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

项目概要/摘要 缺乏有效的方法来治疗与年龄相关的认知能力下降， 健康问题，考虑到它的普遍性与人口老龄化的前所未有的增长。最近， 生活方式的选择，特别是锻炼，已被认为是维持和 增强老年人的大脑健康和认知功能。然而，公众和科学界 关于运动对大脑的决定性益处，还没有达成一致意见。目前正在进行III期临床 试验：IGNITE（调查运动干预试验中神经认知的增益）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 一项辅助研究，以确定运动对参与者大脑中抗氧化状态的影响 从IGNITE，其中临床，成像，遗传，分子和生理措施将获得。我们 将确定抗氧化状态与认知功能和大脑健康的关系， 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能力的潜在机制， 与行为干预和/或老年人新靶向治疗相关的表现，以及2） 提供了新的可能性，直接监测这些紧急治疗方案的影响，通过新的 老年、AD和AD相关疾病中大脑健康的定量、非侵入性神经影像学指标。我们 总的假设是，运动增强了大脑的抗氧化防御，以对抗氧化应激， 通过增加谷胱甘肽（GSH）的水平，从而改善大脑健康， 认知功能GSH是大脑抗氧化系统的关键成分， 细胞对抗氧化损伤，导致脑组织中GSH水平降低。 我们的初步数据表明，大脑GSH与老年人的认知能力有关， 多个领域，降低老化和AD，并增加运动干预后。具体目标 （1）确定运动干预对衰老脑中脑抗氧化状态的影响， (2)以确定大脑抗氧化状态和运动相关性之间的中介关系， 认知功能和大脑健康的改善，以及（3）检查 阿尔茨海默病的遗传/分子标记物对运动后脑抗氧化状态的变化 干预该项目的预期成果是：1）确定一个主要机制，氧化 压力，运动对老年人认知功能和大脑健康的有益影响， 2)鉴定反映神经调节作用的基于机制的神经成像标记物 运动干预和剂量反应效应，以及3）运动干预作为一种 通过增加大脑抗氧化防御来增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.