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

描述(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的进展；淀粉样蛋白导向疗法的结果令人失望。一种有希望的循证和相对无副作用的生活方式正在作为药物治疗的替代或辅助手段出现。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。因为现在已经认识到心血管疾病(CVD)的风险可以催化AD的发展，所以测试被证明降低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化的标志是至关重要的。这样的干预措施可能使那些处于AD早期和临床可辨别的前驱阶段的人受益，例如轻度认知障碍(MCI)。值得注意的是，目前在非裔美国人S(AA)中缺乏这样的数据，他们有较高的心血管疾病风险和AD风险。近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，他获得了两年的资助，在实验室环境下检查每周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调查员能够在以AA为主的样本中展示招募、登记、测试、收集和管理相关神经成像试点数据的能力。虽然这种运动干预研究的实验室方法需要证明因果关系，但这样的设计可能不适合现实生活中的应用，而且对许多在经济和教育上处于不利地位的老年AA来说要求很高，因为他们经历了认知能力下降的早期症状。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，测试在更理想的社区环境中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个月的结果指标将提供试点数据，以告知锻炼对结果指标的剂量和持续时间的影响。除了增加招生人数外，拟议的方法还将促进留住学生。因此，这项先导性研究的目的是探讨一项为期18个月的社区研究(6个月的主动干预和12个月的被动随访)有氧运动训练对AAS MCI受试者神经变性的可行性。我们将通过将受试者随机分成两组来检验我们的假设：1)有氧运动；和2.伸展运动(对照组)。我们认为有氧运动组在认知测验上的表现要好于对照组。其次，我们将确定训练引起的认知变化是否与大脑体积的增加有关。作为解释，我们还将研究对脑脊液生物标记物、选定的心血管危险因素和生物标记物、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)的干预作用，以评估它们对训练诱导的认知改变的中介作用。一个由神经成像、神经学、认知神经科学和运动生理学方面的经验丰富的研究人员组成的团队已经聚集在一起进行这项研究。我们将与哥伦比亚特区老龄办公室(DCOA)、由DCOA运营的第六区老年健康中心主任以及老龄牵头机构(由DCOA支持的社区草根组织)合作，在健康中心招募、登记、随机选择和培训参与者。在获得知情同意并完成初步评估后，参与者将接受初步运动筛查，以确定他们安全运动的能力。在将80名志愿者随机分为有氧运动组(40人)和对照组(40人)后，将获得基线神经心理、神经成像和生物标记物测量。两组都将在健康中心接受为期6个月的3次/周监督小组特定干预。经过最初6个月的积极干预，有氧运动组将遵循 规定自由生活40分钟，每周3次锻炼方案，对照组恢复正常护理。在3个月、6个月后(主动干预期)、9、12和18个月(被动随访期)重复基线测试。只有在基线和6个月时才会进行跑步机、腰椎穿刺术(LP)和脑磁共振成像(MRI)测试。组间认知表现、生物标记物和神经影像测量的变化将使用适当的多变量方法进行比较。虽然我们仍然认识到其他计划中的或正在进行的健康与记忆试验，但拟议的研究在以下方面是独特的：它是我们正在进行的工作的逻辑延伸；在以AA为主的样本中测试拟议的假设，在这些样本中数据仍然缺乏，因此将推动缩小健康差距；将在多个时间点(基线、3、6、9、12和8个月)获得数据，从而能够评估干预持续时间和剂量对结果衡量的影响；测试拟议的干预措施在社区环境中的现实适用性；以及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导致实际和有效的策略，以延缓最高风险人群的认知能力下降，并可以预防或减轻与痴呆相关的身体、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.