Creatine Chemical Exchange Saturation Transfer Imaging and Arterial Spin Labeling in the Study of Peripheral Arterial Disease

The major goal of my research was to develop a creatine chemical exchange saturation transfer (CrCEST) and Arterial Spin Labeling (ASL) imaging protocol for the study of peripheral arterial disease (PAD). Phosphocreatine metabolism is vital in highly oxidative tissues, such as the skeletal muscle of the limbs. Atherosclerotic diseases like PAD compromise downstream tissue perfusion, causing ischemia. 31Phosphorus MR spectroscopy (31P MRS) has demonstrated a delayed phosphocreatine (PCr) recovery time constant after exercise in PAD patients compared to healthy subjects, but this method suffers from low SNR, does not produce an image, and requires multi-nuclear scanner hardware. CrCEST is a developing MRI method capable of quantitatively imaging creatine concentration that does not require multinuclear hardware and can be reliably performed at 3T field strength. This is a particularly unique imaging method for PAD that can provide quantitative functional and spatial information at a muscle group level. This can then be matched to muscle group perfusion quantification using techniques such as arterial spin labeling (ASL). We hypothesized that creatine kinetics provided by CrCEST can both distinguish between PAD patients and healthy controls and differentiate between responders and non-responders to revascularization therapy. The goal of this project was to determine whether a CrCEST time series imaging protocol is capable of studying metabolic dysfunction in the skeletal muscle of patients with PAD and monitor disease progression and functional outcomes. We studied the relationship between metabolism and perfusion using CrCEST and arterial spin labeling MRI (ASL) in patients undergoing revascularization. This combined imaging protocol assessed changes post-procedure in patients undergoing both endovascular angioplasty and surgical bypass to treat intermittent claudication and critical limb ischemia, and correlate imaging findings with functional changes in six-minute walk score metrics. Additionally, we developed a combined ASL and CEST imaging sequence capable of assessing metabolism and perfusion in a single post-exercise session. This allows faster imaging times, and reduced pain for patients with difficulty exercising.
We hypothesized that ischemia in PAD leads to altered creatine concentration decay post-exercise in patients compared to age-matched controls. The effects of PAD on creatine metabolism are not fully understood, but prior studies with 31P MRS show an observable and repeatable difference in metabolism for PAD patients. We also tested the ability of CrCEST to do so on a muscle group basis. Subjects performed plantarflexion ergometry to exhaustion or claudication using a calf ergometer that is capable of uniformly activating the calf muscles.
We hypothesized that the shapes of creatine concentration decays post-exercise will change in response to treatment and provide information that will correlate with disease progression and functional outcomes. We scanned patients before and after surgical and endovascular revascularization, patients not receiving treatment, and receiving inorganic nitrate supplementation. Each imaging session included an exercise CrCEST protocol, followed by exercise-induced hyperemia ASL in order to compare the metabolism information from CrCEST to perfusion. This novel methodology provides a map of vascular and mitochondrial kinetics in the skeletal muscle that can be analyzed down to the muscle group level.
The imaging protocol developed for the revascularization assessment involves two exercise periods to establish sufficient perfusion and metabolic endogenous contrast within the tissue. This extends total scanner use time and is painful for patients. We developed a single imaging sequence that can measure both CEST and ASL signal within the period of post-exercise hyperemia and increased metabolic energetics seen after plantarflexion.