Effects of Standardized Aerobic Exercise-Training on Neurocognitive and Neurodege

描述（由申请人提供）：本初步研究的主要目的是确定患有轻度AD （AD）的非裔美国人（AA）是否可以被招募并保留在为期6个月的有氧运动训练研究中。采用随机对照试验方法，我们将研究有氧运动训练对神经认知功能和脑葡萄糖稳态的影响。患有轻度AD的AAs是否可以被纳入这项研究尚不清楚，在这一人群中，适应性与神经认知功能的关系也没有被系统地研究过。除了评估干预效果的目标外，我们还将评估APOE与有氧健身诱导的神经认知变化的差异关系。我们的长期目标是探索健康适应对神经认知产生影响的机制——值得注意的是，低水平的高密度脂蛋白胆固醇（HDL-C）、炎症（c反应蛋白（CRP）和白细胞介素（IL-1A））升高、葡萄糖稳态紊乱、高血压和内皮功能障碍是小动脉硬化、脑灌注减少和缺氧的先兆，所有这些都可能增加AD的风险。由于许多这些假定的阿尔茨海默病危险因素易受生活方式改变的影响，我们也将评估它们在有氧健身相关的认知功能改善和阿尔茨海默病风险降低中的作用。一个由神经影像学、神经学、心理学、运动生理学、心脏病学和遗传学等领域非常成功的专家组成的团队进行了这项研究。在获得知情同意后，参与者将进行初步的运动筛选，以确定他们安全运动的能力。将112名参与者随机分为干预组（n=56）和对照组（n=56），进行基线神经心理学、神经影像学和生物标志物评估。干预组每周进行3次有监督的有氧运动训练，对照组每周进行3次拉伸运动。在干预组完成为期6个月的有氧运动训练后，在干预组和对照组中重复所有基线测试。将采用适当的多变量方法比较组间认知表现。这项工作有可能增加一种实际有效的策略，以延缓阿尔茨海默病在高危人群中的进展。与我们的假设一致的结果将为大规模临床试验和有氧健身处方提供基础，以预防或减轻与AD相关的身体，心理和经济负担。公共卫生相关性：本初步研究的主要目的是确定患有轻度AD （AD）的非裔美国人（AA）是否可以登记并保持6个月的有氧运动训练。采用随机对照试验方法，我们将研究有氧运动训练对神经认知功能和脑葡萄糖稳态的影响。初步，我们将评估APOE多态性与有氧健身诱导的神经认知功能变化的差异关系。我们的长期目标是研究健康适应对神经认知功能产生影响的机制。尽管抗胆碱酯酶疗法大大改善了AD的对症治疗，但尚未证明它们能显著减缓疾病进展。阿尔茨海默病的高发病率和死亡率继续给家庭和美国带来巨大的经济负担。在最早出现阿尔茨海默病症状的患者中，保持智力灵巧可能会减轻与该疾病相关的身体、情感和经济负担，这是一个重要的公共卫生目标。作为抗胆碱酯酶治疗的替代或辅助手段，一种有希望的循证且相对无副作用的生活方式方法正在出现。具体来说，有氧运动训练已被证明可以改善认知功能。尽管这些研究的效应量惊人地大，结果也相当一致，但样本量很小，而且主要包括高加索人。重要的是，这种效应发生的机制还有待系统地证实。值得注意的是，有氧健身可以改善许多假定的AD危险因素，如高密度脂蛋白胆固醇（HDL-C）、炎症和小动脉硬化。然而，这些假定的危险因素的改善尚未被探索作为有氧训练改善人类认知功能的潜在机制。鉴于AAs: i) AD的发病率和患病率高于白种人，ii)缺乏横断面研究，缺乏关于运动对认知功能有益作用的前瞻性数据；iii)与白种人相比，他们更久坐不动，数据显示运动对白种人有益，因此有空间通过运动来改善风险；对老年AAs患者进行运动和认知的随机对照试验是必要的。

DESCRIPTION (provided by applicant): The primary purpose of this pilot study is to determine whether African Americans (AA) with mild AD (AD) can be enrolled and retained in a 6-month aerobic exercise-training study. Using a randomized controlled trial approach, we will examine the effects of aerobic exercise-training on neurocognitive function, and on cerebral glucose homeostasis. It is yet to be determined whether AAs with mild AD can be recruited into such a study, nor has the relationship of fitness adaptation to neurocognitive function been systematically examined in this population. In addition to the goal of assessing the intervention effects, we will evaluate the differential relationships of APOE to aerobic fitness-induced changes in neurocognition. Our long-term goal is to explore the mechanism by which fitness adaptation exerts an effect on neurocognition -- Notably, low levels of high-density lipoprotein cholesterol (HDL-C), elevated inflammation (C-reactive protein (CRP) and interleukins (IL-1A)), deranged glucose homeostasis, hypertension and endothelia dysfunction are precursors of arteriolosclerosis, decreased cerebral perfusion and oxygen deprivation, all of which may increase AD risk. Because many of these putative AD risk factors are susceptible to lifestyle alterations, we will also assess their roles in aerobic fitness-related improvements in cognitive function and reduction in AD risk. A team of highly successful experts in neuroimaging, neurology, psychology, exercise physiology, cardiology and genetics has been assembled to conduct this study. After obtaining informed consent, participants will undergo initial exercise screening to determine their ability to exercise safely. Following randomization of 112 participants into intervention (n=56) and control (n=56) groups, baseline neuropsychological, neuroimaging and biomarker evaluations will be performed. The intervention group will undergo 3 times/week supervised aerobic exercise-training, while the control group undergoes stretch exercise 3 times/week. At the completion of a 6-month aerobic exercise-training by the intervention group, all baseline tests will be repeated in both the intervention and control groups. Between groups cognitive performance will be compared using appropriate multivariate methods. This proposed work has the potential to add a practical effective strategy to delay progression of AD in populations at most risk. Results consistent with our hypotheses will form the basis for large-scale clinical trials, and the prescription of aerobic fitness to prevent or attenuate the physical, psychological and the economic burden associated with AD. PUBLIC HEALTH RELEVANCE: The primary purpose of this pilot study is to determine whether African Americans (AA) with mild AD (AD) can be enrolled and retained in a 6-month aerobic exercise-training. Using a randomized controlled trial approach, we will examine the effects of aerobic exercise-training on neurocognitive function, and on cerebral glucose homeostasis. Preliminarily, we will evaluate the differential relationships of APOE polymorphism to aerobic fitness-induced changes in neurocognitive function. Our long-term goal is to examine the mechanisms by which fitness adaptation exert an effect on neurocognitive function. Although anticholinesterase therapies have greatly improved symptomatic treatment of AD, they have not been demonstrated to significantly slow disease progression. Excess morbidity and mortality from AD continue to generate an enormous economic burden on families and on the United States. Preservation of intellectual dexterity among those showing earliest symptoms of AD may ameliorate the physical, emotional, and economic burden associated with the disease, and that, is an important public health goal. A promising evidence-based and relatively side-effect free lifestyle approach is emerging as an alternative or adjunct to anticholinesterase therapy. Specifically, aerobic exercise-training has been demonstrated to improve cognitive function. Though, the effect size for these studies is surprisingly large, and the results fairly consistent, however, the sample sizes were small and included mostly Caucasians. Importantly, the mechanism by which an effect occurs is yet to be systematically substantiated. Remarkably, aerobic fitness can improve many of the putative AD risk factors such as high-density lipoprotein cholesterol (HDL-C), inflammation, and arteriolosclerosis. However, improvements in these putative risk factors have not been explored as potential mechanisms by which aerobic training improves cognitive function in humans. Given that AAs: i) have higher incidence and prevalence of AD than Caucasians, ii) have paucity of cross-sectional, and lack prospective data on the beneficial effect of exercise on cognitive function; iii) are more sedentary relative to Caucasians, in whom data show the beneficial effect of exercise, and therefore have room for exercise-induced improvements in risk; a randomized controlled trial of exercise and cognition in older AAs is imperative.