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.

项目总结 对神经系统疾病的代谢途径进行非侵入性成像一直是监测的长期目标 疾病进展或治疗效果。临床医生实际上只有一种代谢成像工具，那就是 正电子发射法检测静脉注射2-18F-氟-2-脱氧-D-葡萄糖 断层扫描(PET)。其无与伦比的灵敏度使FDG-PET成为癌症检测的主要应用 在大脑之外。然而，正常大脑对FDG的高摄取大大降低了图像的对比度。 以及FDG-PET在神经疾病研究中的作用。1H和13C磁共振波谱成像 (MRSI)和超极化~(13)C磁共振成像是很有前途的方法，但由于 由于各种原因，包括技术复杂性和缺乏稳健性和/或敏感性。 几十年来，用氚(2H)标记的底物一直被用来研究人体的整体代谢 通过使用质谱仪检测血浆或组织样本中下游代谢产物中的2H标记 波谱或磁共振波谱(MRS)。我们的首例人体氚代谢成像(DMI) 健康大脑的葡萄糖代谢图和显示“Warburg效应”分布的DMI图 高级别脑瘤患者的研究表明，DMI有可能成为一种广泛适用的脑 影像方法具有较强的临床实用价值。该提案围绕三个具体目标组织，这三个目标将 建立DMI的临床适用性、科学效度和重复性。作为目标1的一部分，基于2H的 葡萄糖代谢的测量将在动物和动物身上用基于~(13)C的‘金标准’MRS进行验证 人脑。负担得起的2H标记底物的可用性，如葡萄糖(和醋酸盐)，以及 DMI数据采集的相对容易极大地加快了向临床3Tesla MRI扫描仪的转变。在……里面 目的优化DMI的临床应用方案，报告DMI的重复性。 代谢图谱，并探讨DMI在诊断为原发性高血压患者中检测到的代谢差异 和继发性脑瘤。 在第三个目标中，我们比较了被诊断为脑肿瘤的患者基于新陈代谢的图像对比 用DMI观察，用FDG-PET检测图像对比度。由完成建议的 我们希望研究有一种简单但强大的代谢成像模式，可以提供3D地图 多种底物在多种神经疾病中的代谢命运。