White Matter Metabolism in the Context of Aging, White Matter Hyperintensities and Alzheimer's Disease

衰老、白质高信号和阿尔茨海默氏病背景下的白质代谢

• 批准号: 10444238
• 负责人: Manu S Goyal
• 金额: $ 228.79万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10444238
• 关键词: Adult; Age; Aging; Alzheimer' s Disease; Animals; Arterial Lines; Arteriosclerosis; Atlases; Attenuated; Axon; Brain; Cerebrovascular Circulation; Cerebrum; Cognitive; Data; Development; Elderly; Failure; Glucose; Glycolysis; Gold; Human; Hypoxia; Image; Impaired cognition; Injury; Laboratories; Magnetic Resonance Imaging; Measurement; Measures; Metabolic; Metabolism; Methods; Mitochondria; Myelin; Nerve Degeneration; Oligodendroglia; Oxygen; Oxygen Consumption; Pathology; Physiology; Positron-Emission Tomography; Resolution; Risk; Role; Specificity; Spottings; Testing; Vascular Dementia; White Matter Disease; White Matter Hyperintensity; aerobic glycolysis; aging brain; amyloid pathology; brain magnetic resonance imaging; cohort; endothelial dysfunction; fluorodeoxyglucose; in vivo; insight; prevent; radiotracer; resilience; sex; theories; white matter; young adult

ABSTRACT White matter hyperintensities (WMH) are ubiquitous in the aging brain. Prevailing theories implicate arteriosclerosis and endothelial dysfunction followed by ischemic and hypoxic injury as a cause, but factors that resist or modify these mechanisms are unknown. Animal studies show that glycolysis is a principal metabolic feature of normal white matter and protective against mitochondrial failure. However, white matter glycolysis has been understudied in in vivo human studies and particularly in the context of WMH. Our laboratory has developed methods, now on a state-of-the-art PET scanner, to quantitatively measure brain glycolysis using multiple radiotracers, including 15O radiotracers to measure cerebral oxygen consumption (CMRO2), cerebral blood flow (CBF) and oxygen extraction fraction (OEF), and 18FDG to measure total glucose use (CMRglc), from which we can derive the rate of aerobic glycolysis (AG). Here we propose to apply these methods to provide gold-standard quantitative estimates of normal human white matter metabolism, and to specifically investigate white matter glycolysis in the context of WMH. In our first two aims, we will compare the topography of metabolic PET measurements to MRI measurements of white matter microstructure and WMH, both in healthy adults without WMH and in adults with WMH. In our third aim, we will analyze longitudinal MRI imaging data in a cohort of adults who have already undergone metabolic PET in our prior and ongoing studies on an older scanner, to test the hypothesis that relative differences in white matter glycolysis will predict subsequent WMH development and progression. Moreover, we will explore potential relationships between neurodegenerative pathology and WMH, which we hypothesize occurs due to effects of the aforementioned pathology on white matter metabolism, thereby reducing its resilience to WMH.

摘要 白质高信号(WMH)在老化的大脑中普遍存在。流行的理论表明 动脉硬化和内皮功能障碍继之以缺血和缺氧损伤为原因，但这些因素 抵抗或修改这些机制是未知的。动物研究表明糖酵解是一种主要的代谢。 正常脑白质的特征和对线粒体故障的保护。然而，白质糖酵解有 在活体人体研究中，特别是在WMH的背景下，研究不足。我们的实验室已经研制出 方法，现在在最先进的PET扫描仪上，使用多个 放射性示踪剂，包括15O放射性示踪剂，用于测量脑氧耗(CMRO2)、脑血流量 (CBF)和氧气提取分数(OEF)，以及18FDG来测量总葡萄糖使用量(CMRglc)，我们从中 可以得出有氧糖酵解的速率(AG)。在这里，我们建议应用这些方法来提供黄金标准 对正常人类脑白质代谢的定量估计，并专门研究脑白质 WMH背景下的糖酵解。在我们的前两个目标中，我们将比较代谢PET的形貌 健康成人脑白质微结构和WMH的MRI测量 WMH和成人WMH。在我们的第三个目标中，我们将分析一组纵向核磁共振成像数据 在我们之前和正在进行的旧扫描仪研究中已经接受代谢PET检查的成年人，以进行测试 假设白质糖酵解的相对差异将预测随后的WMH发展和 进步。此外，我们还将探索神经退行性病变与WMH之间的潜在关系。 我们推测这是由于前述病理对白质代谢的影响而发生的， 从而降低了其对WMH的复原力。