Robust Precision Mapping of Cortical and Subcortical Brain Metabolic Signatures in AD

项目总结/摘要 治疗和照顾美国超过650万患有阿尔茨海默病（AD）的老年人 是医疗保健系统中单一疾病的最大负担，成本超过3200亿美元 AD和相关痴呆（AD/ADRD）。而由于重大疾病（例如，中风，心脏 疾病和癌症）下降，AD和AD相关死亡大幅增加，预计 到2050年，美国经济每年将损失约1万亿美元。虽然AD目前是不可逆的， 治疗方法和预防策略正在进行广泛的研究。超过50%的 目前正在测试的用于AD的药理学药剂靶向异常的脑代谢。因此，必须 建立代谢功能障碍与AD脑病理特征之间的具体关系。 然而，全面的全脑代谢图谱，包括皮质和皮质下脑区， 与AD病理学高度相关，但由于在以下方面存在重大技术挑战， 采集具有足够空间分辨率的高质量磁共振（MR）光谱成像数据 在临床上可接受的扫描时间内扫描整个大脑。在这方面，我们建议建立一个强大的， 可靠的代谢映射的整个大脑，包括皮层区域，通过建立技术 三维回波平面光谱成像（3D-EPSI）的能力。基于我们团队的 在MR技术开发和现有合作方面的开创性工作，我们处于理想的位置， 在减少干扰信号、改进空间编码和实时运动方面的综合技术进步 和B 0校正，以创建最先进的代谢成像方法。基于解剖学的精确区域 还将开发数据分析工具（即MetaSurfer），以提供一种新的基于表面的方法， 处理全脑代谢成像数据因此，该项目提供了全面的全脑代谢 成像软件包，提供从稳健数据采集到新颖数据分析的完整端到端解决方案。使用 开发的软件包，我们将创建人口平均规范的全脑代谢图谱在老龄化 对淀粉样蛋白状态（Aβ-和Aβ+）进行分层后，对人群进行评估，这将为评估 AD中的代谢改变。在我们早期AD的初步临床研究中，我们将研究 脑代谢成像结果和分子、遗传、形态、临床和认知测量， 早期AD患者，利用来自NIA AD研究中心（ADRC）资源的可用数据， 正在进行的AD临床研究。本研究将为未来大规模临床试验提供关键数据， 新的AD治疗策略作为代谢和生物能量医学新兴领域的一部分， AD/ADRD。

PROJECT SUMMARY/ABSTRACT Treating and caring for the more than 6.5 million older adults in the U.S. living with Alzheimer’s disease (AD) presents the largest burden from a single disease on the healthcare system, with costs exceeding $320 billion per year for AD and related dementias (AD/ADRD). While deaths due to major diseases (e.g., stroke, heart disease, and cancers) have declined, AD and AD-related deaths have increased substantially, with a projected cost of about $1 trillion per year to the US economy by 2050. Although AD is currently irreversible, new therapeutic approaches and prevention strategies are under extensive investigation. Over 50% of the pharmacologic agents currently being tested for AD target aberrant brain metabolism. Thus, it is essential to establish a concrete relationship between metabolic dysfunction and pathologic features of AD brains. However, comprehensive whole-brain metabolic mapping, including cortical and subcortical brain regions that are highly relevant to AD pathology, has not been achieved, due to substantial technical challenges in acquiring high-quality magnetic resonance (MR) spectroscopic imaging data with sufficient spatial resolution across the entire brain in clinically acceptable scan time. In this regard, we propose to generate a robust and reliable metabolic mapping of the whole brain, including the cortical regions, by establishing technical capabilities for three-dimensional echo-planar spectroscopic imaging (3D-EPSI). Building on our team’s pioneering work in MR technical development and an existing collaboration, we are ideally positioned to make integrative technical advances in nuisance signal reduction, improved spatial encoding, and real-time motion and B0 correction, to create a state-of-the-art metabolic imaging approach. Accurate anatomy-based regional data analysis tools (namely MetaSurfer) will also be developed to provide a novel surface-based approach to processing whole brain metabolic imaging data. Thus, this project offers comprehensive whole-brain metabolic imaging packages for a full end-to-end solution from robust data acquisition to novel data analysis. Using the developed packages, we will create population-averaged normative whole-brain metabolic atlases in the aging population after stratifying amyloid status (Aβ- and Aβ+), which will provide a statistical basis for assessing metabolic alterations in AD. In our pilot clinical study of early AD, we will investigate the relationship between brain metabolic imaging outcomes and molecular, genetic, morphological, clinical, and cognitive measures in people with early AD, leveraging the available data from NIA AD Research Center (ADRC) resources and ongoing AD clinical studies. This study will provide critical data for future large-scale clinical trials evaluating new AD-treatment strategies as a part of the emerging field of metabolic and bioenergetic medicine for AD/ADRD.