Hyperpolarized 13C metabolic imaging in an endovascular swine model of ischemic stroke

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Ischemic stroke (IS) is the most frequent cause of long-term severe disability, and places an enormous eco- nomic burden on society. One of the primary goals in clinical care of acute stroke is to salvage the so-called penumbra, i.e., tissue that is at risk of irreversible infarction, but is still viable. This can be achieved through various strategies that re-establish the perfusion of the affected tissue. However, there is a tight time window for intervention as well as a risk of cerebral hemorrhage during the establishment of reperfusion and it requires an accurate assessment of the extend of injury as benefits from reperfusion have to be weighed against potential complications arising from treatment. The most widely used tool in identifying the penumbra is magnetic resonance imaging (MRI) and exploiting the “mismatch” in abnormalities as measured with perfusion-weighted and diffusion-weighted MRI. However, multiple studies have found that these surrogate markers have mischaracterized irreversibly infarcted and salvageable tissue and the inaccuracy of these markers may have contributed to both inconclusive results from clinical trials and negative therapeutic outcomes. To this end, a more accurate identification of penumbra and ischemic core that could expand the patient pool that benefit from treatment is needed. The reduced delivery of oxygen and glucose following IS leads to impaired energy metabolism within the affected tissue, one of the hallmarks of the pathology. Therefore, new approaches for quantitative and spatially precise assessment of brain energy metabolism could lead to improved assessment of injury following IS. The recent development of hyperpolarized 13C magnetic resonance spectroscopy and spectroscopic imaging enables for the first time the real-time non-invasive measurement of critical dynamic metabolic processes in vivo. Given pyruvate’s central role in energy metabolism as the link between glycolysis and the Krebs cycle, we propose to use metabolic imaging of co-polarized pyruvate (Pyr) and urea for noninvasive assessment of brain energy metabolism and perfusion in a novel swine IS model. Specifically, we will use injections of co-polarized [1-13C]Pyr and [13C,15N2]urea to quantify cellular energy metabolism and brain perfusion at the time of IS completion in order to identify regions of ischemic core, penumbra, and healthy tissue using histology as the gold standard (Aim 1). Secondly, we will expand our study to include multiple time points during stroke evolution as well as after reperfusion. This will further characterize the temporal and spatial extent of metabolic changes in IS and allow the comparison with the time course of abnormalities as measured with diffusion-weighted MRI (Aim 2). The proposed combination of a novel endovascular swine model of IS and metabolic imaging of hyperpolarized substrates is a unique model system to study the pathophysiology of IS and develop new treatments prior to clinical trials. It also represents the first step in developing a novel neuroimaging approach for assessing ischemic injury in patients and improving treatment selection.