Aerobic Glycolysis in the Development ofAlzheimer's Disease

阿尔茨海默病发展中的有氧糖酵解

• 批准号: 9905334
• 负责人: MARCUS E RAICHLE
• 金额: $ 73.79万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9905334
• 关键词: Address; Adult; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer’s disease biomarker; Amyloid; Amyloid beta-42; Amyloid beta-Protein; Anabolism; Apoptosis; Applications Grants; Area; Biological Markers; Blood Circulation; Brain; Brain Diseases; Cellular biology; Clinical; Clinical assessments; Cognitive; Consumption; Data; Deposition; Development; Disease; Elderly; Epilepsy; Functional disorder; Generations; Glucose; Glycogen; Human; Impaired cognition; Individual; Knowledge; Learning; Lipids; Measures; Membrane; Memory; Metabolic; Metabolism; Methods; Neurons; Nucleic Acids; Oxidative Phosphorylation; Oxygen; Oxygen Consumption; Participant; Pathogenesis; Physiological; Positron-Emission Tomography; Preventive treatment; Proteins; Pump; Reactive Oxygen Species; Role; Senile Plaques; Synapses; Therapeutic; Thinking; Time; Transgenic Mice; Visit; Work; aerobic glycolysis; brain circulation; brain metabolism; clinical biomarkers; cognitive testing; early detection biomarkers; glucose metabolism; improved; in vivo; innovation; insight; middle age; neuroimaging; neurophysiology; neuroprotection; neurotoxicity; novel; pre-clinical; rate of change; response; specific biomarkers; synaptic function; tau Proteins; tumor; β-amyloid burden

PROJECT SUMMARY/ABSTRACT  In this project, we will evaluate the trajectory of changes in regional oxygen consumption and glucose use (total as well as the fraction devoted to aerobic glycolysis or AG) and in brain circulation through the course of preclinical AD to symptomatic AD in late middle-aged and older adults. It is currently established that AG is a marker of a group of metabolic functions which includes biosynthesis, neuroprotection, and apoptosis, which, in the context of the normal brain is involved in synaptic remodeling, learning and memory, and generation of energy for membrane pumps. AG is about 10-15% in the normal adult human brain, and it demonstrates more substantial changes compared to other measures of brain metabolism in response to physiological activation or pathophysiological challenges associated with brain diseases. Our cross-sectional observations in cognitively normal adults suggest that areas of the human brain targeted by AD pathology have uniquely high levels of AG, and higher levels of AG are associated with less PIB deposition, higher levels of CSF Aβ42 and better scores on cognitive tests. In our current project, we will determine the role of AG as a potential early biomarker of evolving AD pathology and predictor of cognitive decline. Our specific aims include estimation for the first time of AG in individuals with mild-to-moderate symptomatic AD combined with that in cognitively normal individuals to evaluate a hypothesis that low baseline AG will be associated with the subsequent development of AD pathology and cognitive decline. We will also determine the relationship between the rate of change in AG and rate of change in clinical assessments and biomarkers of AD. In most cases, this information will be combined with the previously collected data in the same individuals to provide a multipoint trajectory over time. These longitudinal assessments will allow us to evaluate changes in AG and other PET measures of metabolism and circulation during the transition from no AD pathology to preclinical AD, and through the preclinical stages to symptomatic AD. We will evaluate the hypothesis that AG changes prior to other parameters, and that the rate of change in AG will predict progression in AD pathology and cognitive decline. Our work may not only expand significantly our understanding of the role of glucose in brain function beyond providing energy via oxidative phosphorylation, but also provide important new insights into the pathophysiology of AD and neuroprotective potential of AG. This project is innovative because it proposes to combine different biomarkers of AD to address novel questions, in vivo, in humans to produce findings relevant to both clinical disorders and fundamental human neurophysiology. The methods chosen, with which our group has substantial expertise, will allow us to study intrinsic regional brain activity and energy utilization, in vivo, in humans, which appear to be associated with the regional development of AD pathology. This project will evaluate a potential of AG as a highly specific biomarker of synaptic function, and provide novel insight into the development and control of the efficacy of preventive treatments aimed to reduce AD pathology by modulating synaptic function.

项目摘要/摘要 在这个项目中，我们将评估区域氧气消耗和葡萄糖使用变化的轨迹 （（全部以及部署到有氧糖酵解或AG的分数）以及整个脑循环中 在中年晚期和老年人晚期的临床前广告。目前确定AG是 一组代谢功能的标志物，包括生物合成，神经保护和凋亡，这是 在正常大脑的背景下，大脑参与突触重塑，学习和记忆以及产生 膜泵的能量。正常成年人大脑中的AG约为10-15％，它表现出更多 与脑部新陈代谢的其他措施相比，实质性变化响应物理激活 或与脑疾病有关的病理生理挑战。我们在 认知正常的成年人表明，AD病理学靶向的人脑的区域具有独特的高度 Ag水平和较高水平的AG与PIB沉积较少有关，CSFAβ42的水平较高和 认知测试的得分更好。在我们当前的项目中，我们将确定AG作为潜在的早期作用 不断发展的AD病理学的生物标志物和认知能力下降的预测指标。我们的具体目的包括估计 在具有轻度至中度症状广告的个体中，Ag的第一次与认知上的AG相结合 正常个体评估低基线Ag将与后续的假设相关的假设 AD病理学和认知能力下降的发展。我们还将确定费率之间的关系 AG的AG变化和AD临床评估和生物标志物的变化率。在大多数情况下，这个 信息将与同一个人中先前收集的数据合并，以提供多点 随着时间的推移轨迹。这些纵向评估将使我们能够评估AG和其他PET的变化 从没有AD病理学到临床前AD的过渡期间的新陈代谢和循环措施， 通过临床前阶段到有症状的广告。我们将评估以下假设，即Ag之前发生了变化 其他参数，Ag的变化率将预测AD病理和认知的进展 衰退。我们的工作不仅可以显着扩展我们对葡萄糖在大脑功能中的作用的理解 除了通过氧化磷酸化提供能量，但也提供了重要的新见解 AD的AD和神经保护潜力的病理生理学。该项目具有创新性，因为它提出了 将广告的不同生物标志物结合在一起，以在人类中在体内解决新的问题，以产生相关的发现 临床疾病和基本人类神经生理学。选择的方法，我们的小组与之 具有丰富的专业知识，将使我们能够研究固有的区域大脑活动和能量利用，在体内， 人类似乎与AD病理的区域发展有关。这个项目将 评估Ag作为突触功能的高度特异性生物标志物的潜力，并提供新的见解 通过调节旨在减少AD病理的有效疗法的开发和控制 突触功能。