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

D-葡萄糖作为多发性硬化症 MRI 造影剂的开发和转化

• 批准号: 9527559
• 负责人: Xiang Xu
• 金额: $ 9.4万
• 依托单位: HUGO W. MOSER RES INST KENNEDY KRIEGER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9527559
• 关键词: Adverse effects; Affect; Award; Blood - brain barrier anatomy; Brain; Brain region; Cell Nucleus; Chelating Agents; Chemicals; Chronic; Clinic; Clinical; Contrast Media; Data; Deposition; Development; Diagnosis; Disease; Disease Progression; Dose; Enhancing Lesion; Event; Evolution; Fibrosis; Fund Raising; Gadolinium; Gliosis; Glucose; Goals; Image; Imaging Techniques; Inflammation; Inflammatory; Infusion procedures; Intravenous; Intravenous infusion procedures; Kidney Diseases; Kidney Failure; Knowledge; Laboratories; Leadership; Lesion; MRI Scans; Magnetic Resonance Imaging; Measures; Mentors; Mentorship; Methods; Mind; Minor; Monitor; Multiple Sclerosis; Multiple Sclerosis Lesions; Mus; Nerve Degeneration; Noise; Pathologic; Pathology; Patients; Pattern; Periodicity; Permeability; Phase; Physiology; Process; Protocols documentation; Protons; Renal function; Reporting; Research; Research Proposals; Resolution; Risk; Scanning; Series; Signal Transduction; Students; Symptoms; T2 weighted imaging; Techniques; Testing; Time; Tissues; Training; Translating; Translations; Treatment Efficacy; Water; base; biomaterial compatibility; career; career development; clinical practice; cohort; contrast enhanced; contrast imaging; cost; follow-up; glucose uptake; gray matter; human subject; imaging agent; magnetic field; multiple sclerosis patient; nervous system disorder; outcome forecast; peace; programs; recruit; remyelination; skills; sugar; tissue repair; tumor

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.

项目摘要 多发性硬化症（MS）是一种致残性神经系统疾病，估计影响超过230万人 国际吧钆（Gd）对比增强MRI是临床上常规使用的，是最敏感的检查 用于MS疾病的诊断、预后判断和疗效评价。当Gd基 造影剂已被证明是非常安全的，但它们可能对患有以下疾病的患者产生不良反应： 肾脏疾病此外，最近有报道称，Gd试剂可以沉积在深灰色的 对肾功能完整的患者重复给药后，基于这样的问题，有 迫切需要开发安全的替代造影剂，特别是用于MS疾病，因为患者 进行定期扫描。本研究提案的总体目标是开发并转化为 临床使用D-葡萄糖作为静脉内MRI造影剂用于血脑屏障（BBB）成像 此外，由于D-葡萄糖分子的大小小于Gd试剂，它们可能是 更易于泄漏到具有轻微BBB破坏的病变中，因此提供了更灵敏的检测手段 早期病变。 小鼠和人类受试者的初步数据显示，静脉输注D-葡萄糖可提供MRI 使用化学物质将肿瘤和MS病变与未受影响的大脑区域区分开来的对比度 交换饱和转移（CEST）MRI技术。数据显示，CEST对比度增强， 在怀疑BBB破坏的肿瘤和某些MS病变中进行D-葡萄糖输注。目标的实现 徐博士将开发3D全脑，高分辨率CEST MRI技术，适用于 首先在7特斯拉下对MS病变进行成像，随后将该技术转化为3特斯拉扫描仪， 问题研究在R 00期，将比较葡萄糖CEST和Gd的病变增强模式 在MS患者队列中验证使用D-葡萄糖作为造影剂的可行性。 本项目的成功完成将：1）提供一种天然的、可生物降解的MRI造影剂 用于MS病变成像; 2）提供3D全脑CEST MRI方案，用于MS和其他神经系统成像 3）提供了一种可能的手段，以捕捉MS病变在较早的阶段比传统的Gd剂 并加强我们对MS病理与临床MRI表现之间相关性的理解。新 徐博士将在项目培训期间发展的技能和知识不仅对以下方面至关重要： 该项目的成功完成和她的直接科学目标，他们也将成为支柱， 她将在自己的独立实验室建立研究项目。职业发展活动和 在奖励期间的导师将为她的研究领导，指导， 和资金筹集，这对她作为一个独立的研究领导者的职业生涯至关重要。