Antioxidant Imaging Marker of Investigating Gains in Neurocognition in an Intervention Trial of Exercise (AIM-IGNITE)

项目摘要/摘要 缺乏治疗年龄相关性认知衰退的有效方法是一个重要的公众问题。 健康问题，考虑到它无处不在，老龄化人口史无前例地增加。最近， 生活方式的选择，特别是锻炼，被认为是保持和保持健康的潜在有效策略 增强老年人的大脑健康和认知功能。然而，公众和科学界是 目前还没有就运动对大脑的最终益处达成一致。目前为三期临床 试验：IGNITE(在锻炼的干预试验中调查神经认知方面的收益)正在进行中 运动对老年人大脑健康和认知功能影响的模糊性。我们提出了一个 确定运动对受试者大脑抗氧化状态影响的辅助研究 从IGNITE，将获得临床、成像、遗传、分子和生理测量。我们 将决定抗氧化剂状态与认知功能和大脑健康的关系，以及 阿尔茨海默病(AD)的遗传和分子危险因素对这些关系的影响。 我们的长期目标是1)确定改善大脑健康和认知的潜在机制 与老年人的行为干预和/或新的靶向治疗相关的表现，以及2) 为直接监测这些紧急治疗方案的影响提供新的可能性 衰老、AD和AD相关疾病中脑健康的定量、非侵入性神经成像指标。我们的 总体假设是，运动增强了大脑抗氧化防御，以对抗氧化应激 通过增加谷胱甘肽(GSH)的水平来老化大脑，从而改善大脑健康和 认知功能。谷胱甘肽是大脑抗氧化系统的关键组成部分，它的消耗是为了保护 保护细胞免受氧化损伤，从而降低脑组织中的GSH水平。 我们的初步数据表明，大脑GSH与老年人的认知表现有关 多个领域，在衰老和AD中降低，并在运动干预后增加。具体目标 目的：(1)探讨运动干预对衰老脑组织抗氧化状态的影响。 (2)确定大脑抗氧化状态与运动相关的中介关系 改善认知功能和大脑健康，以及(3)检查 阿尔茨海默病的遗传/分子标志物与运动后脑组织抗氧化状态的变化 干预。这个项目的预期结果是：1)确定了一种主要的机制--氧化 压力是锻炼对老年人认知功能和大脑健康有益影响的潜在原因， 2)筛选一种反映神经调节作用的神经影像标记物 运动干预和剂量-反应效应；3)运动干预是一种 通过增加大脑抗氧化防御来加强神经保护的重要策略。

PROJECT SUMMARY / ABSTRACT The absence of effective methods for treating age-relate cognitive decline presents a significant public health problem, considering its ubiquity with unprecedented increases in the aging population. Recently, lifestyle choices, particularly exercise, have been noted as potential effective strategies for maintaining and enhancing brain health and cognitive function in older adults. However, the public and scientific community is yet to reach agreements on the conclusive benefits of exercise on the brain. Currently a Phase III clinical trial: IGNITE (Investigating Gains in Neurocognition in an Intervention Trial of Exercise) is ongoing to address the ambiguity in influences of exercise on brain health and cognitive function in older adults. We propose an ancillary study to determine the impact of exercise on antioxidant status in the brain of participants drawn from IGNITE, in which clinical, imaging, genetic, molecular and physiological measures will be acquired. We will determine the association of antioxidant status with cognitive function and brain health as well as the impact of genetic and molecular risk factors of Alzheimer's disease (AD) on these relationships. Our long-term goal is 1) to identify the underlying mechanisms of improved brain health and cognitive performance associated with behavioral interventions and/or new targeted therapies in older adults, and 2) to offer novel possibilities for directly monitoring the impact of these emergent treatment options through new quantitative, non-invasive neuroimaging indices of brain health in aging, AD and AD-related diseases. Our overall hypothesis is that exercise enhances cerebral antioxidant defenses to fight against oxidative stress in the aging brain by increasing the levels of glutathione (GSH), which leads to improved brain health and cognitive function. GSH is a key component of the cerebral antioxidant system, which is consumed to protect cells against oxidative damage resulting in lower GSH levels in brain tissue. Our preliminary data suggest that brain GSH is related with the cognitive performance of older adults in multiple domains, lowered in aging and AD, and increases after exercise interventions. The Specific Aims are: (1) to determine the influence of exercise intervention on the brain antioxidant status in the aging brain, (2) to determine the mediating relationship between the brain antioxidant status and exercise-associated improvements in cognitive function and brain health, and (3) to examine modulating effects of genetic/molecular markers of Alzheimer's disease on changes in brain antioxidant status after exercise intervention. The expected outcome of this project is 1) the identification of a major mechanism, oxidative stress, underlying the beneficial effects of exercise on cognitive function and brain health seen in older adults, 2) the identification of a mechanism-based neuroimaging marker reflecting neuromodulating effects of exercise intervention and the dose-response effects, and 3) the identification of exercise intervention as an important strategy to enhance neuroprotection via increased cerebral antioxidant defenses.