Longitudinal Investigation of Cardiorespiratory Fitness and AD Biomarkers in an At-Risk Cohort

高危人群心肺健康和 AD 生物标志物的纵向调查

• 批准号: 10064984
• 负责人: OZIOMA C OKONKWO
• 金额: $ 93.14万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-15 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10064984
• 关键词: Abate; Accelerometer; Address; Adult; Aerobic Exercise; Aging; Alzheimer disease prevention; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease risk; Alzheimer' s disease therapy; Alzheimer’s disease biomarker; Amyloid beta-Protein; Attention; Attenuated; Biological Markers; Blood Vessels; Cerebrovascular Circulation; Clinical; Clinical Trials; Cognition; Cognitive; Cohort Studies; Conflict (Psychology); Data; Dementia; Dependence; Disease; Elderly; Enrollment; Epidemic; Etiology; Evaluation; Exercise Test; Failure; Family; Financial compensation; Functional disorder; Future; Gap Junctions; Genetic Risk; Goals; Hippocampus (Brain); Human; Individual; Investigation; Knowledge; Link; Magnetic Resonance Imaging; Measures; Mediating; Nerve Degeneration; Participant; Pathogenicity; Patient Self-Report; Peripheral; Persons; Pharmacotherapy; Phenotype; Physical activity; Physiological; Play; Positioning Attribute; Positron-Emission Tomography; Public Health; Recording of previous events; Registries; Research; Resources; Risk; Role; Seminal; Spinal Puncture; Sum; Symptoms; Target Populations; Testing; Therapeutic; Transducers; Wisconsin; Work; abeta deposition; active lifestyle; age related; animal data; arterial stiffness; baby boomer; brain volume; cardiorespiratory fitness; cohort; effective therapy; epidemiology study; glucose metabolism; hippocampal atrophy; insight; insulin sensitivity; longitudinal design; middle age; mild cognitive impairment; multimodality; neuroprotection; novel; prevent; prospective; resilience; sex; tau Proteins; tau phosphorylation; β-amyloid burden

PROJECT SUMMARY/ABSTRACT Currently-available drug treatments for Alzheimer's disease (AD) are not curative. Furthermore, findings from clinical trials testing novel disease-modifying therapeutics have been disappointing. Accordingly, the urgency of alternative approaches for halting the global crisis posed by AD cannot be overstated. Although data from cohort and epidemiological studies have long suggested a strong link between physical activity and dementia due to AD, the question of whether physical activity modulates the underlying pathophysiology of AD has only recently begun receiving attention. While the emerging evidence appears overall supportive of such a role for physical activity, several critical knowledge gaps persist. First, past studies have been largely cross-sectional. This leaves unresolved the possibility that observed effects simply reflect reverse causation. Second, “physical activity” has been assessed via a variety of approaches including self-report, activity trackers, and maximal graded exercise testing, leading to conflicting findings. Third, because past research has primarily been done in elderly persons, little is known about the potential influence of physical activity on AD risk in midlife, when most AD-related changes begin. Lastly, there is need for a better understanding of the mechanisms by which physical activity exerts its salutary effects. To address these gaps in knowledge (1) we focus this project on cardiorespiratory fitness (CRF), which constitutes the physiological nexus for *habitual* physical activity, (2) we employ a longitudinal design, which would allow us rigorously exclude the possibility of reverse causation, (3) we study a cohort of late-middle-aged adults who are, in principle, potentially only at the inceptive stages of AD, and (4) we investigate vascular and glucoregulatory function as viable transducers of the link between CRF and AD pathophysiology. Importantly, because the participants targeted for this study are being followed longitudinally through the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center, we will be uniquely positioned in the long term to elucidate the impact of midlife CRF on clinical endpoints of mild cognitive impairment and dementia. In sum, the multimodal and integrative study proposed here stands to provide critical insights into CRF as a potentially viable therapeutic for altering disease trajectory in the early stages of AD, prior to pervasive neurodegeneration, thereby delaying the emergence of clinical symptoms.

项目概要/摘要 此外，目前针对阿尔茨海默病（AD）的药物治疗并不能治愈。 测试新的疾病缓解疗法的临床试验令人失望，因此，迫切需要解决这一问题。 尽管数据显示，阻止 AD 造成的全球危机的替代方法不容小觑。 队列和流行病学研究长期以来表明体力活动与痴呆症之间存在密切联系 由于 AD，体力活动是否调节 AD 的潜在病理生理学的问题只有 最近开始受到关注，而新出现的证据似乎总体上支持这种作用。 首先，过去的研究主要是横断面的。 这就留下了一个悬而未决的可能性，即观察到的效应只是反映了反向因果关系。 “活动”通过多种方法进行评估，包括自我报告、活动跟踪器和最大 分级运动测试，导致相互矛盾的结果第三，因为过去的研究主要是完成的。 在老年人中，人们对体力活动对中年 AD 风险的潜在影响知之甚少。 最后，需要更好地理解与 AD 相关的变化的机制。 为了解决这些知识差距（1），我们将这个项目的重点放在身体活动上。 心肺健康 (CRF)，构成*习惯性*身体活动的生理联系，(2) 我们采用纵向设计，这将使我们能够严格排除反向因果关系的可能性， (3) 我们研究了一组中年晚期成年人，原则上，他们可能只处于早期阶段 AD，(4)我们研究血管和葡萄糖调节功能作为可行的传感器之间的联系 重要的是，CRF 和 AD 病理生理学，因为本研究的目标参与者正在被跟踪。 纵向通过威斯康星州阿尔茨海默氏症预防登记处和威斯康星州阿尔茨海默氏症 疾病研究中心，从长远来看，我们将处于独特的地位来阐明中年的影响 CRF 对轻度认知障碍和痴呆的临床终点总而言之，多模式和综合性。 这里提出的研究将为 CRF 作为一种潜在可行的治疗方法提供重要见解 AD 早期阶段的疾病轨迹，在普遍的神经变性之前，从而延迟了 出现临床症状。