Energy Reserves, Physical Activity, and Alzheimer's Disease in the Baltimore Longitudinal Study of Aging

项目摘要 阿尔茨海默病（AD）是痴呆症最常见的原因。潜在的病理和生理 据信，与AD的发作和进展相关的变化在临床治疗前几年出现。 表现。步态异常和运动减慢通常在AD诊断之前十年或更长时间。 更重要的是，提出了令人兴奋的可能性，即步态的变化可能作为AD的早期非侵入性生物标志物。 我们小组以前的工作已经确定了即将和/或加速步态速度下降的关键标志 基于慢走的能量消耗、峰值能量容量和数量的生理测量， 客观测量的自由生活体力活动（PA）模式，使其成为潜在的临床前标志物， 早期AD病理学我们建议使用8年的现有纵向数据和正在进行的/新的数据收集 在巴尔的摩老龄化纵向研究（BLSA）的近1,000名老年人中， 改变能量储备，减少和分散的日常PA作为阿尔茨海默氏症临床标志物的前体 疾病和神经元损伤，包括使用[11 C]-匹兹堡化合物B正电子发射的Aβ沉积 断层扫描、使用结构磁共振成像（MRI）的脑萎缩和认知表现。我们 还将探索将能量储备和PA与这些结果联系起来的潜在血管机制，包括 脑血流量、踝臂指数和脉搏波速度，以及介导或调节的作用 炎症和载脂蛋白E基因型等因素。BLSA是一个连续入组的队列 已经包含认知的重复测量和认知状态的判定的衰老研究， 其中一个子集完成重复的MRI和PiB PET扫描。重要的是，我们的初步横截面数据 来自BLSA的研究表明，能量储备、认知能力、b-淀粉样蛋白负担 以及PA的日变化规律。我们建议调查这些之间的纵向关联 变量，以确定能量储备差的生理阈值，以及减少和碎片化的 昼夜PA作为AD病理学发作和进展的早期前兆。更好地理解 能量储备/PA、亚临床AD病理学和认知能力之间的关联可能阐明 能量储备减少的生理阈值，与认知能力差的风险增加有关。 随着时间的推移，结果，并增加我们对身体下降之间的复杂关联的理解， 和认知功能。此外，揭示日常自由生活的模式PA最常见的 与此阈值相关的一个表型将有助于定义减少和/或片段化PA的表型， AD的出现和进展。考虑到可穿戴设备的扩散，以监测PA在 消费者和研究市场，确定与AD病理学发展一致的PA变化 可以为未来大规模筛查早期发现AD高危人群提供证据。

PROJECT SUMMARY Alzheimer’s disease (AD) is the most common cause of dementia. Underlying pathological and physiological changes related to the onset and progression of AD are believed to emerge several years prior to clinical manifestations. Gait abnormalities and motor slowing typically precede the diagnosis of AD by a decade or more, presenting the exciting possibility that changes in gait may act as early noninvasive biomarkers for AD. Previous work by our group has identified key markers of impending and/or accelerated gait speed decline based on physiological measures of the energy cost of slow walking, peak energy capacity, and quantities and patterns of objectively measured free-living physical activity (PA), making them potential preclinical markers of early AD pathology. We propose to use 8 years of existing longitudinal data, and ongoing/new data collection in nearly 1,000 older adults in the Baltimore Longitudinal Study of Aging (BLSA), to examine the roles of altered energy reserves, and reduced and fragmented daily PA as precursors to clinical markers of Alzheimer’s disease and neuronal injury, which include Aβ deposition using [11C]-Pittsburgh compound B positron emission tomography, brain atrophy using structural magnetic resonance imaging (MRI), and cognitive performance. We will also explore potential vascular mechanisms linking energy reserves and PA to these outcomes, including cerebral blood flow, ankle brachial index, and pulse wave velocity, as well as the role of mediating or modifying factors such as inflammation and the apolipoprotein E genotype. The BLSA is a continuously enrolled cohort study of aging that already contains repeated measures of cognition and adjudication of cognitive status, in which a subset completes repeated MRI and PiB PET scans. Importantly, our preliminary cross-sectional data from the BLSA indicate strong associations among energy reserves, cognitive performance, b-amyloid burden, and diurnal patterns of daily PA. We propose to investigate the longitudinal associations among these variables to identify physiological thresholds of poor energy reserve and reduced and fragmented patterns of diurnal PA as early precursors to the onset and progression of AD pathology. A better understanding of the association between energy reserves/PA, subclinical AD pathology, and cognitive performance may elucidate a physiological threshold of diminished energy reserve that is associated with increased risk of poor cognitive outcomes over time, and increase our understanding of the complex association between declines in physical and cognitive functioning with age. Moreover, uncovering patterns of daily free-living PA most commonly associated with this threshold will help define a phenotype of reduced and/or fragmented PA that signifies impending emergence and progression of AD. Given the proliferation of wearable devices to monitor PA in the consumer and research markets, identifying changes in PA consistent with the development of AD pathology could provide evidence for future wide-scale screening for early detection of persons at high risk of AD.