Supplement for Development and Translation of Specialized Hyperpolarized C-13 MRI Methods for Alzheimer's Disease

项目摘要/摘要 在过去的8年里，母公司生物工程研究伙伴关系在开发 定量超极化(HP)稳定同位素MR分子成像方法监测前列腺 在标准mpMRI检查的基础上，快速增加2分钟的癌症代谢重新编程和治疗反应。 我们阿尔茨海默病(AD)的同事现在想要利用独特的HP MRI测量 大脑能量代谢对大脑功能至关重要，已知会随着AD的发作而降低。这个项目 已由我们的AD多学科团队开发，用于开发HP丙酮酸和尿素MRI作为定量 阿尔茨海默病及相关痴呆患者脑血流灌注和代谢损伤的影像研究 日益严重的公共卫生问题给患者及其家属带来了巨大影响。努力有效地治疗 AD在一定程度上被关于其启动和发展的不同假设所混淆，这反映在 用于研究AD的一系列成像方法，包括正电子发射断层扫描(PET)和磁学 磁共振成像(MRI)。糖代谢紊乱与阿尔茨海默病密切相关，既是早期的，也是关键的 疾病进展的决定因素，以及葡萄糖衍生物[18F]氟脱氧葡萄糖(FDG)已被广泛应用 用于检测AD患者的脑代谢。虽然这可能反映了葡萄糖需求的下降，但它只是 告知摄取，但不提供随着AD减少的糖酵解代谢的准确信息。 此外，FDG-PET在可获得性、成本和准确性方面有很大的限制，并且不提供 关于葡萄糖摄取和磷酸化下游代谢过程的信息。 本补充提案的中心目标是开发和应用测量新陈代谢受损的方法。 在AD中首次使用先进的HP C-13磁共振成像。HP丙酮酸核磁共振是一种新兴的分子成像方法 这提供了FDG-PET所不具备的动态和特定途径的代谢信息。在父级中 BRP，我们开发了极大地提高HP代谢的覆盖率、速度和可靠性的方法 丙酮酸和尿素共极化的成像和技术以同时评估心肌细胞的代谢和血流灌注 前列腺。本附录旨在扩展这一方法以测量AD的代谢损害。 将开发专门的技术来获取使用[2-13C]丙酮酸盐和[13C]尿素的共极化数据， 同时评估人脑的灌流、糖酵解和氧化代谢。这些 然后，这些技术将应用于因AD和AD而导致的轻度认知障碍(MCI)患者的初始队列 与年龄匹配的对照组进行比较，以评估AD的代谢变化的幅度。来自这项试验的数据 该项目将为更大规模的研究奠定基础，以评估HP 13C MRI作为临床评估和 治疗阿尔茨海默病，并将具有广泛的适用性，代谢评估的其他神经生殖疾病。

Project Summary/Abstract The parent Bioengineering Research Partnership has been highly successful over the past 8 years in developing quantitative, hyperpolarized (HP) stable-isotope MR molecular imaging approaches for monitoring prostate cancer metabolic reprogramming and response to therapy in a fast 2-minute addition to standard mpMRI exams. Our Alzheimer’s Disease (AD) colleagues now want to take advantage of the unique HP MRI measurements of cerebral energy metabolism that is critical for brain function and known to decrease with AD onset. This project has been developed by our AD multidisciplinary team to develop HP pyruvate and urea MRI as a quantitative imaging approach to probe cerebral perfusion and metabolic impairment in AD and related dementias that are a growing public health concern with tremendous impact on patients and their families. Efforts to effectively treat AD are partially confounded by different hypotheses regarding its initiation and progression, as reflected by the range of imaging methods used to study AD, including positron emission tomography (PET) and magnetic resonance imaging (MRI). Dysfunctional glucose metabolism is strongly linked to AD as 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 only informs on uptake and does not provide accurate information on glycolytic metabolism that decreases with AD. Furthermore, FDG-PET has significant limitations in accessibility, cost, and accuracy, and provides no information on metabolic processes downstream of glucose uptake and phosphorylation. The central goal of this supplement proposal is to develop and apply methods of measuring impaired metabolism in AD for the first time using advanced HP C-13 MRI. HP pyruvate MRI is an emerging molecular imaging method that provides dynamic and pathway-specific metabolic information not available with FDG-PET. In the parent BRP, we have developed methods to greatly improve the coverage, speed, and reliability of HP metabolic imaging and techniques to co-polarize pyruvate and urea to simultaneously assess metabolism and perfusion in the prostate. This supplement is designed to extend this approach to measure metabolic impairment in AD. Specialized techniques will be developed to acquire co-polarized data using [2-13C]pyruvate and [13C]urea, providing simultaneous assessment of perfusion, glycolysis, and oxidative metabolism in the human brain. These techniques will then be applied to an initial cohort of patients with mild cognitive impairment (MCI) due to AD and compared to age-matched controls to assess the magnitude of metabolic changes in AD. The data from this pilot project will form the foundation for larger studies to evaluate HP 13C MRI as a tool for clinical assessment and treatment of AD and will have broad applicability for metabolic assessment of other neurogenerative diseases.