Novel theranostic approaches for stroke based on hyperpolarized Magnetic Resonance Imaging

Stroke is the third leading cause of death worldwide and the leading cause of disability in the adult. Stroke incidence increases with age and therefore it is a major public health challenge in the context of the current demographic changes. Ischemic stroke, the most common stroke type, resulting from the occlusion of a cerebral artery can be treated by restoring blood flow to the ischemic brain tissue within a narrow 4.5 to 6h time window, either by iv thrombolysis or mechanical recanalisation. Despite promising preclinical results of neuroprotective strategies targeting ischemic cell death mechanism, all clinical neuroprotection trials failed so far to improve the outcome in ischemic stroke patients. Cerebral perfusion and metabolism are essential for normal brain function and are both disturbed in cerebral ischemia.

The aim of this project is to take advantage of hyperpolarization to boost the magnetic resonance (MR) signal of two neuroprotectants, namely xenon and lactate, at therapeutic doses, to understand their biodistribution in vivo and their effect on metabolism in an animal stroke model. This theranostic approach, which uses therapeutic agents as diagnostic tools, will give insight into the mechanisms of neuroprotection. A thorough understanding of the mechanisms involved is an important step in the perspective of a clinical trial. Neuroprotection induced by lactate injection in animal models of stroke has been demonstrated in the Hirt group. Using optimized protocols and dedicated state-of-the-art instrumentation for hyperpolarized (HP) 13C MR imaging, we aim at understanding the underlying mechanism of neuroprotection by recording in vivo in real-time metabolic exchanges and fluxes following the injection of HP 13C-lactate.

These data will provide information on the local biochemical balance through the measurement of the metabolic products pyruvate, alanine and bicarbonate. The neuroprotective properties of xenon are also well-known and radioactive xenon or stable xenon enhanced CT has been used for perfusion imaging in a clinical setting for decades. The 129Xe stable isotope can also be hyperpolarized using the same instrumentation as the one originally developed for preparing HP 13C substrates and in vivo imaging can be performed following the delivery of HP 129Xe. The measurement of cerebral perfusion by HP 129Xe MR will allow characterizing the ischemic core and penumbra in each individual. Both neuroprotective agents will also be co-administered to assess their interplay. The complementary information that can be obtained from perfusion and metabolic imaging should be an invaluable diagnostic tool for evaluating stroke severity while providing neuroprotective effects. To develop this novel method and unravel the neuroprotective mechanisms behind lactate and xenon, we bring together 7-year collaboration on HP methodology, in particular HP 129Xe and MR imaging techniques dedicated to HP substrates, with an established clinical and preclinical expertise on stroke including neuroprotective strategies.