Genes, Exercise, Neurocognitive and Neurodegeneration: Community-Based Approach

描述（由申请人提供）：尽管抗胆碱酯酶疗法极大地改善了阿尔茨海默病（AD）的对症治疗，但尚未证明它们能显著减缓疾病进展；淀粉样蛋白定向治疗的结果令人失望。一种有希望的循证且相对无副作用的生活方式方法正在成为药物治疗的替代或辅助方法。在横断面和前瞻性研究中，以及一些随机对照试验中；有氧运动训练已被证明可以改善老年人的认知能力。然而，这些影响的机制仍然知之甚少。由于现在认识到心血管疾病（CVD）风险可以催化AD的发展，因此测试显示降低CVD风险的生活方式适应是否有利于改变认知轨迹和神经变性标志物是至关重要的。这些干预措施可能有利于那些早期和临床可识别的阿尔茨海默病前驱阶段，如轻度认知障碍（MCI）。值得注意的是，目前缺乏此类数据的非裔美国人（AA），他们有较高的心血管疾病风险和AD。10年来，首席研究员一直在研究健身适应对心血管（CV）健康的影响。最近，他获得了2年的资助，在实验室环境下研究每周3次、为期6个月的有氧运动训练对认知的影响。这项正在进行的研究使首席研究员能够在主要的AA样本中展示招募、注册、测试、收集和管理相关神经影像学试点数据的能力。虽然需要这种实验室方法来证明运动干预研究的因果关系，但这种设计可能不适合实际应用，并且需要许多经济和教育上处于不利地位的老年AAs经历早期认知衰退症状。为了合理地扩展这项正在进行的工作，他试图启动一项为期18个月的研究，在一个更理想的社区环境中测试运动适应对记忆的影响在现实生活中的适用性。收集基线、3个月、6个月、9个月、12个月和18个月的结果测量值将提供试点数据，以告知运动剂量和持续时间对结果测量的影响。除了增加入学人数外，拟议的方法还将提高学生的保留率。因此，本初步研究的目的是检验基于社区的18个月研究（6个月主动干预和12个月被动随访）有氧运动训练对AAs MCI受试者神经退行性变的可行性。我们将通过将受试者随机分为两组来检验我们的假设：1.有氧运动；2)伸展运动（控制）。我们提出有氧运动组在认知测试方面的表现优于对照组。其次，我们将确定训练引起的认知变化是否与脑容量增加有关。我们还将研究干预对脑脊液（CSF）生物标志物、选定的心血管疾病危险因素和生物标志物、脑氧合和缺氧诱导因子（HIF-1α）基因表达和载脂蛋白E基因（APOE）的影响，以评估它们对训练诱导的认知变化的介导作用。一组在神经影像学、神经学、认知神经科学和运动生理学方面经验丰富的研究人员被召集起来进行这项研究。我们将与哥伦比亚特区老龄问题办公室（DCOA）、由DCOA运营的6号病房老年人健康中心主任以及老龄问题领导机构（DCOA支持的社区基层组织）合作，在该健康中心招募、招募、随机分配和培训参与者。在获得知情同意并完成初步评估后，参与者将进行初步运动筛选，以确定他们安全运动的能力。80名志愿者随机分为有氧运动组（40名）和对照组（40名）；基线神经心理学，神经影像学和生物标志物测量将获得。两组都将在健康中心接受为期6个月、每周3次的有监督的群体特定干预。在最初6个月的积极干预后，有氧运动组将遵循一个

DESCRIPTION (provided by applicant): Although anticholinesterase therapies have greatly improved the symptomatic treatment of Alzheimer's disease (AD), they have not been demonstrated to significantly slow the disease progression; and amyloid- directed therapies have produced disappointing results. A promising evidence-based and relatively side-effect free lifestyle approach is emerging as an alternative or adjunct to drug therapy. In cross-section and prospective studies, and a few randomized controlled trials; aerobic exercise-training has been demonstrated to improve cognition in older subjects. However, the mechanisms of these effects remain poorly understood. Because it is now recognized that cardiovascular disease (CVD) risks can catalyze AD development, it is vital to test whether lifestyle adaptation shown to reduce CVD risks can favorably modify cognitive trajectories and markers of neurodegeneration. Such interventions may benefit those at an early and clinically discernible prodromal stage of AD such as mild cognitive impairment (MCI). Notably, such data are currently lacking in African Americans (AA)s who harbor higher rate of CVD risks and AD. For ~10 years, the Principal Investigator has conducted studies on the effects of fitness adaptation on cardiovascular (CV) health. Recently, he received 2 years of funding to examine the effects of 3-times/week 6-month aerobic exercise-training on cognition in the laboratory setting. This ongoing study has allowed the Principal Investigator to demonstrate the ability to recruit, enroll, test, collect and manage related neuroimaging pilot data in a predominantly AA sample. While such a laboratory approach to exercise intervention study is required to prove causation, such a design may not lend itself to real-life application, and is demanding for many economically and educationally disadvantaged older AAs experiencing early symptoms of cognitive deterioration. To logically extend this ongoing work, he seeks to initiate an 18-month study, testing real-life applicability o the effects of exercise adaptation on memory in a more ideal community setting. Collection of outcome measures at baseline, 3- month, 6-month, 9-month, 12-month and 18-month will provide pilot data to inform dose and duration effects of exercise on outcome measures. In addition to augmenting enrollments, the proposed approach will bolster retention. The objectives of this pilot study, therefore, are to examine the feasibility of a community-based 18-month study (6-month active intervention and 12-month passive follow-up) aerobic exercise-training on neurodegeneration in AAs MCI subjects. We will test our hypotheses by randomizing subjects into one of 2 groups: 1.) aerobic-exercise; and 2.) stretch-exercise (control). We proposed that the aerobic-exercise group will perform better than control group on cognitive measures. Secondarily, we will determine whether training- induced changes in cognition relate to increases in brain volume. Explanatorily, we will also investigate intervention effects on cerebrospinal fluid (CSF) biomarkers, selected CVD risk factors and biomarkers, cerebral oxygenation and Hypoxia-Inducible Factors (HIF-1α) gene expression, and Apolipoprotein E gene (APOE), to assess their mediation of training-induced changes in cognition. A team of experienced investigators in neuroimaging, neurology, cognitive neuroscience, and exercise physiology has been assembled to conduct this study. Working collaboratively with the District of Columbia Office on Aging (DCOA), the Directors of the Ward 6 Senior Wellness Center operated by DCOA, and the lead agencies on aging (community grassroots organizations supported by DCOA), we will recruit, enroll, randomize, and train participants at the wellness center. After obtaining informed consent and completing an initial assessment, participants will undergo initial exercise screening to determine their ability to exercise safely. Following randomization of 80 volunteers into aerobic-exercise (40) and control (40); baseline neuropsychological, neuroimaging and biomarker measurements will be obtained. Both groups will undergo 3 times/week supervised group-specific intervention at the wellness center for 6 months. After the initial 6 months of active intervention, the aerobic-exercise group will follow a prescribed but free living 40 minutes, 3 time/week exercise regimen, while the control group returns to usual care. Baseline tests will be repeated at 3 month, after 6 months (active intervention period); and at 9, 12 and 18 months (passive follow-up period). Treadmill, lumber puncture (LP) and brain magnetic resonance imaging (MRI) tests will occur only at baseline and 6 months. Between groups changes in cognitive performance, biomarkers, and neuroimaging measurements will be compared using appropriate multivariate methods. While we remain cognizant of other planned or ongoing fitness and memory trial, the proposed study is unique in the sense that: it is a logical extension of our ongoing work; tests the proposed hypotheses in predominantly AA sample in whom paucity of data remains, and therefore, will advance reduction in health disparity; will obtain data at multiple time-points (baseline, 3, 6, 9, 12 and 8 months) and therefore allow for the assessments of the effects of duration and dose of intervention on outcome measures; test the real-life applicability of the proposed intervention in a community setting; and generate pilot data on the mechanisms by which these interventions affects memory. Importantly, outcomes from this study may lead to practical and effective strategy to delay cognitive decline in populations at most risk, and can prevent or attenuate the physical, psychological and the economic burden associated with dementia in AAs.