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.

项目总结/摘要 在这个项目中，我们将评估局部耗氧量和葡萄糖利用的变化轨迹 （总的以及用于有氧糖酵解或AG的部分）和脑循环中的糖酵解过程。 临床前AD到症状性AD在中年晚期和老年人。目前确定AG是一个 一组代谢功能的标志物，包括生物合成、神经保护和凋亡， 在正常大脑的情况下，参与突触重塑，学习和记忆，以及 隔膜泵的能量。AG在正常成人大脑中约为10-15%，并且它显示出更多的 与响应生理激活的脑代谢的其他测量相比， 或与脑部疾病相关的病理生理挑战。我们的横截面观察 认知正常的成年人表明，AD病理学靶向的人类大脑区域具有独特的高 AG水平较高，且AG水平较高与PIB沉积较少、CSF Aβ42和 在认知测试中取得更好的成绩在我们目前的项目中，我们将尽早确定AG作为潜在的 发展中的AD病理学的生物标志物和认知下降的预测因子。我们的具体目标包括估计 轻度至中度症状性AD患者首次出现AG，同时伴有认知障碍 正常个体，以评估低基线AG将与随后的 AD病理学的发展和认知能力下降。我们还将确定利率之间的关系 AG的变化以及AD临床评估和生物标志物的变化率。大多数情况下这 信息将与先前收集的相同个体的数据相结合， 时间轨迹这些纵向评估将使我们能够评估AG和其他PET的变化 从无AD病理转变为临床前AD期间的代谢和循环指标，以及 从临床前阶段到症状性AD。我们将评估以下假设，即AG在 其他参数，并且AG的变化率将预测AD病理学和认知功能的进展。 下降我们的工作不仅可以大大扩展我们对葡萄糖在大脑功能中作用的理解， 除了通过氧化磷酸化提供能量，还提供了重要的新见解， AD的病理生理学和AG的神经保护潜力。这个项目是创新的，因为它提出， 联合收割机不同的AD生物标志物，以解决新的问题，在体内，在人类中产生相关的发现 临床疾病和基本的人类神经生理学。我们小组所选择的方法 具有丰富的专业知识，将使我们能够研究内在的区域大脑活动和能量利用，在体内， 人类，这似乎与AD病理学的区域发展有关。该项目将 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， 开发和控制预防性治疗的有效性，旨在通过调节 突触功能