The overall goals of this proposal are to develop and validate a novel magnetic resonance imaging (MRI) method for mapping tissue pH and phosphocreatine (PCr) and creatine (Cr) content and to apply this method to characterize exercise-induced changes in muscle metabolism in healthy and diseased states. The ability to assess such fundamental biophysical characteristics will have a broad range of clinical and preclinical applications. These include glycogen storage diseases, diabetes, and, most notably for this application, peripheral artery disease (PAD), a disease characterized by blood flow and intrinsic muscle mitochondrial deficits. The proposed methods for achieving this objective include a significant and novel reformulation of chemical exchange saturation transfer (CEST) imaging. There are inherent and critical technical obstacles to the widespread application of CEST methods and major limitations on their use in practice. CEST suffers from a lack of quantification and is highly susceptible to artifacts originating from static field inhomogeneities, lipid content, spectral overlap of multiple metabolites signals, and the inherently asymmetric background macromolecular resonance. Chemical exchange rotation transfer (CERT) is our proposed reformulation of CEST that overcomes the shortcomings of CEST. Furthermore, CERT can act as an exchange rate filter and can separate the contribution of Cr from that of other overlapping metabolites, such as PCr. We will 1) develop, optimize, and validate CERT imaging methods;2) quantify tissue changes in PCr and Cr content and pH in rat models of varied Cr content and exercise;and 3) quantify tissue changes in PCr, and Cr content and pH in human studies of exercise and peripheral artery disease.
The goal of this proposal is to develop novel magnetic resonance imaging (MRI) methods for the biochemical characterization of muscle using the endogenous exchange of amide and amine protons with water to determine creatine and phosphocreatine content and pH. Such imaging methods will provide a new tool for studying disease progression, with particular relevance to studies of muscle pathology, most notably peripheral artery disease.