Imaging cerebral metabolic impairment in AD using Deuterium MRI

使用氘 MRI 对 AD 中的脑代谢损伤进行成像

• 批准号: 10608908
• 负责人: Myriam Marianne Chaumeil
• 金额: $ 71.92万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10608908
• 关键词: 3-Dimensional; APP-PS1; Acetates; Age; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Automobile Driving; Biological Markers; Brain; Cerebrum; Chemical Shift Imaging; Clinical; Clinical Management; Clinical Research; Data; Deoxyglucose; Detection; Deuterium; Disease; Disease Progression; Evaluation; Family; Foundations; Fumarates; Future; Glucose; Glutamates; Glutamine; Goals; Human; Human Volunteers; Hydrogen; Image; Imaging Phantoms; Impairment; Intervention; Ionizing radiation; J20 mouse; Label; Lead; Magnetic Resonance Imaging; Measures; Metabolic; Metabolism; Methods; Monitor; Mus; Outcome; Pathogenesis; Patients; Persons; Phosphorylation; Physiologic pulse; Play; Positron-Emission Tomography; Pre-Clinical Model; Process; Public Health; Quality of life; Regimen; Research; Role; Safety; System; Techniques; Therapeutic; Translations; Visualization; Water; Wild Type Mouse; brain metabolism; clinical translation; clinically relevant; cost; experimental study; fluorodeoxyglucose; fluorodeoxyglucose positron emission tomography; glucose metabolism; glucose uptake; healthy volunteer; imaging approach; imaging modality; improved; in vivo; metabolic imaging; metabolomics; molecular imaging; mouse model; nervous system disorder; novel; patient stratification; personalized therapeutic; pre-clinical; precision medicine; response; sex; spectroscopic imaging; stable isotope; success; therapy development; tool; treatment response; uptake

Project Summary/Abstract This project will investigate deuterium (2H) metabolic imaging (DMI) as a quantitative, stable-isotope MR molecular imaging approach to probe cerebral metabolic impairment in Alzheimer’s Disease (AD). AD and related dementias represent a growing public health concern with tremendous impact on patients and their families. Efforts to treat AD effectively are partially confounded by different hypotheses regarding its initiation and progression, as reflected by the range of highly informative imaging methods used to study AD, including positron emission tomography (PET) and advanced magnetic resonance imaging (MRI). Dysfunctional glucose metabolism is both an early and critical determinant of disease progression, and the glucose derivative [18F]Fluorodeoxyglucose (FDG) has been widely used to probe cerebral metabolism in AD patients. While this may reflect a decrease in glucose demand, it does not inform on metabolism itself. Furthermore, FDG-PET has significant limitations in accessibility, cost and accuracy, and provides no information on metabolic processes beyond glucose uptake and phosphorylation. Thus, while FDG-PET shows the potential of a metabolic biomarker, a sensitive and practical imaging method is critically needed. Deuterium MRI is a novel and quantitative metabolic imaging approach that provides direct visualization of the uptake and meteabolic fate of glucose on timescales and sensitivities that are not achievable with 1H or hyperpolarized 13C MR spectroscopic imaging. Our initial data using DMI in a J20 mouse model of AD show that reduced glucose metabolism to lactate and reduced HDO enrichment can be observed compared to age- matched healthy controls. Building on these results, we propose to develop new DMI approaches for assessment of glucose metabolism in the live brain, and validate these techniques in healthy and AD mice, as well as in healthy volunteers. In Aim 1, we will investigate three separate strategies to assess glucose metabolism with 2H MRI: metabolism using [6,6’-2H]glucose, HDO enrichment using [U-2H]glucose, and accumulation using [2,2’- 2H2]2-deoxyglucose. In Aim 2, we will apply these three approaches to preclinical models of AD and compare results to FDG-PET. In Aim 3, we will develop hardware for human translation at 7T and will characterize brain metabolism in healthy volunteers using [6,6’-2H]glucose and [U-2H]glucose. Successful completion of this project will improve our understanding of glucose metabolism in AD, provide a foundation for future clinical studies in patients with AD, improve clinical management, help refine therapy regimens and, ultimately lead to better outcome and quality of life for people living with AD.

项目摘要/摘要 该项目将研究氘（2H）代谢成像（DMI）作为定量，稳定的同位素MR 探测阿尔茨海默氏病（AD）探测大脑代谢损害的分子成像方法。 相关的痴呆症代表了对患者及其的极大关注的公共卫生问题 有效治疗广告的家庭是由差异的假设造成的 和进步，如用于研究AD的一系列高度信息方法所反映的，包括 正电子发射断层扫描（PET）和晚期磁共振成像（MRI） 代谢既是疾病进步的早期和关键决定因素，又是葡萄糖衍生物 [18F]氟脱氧葡萄糖（FDG）已被广泛用于探测AD特定性的脑代谢。 它可能反映了葡萄糖需求的减少，它可以告知新陈代谢。 可访问性，成本和准确性的含义限制，并且没有提供有关for Forric Processesssessessessessessessessess的限制 除了葡萄糖摄取和磷酸化之外，FDG-PET显示了代谢生物标志物的潜力 需要一种敏感且实用的成像方法。 氘先生是一种没有新颖而定量的代谢成像成像应用直接直接指向。 在时间尺度和敏感性上，葡萄糖的吸收和含量命运是无法通过1H或或或或以或或或或或或或或或或或或或或什么来实现的 超极化13c MR光谱成像。 与年龄相比 匹配的健康对照。 活大脑中的葡萄糖代谢，并验证健康和AD小鼠的技术 健康的志愿者。 MRI：使用[6,6'-2H]葡萄糖，使用[U-2H]葡萄糖的HDO富集以及使用[2,2' - - 2H2] 2-脱氧葡萄糖。 fdg-pet的结果。 使用[6,6'-2H]葡萄糖和[U-2H]葡萄糖的健康志愿者中的代谢。 将提高我们对AD中葡萄糖代谢的理解，为将来的临床研究奠定了基础 AD患者，改善临床管理，帮助精炼治疗方案，并最终导致更好 享有广告的人的结果和生活质量。