Multiple sclerosis (MS) is a disabling neurological disorder that is estimated to affect more than 2.3 million people worldwide. Gadolinium (Gd) contrast enhanced MRI is routinely used in the clinics and is the most sensitive test for establishing diagnosis, predicting prognosis and evaluating treatment efficacy of MS disease. While Gd based contrast agents have demonstrated to be very safe, they have the potential for adverse effects in patients with kidney diseases. In addition, it recently has been reported that the Gd agent can be deposited in deep gray matter nuclei after repeated administration to patients with intact renal function. Based on such issues, there is an urgent need to develop safe alternative contrast agents, especially for MS disease since patients are subjected to periodic scans. The overall goal for this research proposal is to develop and translate to the clinic the use of D-glucose as an intravenous MRI contrast agent for imaging blood-brain-barrier (BBB) disruption in MS. In addition, since the size of D-glucose molecules are smaller than Gd agents, they may be more amenable to leak into lesions with minor BBB disruption, hence provide a more sensitive means to detect lesions at an earlier stage. Preliminary data on mice and human subjects show that intravenous infusion of D-glucose provides MRI contrast that distinguishes the tumor and MS lesions from the unaffected brain region using the chemical exchange saturation transfer (CEST) MRI technique. The data shows that the CEST contrast is enhanced upon D-glucose infusion in tumors and some MS lesions where BBB disruption is suspected. To achieve the goal of the proposal, Dr. Xu will develop 3D whole brain, high resolution CEST MRI techniques that are suitable for imaging MS lesions first at 7 Tesla and subsequently translate the technique to 3 Tesla scanners for patient studies. During the R00 phase, the lesion enhancement patterns for both glucose CEST and Gd will be compared in a cohort of MS patients to validate the feasibility of using D-glucose as a contrast agent. The successful completion of this project will: 1) provide a natural and biodegradable MRI contrast agent for imaging MS lesions; 2) provide a 3D whole brain CEST MRI protocol for imaging MS and other neurological disorders; 3) provide a possible means to capture MS lesions at an earlier stage than conventional Gd agents and enhance our understanding of the correlation between MS pathology and clinical MRI findings. The new skills and knowledge that Dr. Xu will develop during the training period of the project will not only be crucial for the successful completion of the project and her immediate scientific goals, they will also become the pillars for the research program she will build in her own independent laboratory. The career development activity and mentorship during the award period will prepare her for the practical aspects of research leadership, mentoring and fund raising, which are critical for her career as an independent research leader.
The Gadolinium base MRI contrast agents that are routinely used in in the clinics for diagnosing and monitoring multiple sclerosis cannot be used in patients with renal insufficiency and has been found to deposit in the gray matter after repeated administration. We propose to develop the use of D-glucose as a biocompatible contrast agent for imaging MS physiology with MRI via the chemical exchange saturation transfer mechanism. If successful, the proposed study will provide a safer, low cost alternative contrast agent for MRI of MS with the potential to capture lesions at their early stages and bring peace of mind to patients knowing they were given a dose of natural sugar instead of a synthetic compound during a MRI scan.
