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

项目总结 阿尔茨海默病(AD)是导致痴呆症的最常见原因。潜在的病理和生理 与阿尔茨海默病的发生和发展有关的变化被认为出现在临床之前的几年 表现形式。步态异常和运动减慢通常比AD的诊断早十年或 更令人兴奋的是，步态的改变可能会作为AD的早期非侵入性生物标志物。 我们小组之前的工作已经确定了步态速度即将和/或加速下降的关键标志 基于慢走的能量成本、峰值能量容量和数量的生理测量，以及 客观测量的自由生活体力活动(PA)的模式，使它们成为潜在的临床前标志物 公元早期病理学。我们建议使用8年的现有纵向数据和持续/新的数据收集 在巴尔的摩老龄化纵向研究(BLSA)的近1000名老年人中，研究了 能量储备改变、每日PA减少和碎片化可作为阿尔茨海默病临床标记物的先兆 疾病和神经元损伤，包括使用[11C]-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，以及认知能力。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、脉搏波速度及其调节或调节作用 炎症和载脂蛋白E基因等因素。BLSA是一个不断加入的队列 已经包含认知和认知状态判断的重复测量的衰老研究，在 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-淀粉样蛋白负荷、 和日PA的日变化规律。我们建议研究它们之间的纵向联系 确定能量储备不足的生理阈值和减少和碎片化的模式的变量 昼夜PA是AD病理发生和发展的早期先兆。更好地理解 能量储备/PA、亚临床阿尔茨海默病病理和认知能力之间的关系可能会阐明 与认知不良风险增加相关的能量储备减少的生理阈值 随着时间的推移，结果，并增加我们对体能下降之间的复杂联系的理解 以及随年龄增长的认知功能。此外，最常见的是揭示日常自由生活的PA的模式 与此阈值相关联将有助于定义PA减少和/或碎片化的表型 阿尔茨海默病即将出现和发展。鉴于可穿戴设备的激增，可在 消费者和研究市场，确定PA的变化与AD病理的发展一致 可为今后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.