Deuterium metabolic imaging (DMI) of neurological disease

神经系统疾病的氘代谢成像 (DMI)

• 批准号: 9912746
• 负责人: ROBIN A DE GRAAF
• 金额: $ 66.12万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-15 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9912746
• 关键词: 3-Dimensional; Acetates; Alzheimer' s Disease; Anesthesia procedures; Animals; Biological Markers; Brain; Brain Mapping; Brain Neoplasms; Brain imaging; Cancer Detection; Cerebrum; Clinic; Clinical; Clinical Research; Data; Deoxyglucose; Detection; Deuterium; Development; Diagnosis; Disease Progression; Epilepsy; Glucose; Glutamates; Glutamine; Goals; Gold; Heating; Human; Human body; Image; Imaging Device; Imaging Techniques; Intake; Intravenous; Label; Left; Lesion; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Maps; Mass Spectrum Analysis; Measurement; Metabolic; Metabolic Pathway; Metabolic dysfunction; Metabolism; Metastatic malignant neoplasm to brain; Methodology; Methods; Monitor; Multiple Sclerosis; Neurodegenerative Disorders; Noise; Nutrient; Oral; Pathogenesis; Pathway interactions; Patients; Physiologic pulse; Plasma; Play; Positron-Emission Tomography; Primary Brain Neoplasms; Protocols documentation; Publications; Rattus; Reaction; Reporting; Reproducibility; Research; Resolution; Rodent; Role; Science; Signal Transduction; Techniques; Three-Dimensional Imaging; Tissue Sample; Translations; Traumatic Brain Injury; Treatment Efficacy; Warburg Effect; Water; base; brain metabolism; clinical application; clinical practice; clinically significant; contrast imaging; data acquisition; drinking; first-in-human; glucose metabolism; glucose uptake; human data; human disease; imaging modality; insight; magnetic field; metabolic imaging; metabolic rate; nervous system disorder; new therapeutic target; non-invasive imaging; novel; pre-clinical research; quantitative imaging; radio frequency; reconstruction; relating to nervous system; spectroscopic imaging; therapy development; tool; tumor; tumor metabolism; uptake

PROJECT SUMMARY Non-invasive imaging of metabolic pathways in neurological disease has been a long-standing goal to monitor disease progression or therapy efficacy. Clinicians have in reality only one metabolic imaging tool, which is detection of intravenously administered 2-18F-fluoro-2-deoxy-D-glucose (FDG) with positron emission tomography (PET). Its unrivaled sensitivity makes FDG-PET a mainstay application for cancer detection outside of the brain. However, the high uptake of FDG by normal brain drastically reduces the image contrast and the usefulness of FDG-PET in studying neurological disease. 1H and 13C MR spectroscopic imaging (MRSI), and hyperpolarized 13C MRSI are promising methods but have failed to reach clinical significance due to a variety of reasons including technical complexity and lack of robustness and/or sensitivity. Substrates labeled with deuterium (2H) have been used for decades to study whole body human metabolism by detecting the 2H label in downstream metabolic products in plasma or tissue samples using mass spectroscopy or magnetic resonance spectroscopy (MRS). Our first-in-man deuterium metabolic imaging (DMI) maps of glucose metabolism in healthy brain and DMI maps showing the distribution of the “Warburg-effect” in patients with high grade brain tumors illustrate that DMI has the potential to become a widely applicable brain imaging method with strong clinical utility. The proposal is organized around three specific aims that will establish the clinical applicability, scientific validity and reproducibility of DMI. As part of Aim 1, the 2H-based measurement of glucose metabolism will be validated with `gold-standard' 13C-based MRS on animal and human brain. The availability of affordable 2H-labeled substrates, such as glucose (and acetate), together with the relative ease of DMI data acquisition greatly expedites the translation to a clinical 3 Tesla MRI scanner. In Aim 2 we will optimize the protocol for use of DMI in the clinic, report on reproducibility of the DMI-based metabolic maps, and explore the metabolic differences detected with DMI in patients diagnosed with primary and secondary brain tumors. In the third aim we compare in patients diagnosed with brain tumors the metabolism-based image contrast observed using DMI with the image contrast detected using FDG-PET. By the completion of the proposed studies we expect to have a simple, but robust metabolic imaging modality that can provide 3D maps of the metabolic fate of multiple substrates in a wide range of neurological disorders.

项目摘要 神经疾病中代谢途径的非侵入性成像一直是监测的长期目标 疾病进展或治疗有效性。临床医生实际上只有一种代谢成像工具，那就是 检测静脉注射的2-18F-Fluoro-2-脱氧-D-葡萄糖（FDG），并具有正电子发射 断层扫描（宠物）。它无与伦比的灵敏度使FDG-PET成为癌症检测的主要应用 在大脑外。但是，正常大脑对FDG的高吸收大大降低了图像对比度 FDG-PET在研究神经系统疾病中的有用性。 1H和13C MR光谱成像 （MRSI）和超极化13c MRSI是有希望的方法，但未能达到临床意义 出于多种原因，包括技术复杂性以及缺乏鲁棒性和/或灵敏度。 用氘（2H）标记的底物已使用数十年来研究全身人体代谢 通过检测使用质量的血浆或组织样品中下游代谢产物中的2H标记 光谱或磁共振光谱（MRS）。我们的第一个人氘代谢成像（DMI） 健康大脑和DMI图中葡萄糖代谢的地图，显示了“沃伯格效应”的分布 高级脑肿瘤的患者说明DMI有可能成为广泛适用的大脑 具有强临床实用性的成像方法。该提案是围绕三个特定目标组织的 建立DMI的临床适用性，科学有效性和可重复性。作为AIM 1的一部分，基于2H 葡萄糖代谢的测量将通过基于“黄金标准”的13C MRS验证 人脑。负担得起的2H标记的底物（例如葡萄糖（和乙酸盐））的可用性以及 DMI数据采集的相对易于性大大加快了转换为临床3 Tesla MRI扫描仪。在 AIM 2我们将优化在诊所中使用DMI的方案，有关基于DMI的可重复性的报告 代谢图，并探索被诊断为原发性的患者中DMI检测到的代谢差异 和继发性脑肿瘤。 在第三个目标中，我们比较被诊断为脑肿瘤的患者基于新陈代谢的图像对比度 使用DMI与使用FDG-PET检测到的图像对比度观察到。根据提议的完成 我们期望具有简单但强大的代谢成像方式的研究，可以提供3D地图 多种神经系统疾病的多个底物的代谢命运。