Project Summary Ischemic stroke is the leading cause of long-term disability in the United States. Fortunately, the landscape of stroke patient management has been changing by endovascular mechanical thrombectomy (EVT) in recent years. EVT is an interventional procedure to remove a stroke-causing thrombus (clot) from a cerebral artery to induce recanalization. It stands to reason that further improvements of EVT in safety and efficacy will continue to improve stroke outcomes. One key to the success of EVT is patient selection using perfusion imaging that assesses the viability of the downstream vascular bed and collaterals. Salvageable tissue will likely benefit from reperfusion by EVT, whereas the risk of post-recanalization hemorrhagic transformation (HT) is larger when infarct (dead tissue) size is large (>50–70 ml). Cerebral collateral circulation keeps salvageable tissue viable and slows down the infarct core growth; however, the strength of the collateral circulation varies strongly between patients and it is expected to become insufficient over time (even within the time window in which EVT is offered). Therefore, it is essential to assess the risk–benefit ratio of EVT for each patient using perfusion imaging; however, the problem with the current standard of care is an inability to perform real-time, intra-operative brain perfusion imaging. In this project, we propose to develop a novel method called IPEN v2 to perform quantitative brain perfusion imaging in the interventional suite using standard x-ray angiography images. IPEN (Intra-intervention PErfusion with No gantry rotation) will provide the interventional radiologist critical, real-time, information to take multiple steps to perform EVT safely and more effectively. Under an R21 project, we developed IPEN v1 which can assess the 3D tissue perfusion of multiple volumetric regions-of- interest (ROIs) directly from angiography images. A simulation study for liver tumor oncology showed that the perfusion indices were accurate even though ROIs were overlapped in angiography images. Building upon this foundation, Specific Aim 1 of this project is to develop IPEN v2 for brain perfusion assessment. Specific Aim 2 is to validate IPEN v2 using patient data. We will retrospectively access 300 sets of stroke patient data acquired via standard of care and validate IPEN with multiple aspects. Specific Aim 3 is to assess IPEN v2 using computer simulated data. By the end of this project, we will have IPEN v2 fully developed and validated to enable the necessary improvements of EVT. We will then start the conversation with manufactures for implementing IPEN in their angiography systems.