Development and Translation of D-glucose as an MRI Contrast Agent for Multiple Sclerosis

项目摘要 多发性硬化症(MS)是一种致残的神经系统疾病，估计有超过230万人受到影响 全世界。Gd增强MRI是临床上常用的检查方法，也是最敏感的检查方法。 用于MS病的诊断、预后预测和疗效评估。而以Gd为基础 造影剂已被证明是非常安全的，它们可能会对患有 肾脏疾病。此外，最近有报道称，Gd试剂可以沉积成深灰色 肾功能完整的患者反复给药后的物质核。基于这样的问题，有 迫切需要开发安全的替代造影剂，特别是针对多发性硬化症，因为患者 接受定期扫描。这项研究提案的总体目标是开发并转换为 D-葡萄糖静脉注射成像血脑屏障的临床应用 此外，由于D-葡萄糖分子的大小比Gd试剂小，它们可能是 更容易泄漏到血脑屏障轻微中断的病变中，因此提供了一种更灵敏的检测手段 早期的损害。 在小鼠和人体上的初步数据显示，静脉输注D-葡萄糖可以提供MRI 使用化学物质区分肿瘤和多发性硬化症病变与未受影响的脑区的对比 交换饱和转移(CEST)MRI技术。数据显示，CEST对比度在 D-葡萄糖输注在肿瘤和一些怀疑血脑屏障中断的多发性硬化病变中。实现…的目标 在该提案中，徐博士将开发适用于 首先在7特斯拉对MS病变进行成像，然后将该技术移植到3台特斯拉扫描仪上 学习。在R00阶段，将比较葡萄糖CEST和Gd的病变增强模式 在一组MS患者中验证使用D-葡萄糖作为造影剂的可行性。 该项目的成功完成将：1)提供一种天然的、可生物降解的磁共振造影剂 用于MS病变的成像；2)提供3D全脑CEST MRI方案，用于MS和其他神经系统的成像 疾病；3)提供了一种可能的手段，在比传统的Gd试剂更早的阶段捕捉MS病变 提高对MS病理与临床MRI表现相关性的认识。新的 徐博士将在项目培训期间发展的技能和知识不仅对 该项目的成功完成和她近期的科学目标，也将成为 她将在自己的独立实验室建立研究计划。职业发展活动和 获奖期间的指导将为她在研究领导、指导 以及募集资金，这对她作为独立研究领导者的职业生涯至关重要。

Project Summary 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.