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氏病（AD）的对症治疗，但尚未证明其显著减缓疾病进展;淀粉样蛋白定向疗法产生了令人失望的结果.一种有前途的循证和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。因为现在人们认识到心血管疾病（CVD）风险可以催化AD的发展，所以测试降低CVD风险的生活方式适应是否可以有利地改变认知轨迹和神经退行性疾病的标志物至关重要。这些干预措施可能有利于那些在早期和临床上可辨别的前驱阶段的AD，如轻度认知障碍（MCI）。值得注意的是，这些数据目前缺乏非洲裔美国人（AA）谁拥有较高的心血管疾病风险和AD率。大约10年来，主要研究者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年的资金，以研究在实验室环境中每周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主要研究者能够证明在主要AA样本中招募、入组、检测、收集和管理相关神经影像学初步数据的能力。虽然这种实验室的方法来运动干预研究需要证明因果关系，这样的设计可能不适合现实生活中的应用，并要求许多经济和教育上处于不利地位的老年AA经历早期症状的认知恶化。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的现实适用性。收集基线、3个月、6个月、9个月、12个月和18个月时的结局指标将提供初步数据，以了解运动对结局指标的剂量和持续时间影响。除了增加入学人数外，拟议的办法还将加强保留率。因此，这项试点研究的目的是研究以社区为基础的18个月研究（6个月的主动干预和12个月的被动随访）的可行性，有氧运动训练的神经退行性病变的AAs MCI科目。我们将通过将受试者随机分为两组来测试我们的假设：1.）有氧运动; 2.）伸展运动（对照）。我们认为有氧运动组在认知测量上的表现优于对照组。其次，我们将确定训练引起的认知变化是否与脑容量的增加有关。此外，我们还将研究对脑脊液（CSF）生物标志物、选定的CVD危险因素和生物标志物、脑氧合和缺氧诱导因子（HIF-1α）基因表达以及载脂蛋白E基因（APOE）的干预效果，以评估它们对训练诱导的认知变化的介导作用。一个由神经影像学、神经病学、认知神经科学和运动生理学方面经验丰富的研究人员组成的团队进行了这项研究。与哥伦比亚特区老龄化办公室（DCOA），由DCOA运营的病房6高级健康中心的董事，以及老龄化的领导机构（由DCOA支持的社区基层组织）合作，我们将招募，登记，随机化，并在健康中心培训参与者。在获得知情同意并完成初步评估后，参与者将接受初步运动筛查，以确定他们安全运动的能力。将80名志愿者随机分为有氧运动组（40名）和对照组（40名）;将获得基线神经心理学、神经影像学和生物标志物测量结果。两组都将在健康中心接受每周3次的监督组特定干预，为期6个月。在最初的6个月的积极干预后，有氧运动组将遵循 规定但自由生活40分钟，3次/周的运动方案，而对照组返回到常规护理。将在3个月、6个月后（主动干预期）和9、12和18个月（被动随访期）重复基线检查。仅在基线和6个月时进行跑步机、腰椎穿刺（LP）和脑磁共振成像（MRI）检查。将使用适当的多变量方法比较组间认知表现、生物标志物和神经影像学测量的变化。虽然我们仍然认识到其他计划或正在进行的健身和记忆试验，但拟议的研究在某种意义上是独特的：它是我们正在进行的工作的逻辑延伸;在数据仍然缺乏的主要AA样本中测试拟议的假设，因此，将促进健康差距的减少;将在多个时间点获得数据（基线、3、6、9、12和8个月），因此可以评估干预的持续时间和剂量对结果测量的影响;测试拟议干预在社区环境中的实际适用性;并生成关于这些干预措施影响记忆的机制的试点数据。重要的是，这项研究的结果可能会导致实际和有效的策略，以延迟最高风险人群的认知能力下降，并可以预防或减轻与老年痴呆症相关的身体，心理和经济负担。

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.