ABSTRACT An estimated 8.5 million Americans suffer from peripheral artery disease (PAD) and it not only interferes with one’s active lifestyle; but also increases the risks for heart attacks and strokes. Most PAD patients are asymptomatic, present with atypical pain, and a minority face serious consequence of a threatened limb. Once diagnosed with PAD, a range of evidence-based therapeutic and interventional options are available, which includes supervised exercise, antithrombotic medications, and restoring circulation through catheter and surgical interventions are available. These have potentials to improve the functional status of the patient and reduce the mortality. Oxidative phosphorylation (OXPHOS) capacity in skeletal muscle are known to get compromised in PAD and hence, tools (imaging or otherwise) are needed for aiding in the early identification of patients with PAD and to monitor the effect of supervised exercise and revascularization. Phosphorus (31P) magnetic resonance spectroscopy (31PMRS) has traditionally been used as a noninvasive tool to evaluate the OXPHOS capacity and the change in intracellular pH of exercised skeletal muscle. However, it suffers from low coverage, poor spatial resolution and a very high coefficient of variation (COV) (~20-30%) with respect to half-life of phosphocreatine recovery (τPCr). Our team previously developed a novel 2D MRI method, named creatine chemical exchange saturation transfer (CrCEST) imaging, as an alternative with improved spatial resolution (~1x1 mm2) and a temporal resolution (τRes) of ~30s. Recently, we further improved on this method to enable the 3D coverage while maintaining the same τRes of 30s. The estimation of creatine recovery half-time (τCr) on a voxel-wise basis is currently not feasible due to the coarse temporal resolution (30s) combined with the low effective signal to noise ratio (eSNR) (<20) of 3D-CrCEST time-series. Rather, we performed muscle-group-specific fit, where the useful information in form of a voxel-wise inherent anatomic/physiological variation were sacrificed in return for increased SNR. In another important development, we developed a spatial regularized reconstruction approach and showed the feasibility of a noise robust reconstruction, provided τCr ≳4τRes. Given that the typical τCr of healthy control is ~45-80s for our plantar flexion exercise protocol, there is a need to improve on τRes ~10-12s. In this proposal, we aim to improve on the temporal resolution: τRes of CrCEST by implementing keyhole imaging in combination with the alteration in frequency offset (FO) schemes. By aiming to improve τRes by a factor of ~2-3x, the information content present in CrCEST time series would be sufficiently increased to enable a noise robust reconstruction of τCr-map. To reduce the component of variability with physiological origins, we plan to adjust the exercise load to avoid unpredictable and drastic changes in perfusion profile. For the validation, we will compare the findings from the proposed approach against our current 3D CrCEST protocol for comparable region of interest (ROI). Finally, we will test our hypothesis that clinical significant changes in function status of PAD patients post revascularization will be reflected by measurable changes in τCr‘s.

Narrative Though 3D creatine CEST provides a unique opportunity to assess the compromised oxidative phosphorylation (OXPHOS) capacity in exercised skeletal muscle with sufficient spatial resolution (1x1x5 mm3), the temporal resolution of 30s is still coarse for estimating the creatine recovery half time on a voxel wise basis. We propose technical modifications to reduce the temporal resolution and also aim to optimize the exercise load so that peripheral artery disease (PAD) patient can comply with that. Finally, we will test our hypothesis that clinically significant change in function status of PAD patient’s will be reflected by the change in measurable creatine recovery constants.