practice treats stroke without regard to potential sex differences. Is this the best approach? Standard of care image processing thresholds are uniformly applied across all patients to identify potentially salvageable versus irreversibly infarcted brain tissue. However, women experience ischemic stroke differently than men with known physiological differences originating at the cellular level. As such, the long-term research goal is to characterize acute ischemic tissue evolution for men and women in the context of personalized imaging selection of patients for acute reperfusion therapy and trials. It is well established that the benefit of treatment for acute ischemic stroke declines with longer onset to treatment times. Delayed patient presentation is the major treatment limitation with only one-third of all acute ischemic stroke patients presenting within 8 hours of symptoms. Sex disparities exist in ischemic stroke. Women have worse functional and patient-reported outcomes. Although women's higher age, greater stroke severity, and poorer health at the time of stroke partially explain these disparities, a substantial knowledge gap remains. Women present more often with treatable ischemic strokes than men. Women also have better-functioning collateral networks and slower infarct growth untreated. Why do women suffer from more disability if they are presenting with favorable imaging profiles? Does this paradox stem from the imaging-defined thresholds used to identify infarcted tissue and potentially salvageable tissue? Could these thresholds differ for men and women? Recent trials have demonstrated the utility of imaging thresholds to identify patients that will respond to treatment If the optimal thresholds for ischemic core, salvageable penumbra, and time from onset are different for men and women, are we denying patients the benefits of treatment by not incorporating sex-specific treatment thresholds into treatment selection algorithms? In line with NINDS's mission to seek fundamental knowledge about the brain and nervous system and to use that knowledge to reduce the burden of neurological disease, this project proposes to addresses these knowledge gaps and test the hypothesis that acute ischemic tissue evolution is different between men and women. Imaging features of cerebral hemodynamics will be directly related to infarct evolution to evaluate sex differences in acute ischemic stroke in the context of imaging selection of patients for acute reperfusion therapy and trials. This will address the paucity of studies on sex differences in ischemic stroke, overcoming limitations in translational relevance of clinical trials. The proposed project will result in generalizable evidence on the influence of sex on ischemic tissue evolution and inform on the selection of imaging-based thresholds currently used to identify infarcted tissue and potentially salvageable tissue. Establishing evidence of sex differences in objective imagin...