Aerobic Glycolysis in the Development ofAlzheimer's Disease

项目摘要/摘要： 在这个项目中，我们将评估区域耗氧量和葡萄糖使用量的变化轨迹 (总以及用于有氧糖酵解或AG的部分)和在以下过程中的脑循环 中老年晚期临床前AD与症状性AD的关系。目前已确定AG是一家 一组代谢功能的标记物，包括生物合成、神经保护和细胞凋亡， 在正常情况下，大脑参与突触重塑、学习和记忆，并产生 隔膜泵的能量。在正常成年人的大脑中，银含量约为10%-15%，而且它显示出更多 与其他脑代谢指标相比，对生理激活的反应有实质性的变化 或与脑部疾病相关的病理生理挑战。我们的横断面观测结果 认知正常的成年人认为，阿尔茨海默病病理所针对的人脑区域具有独特的高密度 AG水平和较高水平的AG与较少的PIB沉积、较高的脑脊液Aβ42和 在认知测试中取得更好的成绩。在我们目前的项目中，我们将在早期确定AG的潜在角色 阿尔茨海默病病理演变的生物标志物和认知功能衰退的预测因子。我们的具体目标包括估计 轻、中度症状性阿尔茨海默病合并认知障碍患者的首次AG 评估一个假设，即低基线AG与随后的 阿尔茨海默病的病理发展与认知功能下降。我们还将确定利率之间的关系 AG的变化以及AD的临床评估和生物标记物的变化率。在大多数情况下，这 信息将与之前收集的相同个人的数据相结合，以提供多点 随着时间的推移形成轨迹。这些纵向评估将使我们能够评估AG和其他PET的变化 无阿尔茨海默病向临床前期阿尔茨海默病过渡过程中代谢和循环的测量 通过临床前期到症状性AD。我们将评估AG发生变化之前的假设 其他参数，AG的变化率将预测AD病理和认知的进展 拒绝。我们的工作不仅可以显著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之外，还提供了对 阿尔茨海默病的病理生理和AG的神经保护作用。这个项目具有创新性，因为它提出了 结合AD的不同生物标记物，在人体内解决新的问题，以产生相关的发现 临床疾病和基本的人类神经生理学。所选择的方法，我们团队用来 拥有丰富的专业知识，将使我们能够研究内在的局部大脑活动和能量利用，在体内，在 人类，这似乎与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，并提供对 通过调控减少AD病理的预防性治疗的有效性的发展和控制 突触功能。

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.