Acute exercise and the cerebral metabolic response in aging and Alzheimer's Disease

摘要/项目总结 有证据表明，身体活动和锻炼有益于大脑，但其机制 利益不明确。运动的长期益处可能是谨慎的产物，急性反应， 运动相关的血液生物标志物和大脑代谢。这种急性运动反应并没有被 老年痴呆症（AD）的发病率。众所周知，剧烈运动会激发一种强大的外周神经系统， 在年轻的队列中，运动相关的生物标志物，如葡萄糖和乳酸，很容易渗透到 个脑袋因此，需要研究老年人和AD患者的这些影响。关键是要描述和 了解运动的急性效应，包括不同的运动强度，在外周 代谢反应及与脑代谢的关系。这将有助于确定潜在机制， 运动对大脑的益处，并更好地为未来的临床试验设计提供信息。我们的首要目标是 表征急性运动反应的脑葡萄糖代谢和运动相关的血液生物标志物。 我们将描述大脑代谢反应的急性发作中度和更高强度的运动 并描述非痴呆（ND）老年人和AD个体之间的差异程度。 与这一主要目标相关，我们将量化外周生物标志物对中度和更高的反应。 强度运动以及这与两组大脑代谢变化的关系。我们将恳求一个严格的 实验设计，严格控制时间。我们会做一个抽血的时间表， 在ND和AD受试者的运动期间和运动后，以探索疾病相关的差异。我们将集中在一个 具体的运动生物标志物，乳酸，但我们也将表征更广泛的运动相关生物标志物。 我们将通过利用乳酸钳夹程序扩展我们的运动研究，在那里我们可以描述 诊断组之间乳酸摄取和使用（周转）的差异。通过使用稳定同位素， 乳酸钳夹将允许我们同时检查能量代谢的复杂动力学，例如乳酸 出现，消失和氧化，并评估AD受试者是否以不同的方式使用这种关键代谢物。它 还允许在没有其他运动效应的情况下表征乳酸盐对认知的急性效应。 总之，这些研究将使我们能够阐明可量化的血液生物标志物之间的关系， 和大脑对运动的急性反应，以及运动强度如何可能是重要的。通过深入 这些生理反应在老化和AD的表征，我们将获得重要的信息 关于相对非侵入性的结果，如心率和血液生物标志物反应，如何与 关键的大脑结果指标（大脑葡萄糖代谢）。通过表征响应阈值， 这些生物标志物是引发急性大脑变化所需的，这可以为未来的设计提供见解。 长期运动干预研究，最有可能有益于大脑（即中度与高度 强度锻炼、响应的参与者的特征等）以最大化目标参与。

ABSTRACT / PROJECT SUMMARY There is evidence that physical activity and exercise benefit the brain, but the mechanisms for this benefit are unclear. The chronic benefits of exercise are likely a product of discreet, acute responses in exercise-related blood biomarkers and brain metabolism. This acute exercise response has not been compared in aging and Alzheimer’s Disease (AD). It is known that acute exercise elicits a powerful peripheral response in young cohorts, and exercise-related biomarkers such as glucose and lactate readily penetrate the brain. Thus, studies of these effects in aged and AD individuals are needed. It is critical to characterize and understand the acute effects of exercise, including different exercise intensities, in terms of the peripheral metabolic response and relationship with brain metabolism. This will help determine potential mechanisms for brain benefits of exercise and better inform the design of future clinical trials. Our primary goal is to characterize the acute exercise response of brain glucose metabolism and exercise-related blood biomarkers. We will characterize the brain metabolic response to an acute bout of moderate and higher intensity exercise and characterize the extent to which this differs between nondemented (ND) elderly and AD individuals. Related to this primary goal, we will quantify the peripheral biomarker response to moderate and higher intensity exercise and how this relates to brain metabolic change in both groups. We will implore a rigorous experimental design, with tightly controlled timings. We will generate a timecourse of blood draws prior to, during, and following exercise in ND and AD subjects to explore disease-related differences. We will focus on a specific exercise biomarker, lactate, but we will also characterize a wider panel of exercise-related biomarkers. We will expand on our exercise studies by leveraging a lactate clamp procedure, where we can characterize differences in lactate uptake and use (turnover) between diagnosis groups. By using stable isotopes, the lactate clamp will allow us to simultaneously examine complex dynamics of energy metabolism, such as lactate appearance, disappearance, and oxidation, and evaluate if AD subjects use this key metabolite differently. It also allows characterization of acute effects of lactate on cognition in the absence of other exercise effects. Taken together, these studies will allow us to elucidate the relationship between quantifiable blood biomarkers and brain acute response to exercise, and how exercise intensity may be important. Through in-depth characterization of these physiological responses in aging and AD, we will obtain important information regarding how relatively non-invasive outcomes, such as heart rate and blood biomarker response, relate to a key brain outcome measure (cerebral glucose metabolism). By characterizing thresholds for response of biomarkers that are needed to elicit acute brain changes, this could provide insight for the design of future long-term exercise intervention studies that are most likely to benefit the brain (i.e. moderate vs. higher intensity exercise, characteristics of participants who respond, etc) to maximize target engagement.