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

急性运动与衰老和阿尔茨海默病中的大脑代谢反应

• 批准号: 9886905
• 负责人: Jill Kathleen Morris
• 金额: $ 47.6万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-15 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9886905
• 关键词: Acute; Aerobic Exercise; Affect; Aging; Alzheimer' s Disease; Appearance; Area Under Curve; Automobile Driving; Biological Markers; Blood; Brain; Cerebrum; Characteristics; Chronic; Clinical Trials; Closure by clamp; Cognition; Complex; Diagnosis; Diagnostic; Disease; Drops; Elderly; Energy Metabolism; Exercise; Experimental Designs; Fasting; Fibrinogen; Future; Glucose; Goals; Heart Rate; Heterogeneity; Hour; Individual; Individual Differences; Infusion procedures; Intervention; Intervention Studies; Intervention Trial; Ketones; Mediating; Memory; Metabolic; Metabolism; Neuroglia; Neurons; Outcome; Outcome Measure; Participant; Peripheral; Permeability; Physical Exercise; Physical activity; Physiological; Population; Positioning Attribute; Procedures; Production; Rest; Signal Pathway; Time; aged; brain health; brain metabolism; cardiorespiratory fitness; cognitive benefits; cognitive performance; cohort; design; executive function; exercise intensity; exercise intervention; exercise prescription; exercise program; exercise regimen; glucose metabolism; improved; insight; non-demented; oxidation; peripheral blood; post intervention; prevent; response; response biomarker; stable isotope; trial design; uptake

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.

摘要 /项目摘要 有证据表明体育锻炼和运动使大脑受益，但这种机制 好处尚不清楚。锻炼的慢性益处可能是谨慎，急性反应的产物 与运动有关的血液生物标志物和大脑代谢。这种急性运动的反应还没有 在衰老和阿尔茨海默氏病（AD）中进行了比较。众所周知，急性运动会引起强大的外围 年轻同类的反应和与运动有关的生物标志物（例如葡萄糖和裂缝）很容易穿透 脑。这是需要在老年和AD个体中对这些影响的研究。表征和 了解锻炼的急性影响，包括不同的运动强度 代谢反应和与脑代谢的关系。这将有助于确定潜在的机制 运动的大脑益处，并更好地告知未来临床试验的设计。我们的主要目标是 表征脑葡萄糖代谢和与运动有关的血液生物标志物的急性运动反应。 我们将表征大脑代谢反应对中等强度运动的急性回合 并表征了这种差异（ND）和AD个人之间的这种差异的程度。 与这一主要目标有关，我们将量化外围生物标志物对中等和更高的响应 强度运动以及这与两组的大脑代谢变化的关系。我们将恳求严格的 实验设计，具有严格控制的时间。在 在ND和AD受试者中进行运动和之后，以探索与疾病相关的差异。我们将专注于 特定的运动生物标志物，缝制，但我们还将表征更广泛的与运动有关的生物标志物。 我们将通过利用缝制夹程序来扩展我们的运动研究，我们可以在其中表征 诊断组之间的差异和使用（营业额）的差异。通过使用稳定的同位素， 乳酸夹将使我们能够简单地检查能量代谢的复杂动力学，例如乳酸 外观，消失和氧化，并评估AD受试者是否使用此关键代谢产物。 还允许在没有其他运动作用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 和大脑对运动的急性反应，以及运动强度可能很重要。通过深入 在衰老和AD中的这些身体反应的表征，我们将获得重要信息 关于与A有关 关键的大脑结局度量（脑葡萄糖代谢）。通过表征阈值的响应 引起急性大脑变化所需的生物标志物，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使大脑受益（即中度与更高 强度运动，响应参与者的特征等），以最大程度地提高目标参与。