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

摘要/项目摘要 有证据表明，体育活动和锻炼有益于大脑，但其机制 好处还不清楚。运动的长期益处很可能是对运动的谨慎、尖锐反应的产物 运动相关的血液生物标记物和脑代谢。这种剧烈的运动反应还没有 在衰老和阿尔茨海默病(AD)方面进行了比较。众所周知，剧烈运动能产生强大的外周神经。 年轻队列中的反应，与运动相关的生物标记物，如葡萄糖和乳酸，很容易穿透 大脑。因此，需要研究这些对老年人和阿尔茨海默病患者的影响。重要的是要确定和确定 了解运动的急性影响，包括不同的运动强度，就外围设备而言 代谢反应及其与脑代谢的关系。这将有助于确定潜在的机制 锻炼对大脑的好处，并更好地为未来临床试验的设计提供信息。我们的主要目标是 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。 我们将描述急性中强度和高强度运动的大脑代谢反应。 并描述了非痴呆症(ND)老年人和AD患者之间的差异程度。 与这个主要目标相关，我们将把外周生物标记物的反应量化为中等和更高 两组的强度运动及其与大脑代谢变化的关系。我们将恳求一个严格的 实验设计，严格控制计时。我们将在之前生成一个抽血的时间轨迹， 探讨ND和AD受试者在运动中和运动后与疾病相关的差异。我们将专注于一个 具体的运动生物标记物乳酸，但我们也将表征更广泛的运动相关生物标记物。 我们将利用乳酸盐钳夹程序来扩展我们的运动研究，在那里我们可以表征 诊断组之间乳酸摄取和使用(周转率)的差异。通过使用稳定的同位素， 乳酸钳将允许我们同时检查复杂的能量代谢动力学，例如乳酸 出现、消失和氧化，并评估AD受试者是否以不同方式使用这种关键代谢物。它 也可以在没有其他运动影响的情况下表征乳酸对认知的急性影响。 综上所述，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 以及大脑对运动的急性反应，以及运动强度可能有多重要。通过深入了解 表征这些生理反应在衰老和阿尔茨海默病中，我们将获得重要的信息 关于相对无创的结果，如心率和血液生物标记物反应，如何与 关键的大脑结果测量(大脑葡萄糖代谢)。通过表征响应的阈值 引发急性大脑变化所需的生物标志物，这可能为未来的设计提供洞察力 最有可能对大脑有益的长期运动干预研究(即中等与较高 强度运动，参与者的反应特征等)，以最大限度地提高目标参与度。

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.