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: 10268261
• 负责人: Xiang Xu
• 金额: $ 24.88万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10268261
• 关键词: 3-Dimensional; 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; 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; Nephrogenic Systemic Fibrosis; Nerve Degeneration; Noise; Pathologic; Pathology; Patients; Pattern; Periodicity; Permeability; Phase; Physiology; Process; Prognosis; 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; blood-brain barrier disruption; 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; 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.

项目概要 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 全世界。钆 (Gd) 对比增强 MRI 常用于临床，是最敏感的测试 用于多发性硬化症的诊断、预测预后和评估治疗效果。而Gd基 造影剂已被证明非常安全，但它们可能对患有以下疾病的患者产生不良影响： 肾脏疾病。另外，最近有报道称Gd剂可以沉积在深灰色中 对肾功能完好的患者重复给药后的物质核。基于此类问题，有 迫切需要开发安全的替代造影剂，特别是对于多发性硬化症，因为患者 进行定期扫描。本研究计划的总体目标是开发并转化为 临床使用 D-葡萄糖作为静脉 MRI 造影剂用于血脑屏障 (BBB) 成像 MS 的中断。此外，由于 D-葡萄糖分子的尺寸小于 Gd 剂，因此它们可能是 更容易渗漏到具有轻微 BBB 破坏的病变中，因此提供了更灵敏的检测方法 早期病变。 对小鼠和人类受试者的初步数据表明，静脉输注 D-葡萄糖可提供 MRI 使用化学物质将肿瘤和多发性硬化症病变与未受影响的大脑区域区分开来的对比 交换饱和转移（CEST）MRI 技术。数据显示，CEST 对比度增强 在怀疑 BBB 破坏的肿瘤和一些 MS 病变中输注 D-葡萄糖。为了实现以下目标 根据提案，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，然后将该技术转化为患者的 3 特斯拉扫描仪 研究。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）提供天然且可生物降解的MRI造影剂 用于多发性硬化症病变成像； 2) 提供 3D 全脑 CEST MRI 协议，用于 MS 和其他神经系统成像 疾病； 3) 提供了一种比传统 Gd 制剂更早捕获 MS 病变的可能方法 并增强我们对 MS 病理学与临床 MRI 结果之间相关性的理解。新的 徐博士在项目培训期间培养的技能和知识不仅对于 该项目的成功完成和她近期的科学目标，也将成为她的支柱 她将在自己的独立实验室中建立研究计划。职业发展活动和 颁奖期间的指导将为她在研究领导、指导等实际方面做好准备 以及资金筹集，这对于她作为独立研究领导者的职业生涯至关重要。