Dual Contrast pH-Weighted MRI for Stroke Imaging

PROJECT SUMMARY/ABSTRACT The goal of this proposal is to develop a non-invasive imaging technique with high pH sensitivity to predict the tissue fate for stroke, the leading cause of long-term disability. In acute ischemic stroke, a key therapeutic target is to rescue the penumbra (i.e., tissue at risk of infarction) by restoring blood flow, however, the approval of recanalization therapies has been limited to a time window of several hours because the risk-to-benefit ratio of these therapies increases as time elapses. Given the large variations in infarct progression across individuals, the benefit of treatment may outweigh the risk for some patients who were excluded by the currently prescribed time window. To identify these patients and guide personalized therapy, there is an urgent need to develop a metabolic imaging tool to 1) map the penumbra and 2) evaluate the risk of reperfusion injury. Recently, amide proton transfer-weighted MRI (APTw) has shown pH sensitivity and gained increasing interest in the assessment of ischemic tissue status. However, APTw suffers from contamination by large confounding effects which precludes precise delineation of the mildly acidotic penumbra. Many approaches have been proposed to minimize these confounding effects, but these approaches usually sacrifice pH sensitivity or lengthen scan time, hindering their application to acute stroke imaging. Another intrinsic limitation is that the APT contrast in ischemic tissue decreases exponentially with pH and becomes very low in the severe acidosis domain, affecting the accuracy of predicting reperfusion injury. In this project, we will develop a ratiometric dual contrast (Rdual) pH- weighted MRI approach that utilizes pH-sensitive signals from the amide and the guanidinol groups of biomolecules while minimizing contamination from non-pH related effects, thus, greatly enhancing pH sensitivity in both the mild and severe acidosis regimes. Our first Specific Aim is to develop and validate Rdual for better probing of the tissue acidosis expected in the ischemic penumbra and the core. In the second and third Specific Aims, permanent and transient MCAO animals will be studied to validate our hypotheses that Rdual MRI can delineate the at-risk tissue with higher accuracy than conventional diffusion and perfusion-based methods, while improving the prediction of the severity of reperfusion injuries. Our long-term goal is to refine this metabolic imaging tool to help the clinical decision-making of recanalization therapies neuroprotective drugs in preclinical research. and the development of