Aerobic Glycolysis: A Marker of BrainResilience to Aging and Alzheimer's Disease

项目摘要/摘要 阿尔茨海默病(AD)在老龄化人口中的患病率不断上升，这加剧了对 确定影响健康脑老化及其向神经病理转变的病因和修饰因素 进程，如AD。人脑的衰老是一个多方面的、复杂的过程，可能容易受到 各种变化/疾病，也是AD的最大风险因素。脑研究的一种综合方法 衰老对于更好地理解健康变化和神经退化过程(如AD)至关重要。一个 关键的问题是，为什么一些AD患者比其他人更早出现认知症状，即使是在 面对相似程度的AD病理？此外，为什么某些大脑区域更容易受到AD病理的影响 比其他人好吗？我们认为，研究大脑新陈代谢，作为对要求苛刻和动态的 在整个生命周期中发生在大脑中的生理学，可能为这些问题提供关键的见解 衰老和阿尔茨海默病的病理生理学。 我们的项目旨在利用大脑新陈代谢来揭示影响 脑老化与阿尔茨海默病的发生发展。脑葡萄糖摄取的同步测量 使用正电子发射断层扫描(PET)的氧气利用可以计算大脑的有氧糖酵解 (葡萄糖代谢超过氧化磷酸化或AG)，这是突触可塑性和 神经保护。脑AG随着年龄的增长而减少，并识别随后成为AD病理靶点的区域。在……里面 在这个项目中，我们建议结合我们独特的多示踪PET成像来评估大脑新陈代谢- 尤其是AG-与健康衰老期间的大脑结构和认知有关，以及在临床前和 阿尔茨海默病的症状阶段。基于我们的正电子发射计算机断层扫描测量，我们还将计算出“代谢性脑年龄”和 研究其与生物年龄以及结构、功能和认知评估的关系。我们将测试 我们的假设是大脑新陈代谢可能会预测与衰老相关的大脑结构和功能的变化。我们 将评估大脑代谢的个体间差异是否与大脑代谢的个体间差异相关 皮质体积、连接性和认知功能。我们的假设是，低脑AG与 更快出现AD的影像和认知特征。相反，高AG将与 增强了对大脑老化和阿尔茨海默病进展影响的适应能力。 因此，该项目将确定大脑新陈代谢在确定是什么导致选择性易感性方面的作用。 某些大脑区域和个体与衰老和阿尔茨海默病有关，这样做可能提供一种途径来识别 影响脑老化和阿尔茨海默病发展轨迹的可改变因素。

PROJECT SUMMARY/ABSTRACT The growing prevalence of Alzheimer’s disease (AD) within an aging population has heightened the need to determine the etiologic and modifying factors that influence healthy brain aging and its shift to neuropathological processes such as AD. Aging of the human brain is a multifaceted, complex process that might be vulnerable to various changes/illnesses and is also the biggest risk factor for AD. An integrative approach to the study of brain aging is essential to better understand both healthy changes and neurodegenerative processes such as AD. A critical question is why do some individuals with AD develop cognitive symptoms earlier than others, even in the face of similar degrees of AD pathology? Also, why are certain brain regions more vulnerable to AD pathology than others? We believe that investigating brain metabolism, as a reflection of the demanding and dynamic physiology occurring in the brain throughout the lifespan, might provide key insights into these questions and of the pathophysiology of aging and AD in general. Our project is aimed at using brain metabolism to reveal sources of inter-individual differences that influence brain aging and the development and progression of AD. Simultaneous measurement of brain glucose uptake and oxygen utilization using positron emission tomography (PET) allows calculation of brain aerobic glycolysis (glucose metabolism in excess of oxidative phosphorylation or AG), which is a marker of synaptic plasticity and neuroprotection. Brain AG decreases with age and identifies regions subsequently targeted by AD pathology. In this project, we propose to combine our unique, multi-tracer PET imaging to evaluate how brain metabolism — in particular AG — relates to brain structure and cognition during healthy aging and in the preclinical and symptomatic stages of AD. Based on our PET measurements we will also calculate a “metabolic brain age” and investigate its relationship with biological age and structural, functional and cognitive assessments. We will test our hypothesis that brain metabolism might predict aging-related changes in brain structure and function. We will evaluate whether inter-individual differences in brain metabolism correlate with inter-individual differences in cortical volume, connectivity and cognitive function. Our hypothesis is that low brain AG is associated with a more rapid appearance of imaging and cognitive features of AD. Conversely, high AG will be associated with increased resilience to the effects of brain aging and progression of AD. This project will thus establish the role of brain metabolism in determining what causes selective vulnerability of certain brain regions and individuals to aging and AD, and in doing so may provide an avenue to identify modifiable factors that influence the trajectory of brain aging and AD.