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

项目总结/摘要 老年人中阿尔茨海默病（AD）的发病率不断增加，这增加了对 确定影响健康脑老化及其向神经病理性转变的病因和修饰因素 如AD。人类大脑的衰老是一个多方面、复杂的过程，可能容易受到影响 各种变化/疾病，也是AD的最大风险因素。脑的综合研究 衰老对于更好地理解健康变化和神经退行性过程如AD是必不可少的。一 关键问题是，为什么有些AD患者比其他人更早出现认知症状，即使在 面临着类似程度的AD病理？此外，为什么某些大脑区域更容易受到AD病理学的影响 比其他人多吗我们认为，调查大脑代谢，作为一个要求和动态的反映， 在整个生命周期中发生在大脑中的生理学，可能会为这些问题提供关键的见解， 衰老和AD的病理生理学。 我们的项目旨在利用大脑代谢来揭示个体间差异的来源， 脑老化与AD的发生发展脑葡萄糖摄取的同时测量 利用正电子发射断层扫描（PET）可以计算大脑有氧糖酵解 （葡萄糖代谢超过氧化磷酸化或AG），其是突触可塑性的标志物， 神经保护脑AG随着年龄的增长而降低，并确定了随后被AD病理学靶向的区域。在 在这个项目中，我们建议将我们独特的多示踪PET成像结合联合收割机来评估大脑代谢- 特别是AG -与健康老龄化过程中以及临床前和 AD的症状阶段。根据我们的PET测量，我们还将计算“代谢脑年龄”， 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，即大脑代谢可能预测大脑结构和功能的衰老相关变化。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 皮质容量、连通性和认知功能。我们的假设是，低大脑AG与 AD的影像学和认知功能更快出现。相反，高AG将与 增加对大脑老化和AD进展影响的恢复力。 因此，该项目将确定大脑代谢在确定是什么导致选择性脆弱性方面的作用。 某些大脑区域和个体对衰老和AD的影响，这样做可能会提供一种识别 影响大脑老化和AD轨迹的可变因素。

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.