Role of Sleep Apnea in Cognition and Alzheimer's Disease Biomarkers in WTC Responders

项目摘要 认知功能减退是阿尔茨海默病(AD)的标志，是测量淀粉样β蛋白(Aβ)或 Tau负荷越来越多地被用来在认知能力出现之前识别早期(临床前)AD风险 减损。睡眠障碍在阿尔茨海默病、轻度认知障碍以及正常老年人中也很常见 Aβ阳性生物标志物。这表明：i)睡眠障碍会导致阿尔茨海默病(AD)神经变性(即睡眠 阻塞性睡眠呼吸暂停(OSA)等障碍是AD的可改变的危险因素)；或，ii)睡眠 对Aβ和神经原纤维缠绕病理特别敏感(即睡眠障碍是 广告)，影响生活质量。我们公布的数据显示，认知正常的老年人OSA严重程度增加 受试者与增加的Aβ负担有关。我们的初步数据还显示，OSA与 脑脊液(CSF)tau升高，这一发现可能与认知能力下降有更强的联系。我们有 最近证实，新发OSA在世贸中心(WTC)粉尘中的患病率增加(75%)。 暴露的受试者(即应答者)与一般人群相比。世界旅游中心的应答者队伍正在老化， 有证据表明，与年龄匹配的人相比，早期认知障碍和认知衰退的发生率较高。 规范。这一队列是独一无二的，因为它的阻塞性睡眠呼吸暂停的高患病率，关于存在和 阻塞性睡眠呼吸暂停持续时间以及其他与AD相关的风险因素的信息，如抑郁和后抑郁 创伤应激障碍(PTSD)，并提供了一个独特的机会来评估睡眠与 干扰，AD风险和认知的生物标记物。本提案的目的是审查其影响 WTC患者阻塞性睡眠呼吸暂停严重程度与睡眠对AD血浆生物标志物、tau负荷和认知的影响 使用新的方法，调整潜在的混杂因素。目标1将检查以下方面的纵向变化 受试者合并和不合并阻塞性睡眠呼吸暂停综合征患者的血浆tau和tau负荷 用PET-MR成像与(I)血浆tau的变化和(Ii)较大的纵向tau负荷相关 使用18F-PI2620。目标2将使用视觉空间记忆来研究阻塞性睡眠呼吸暂停和认知之间的关系 测试(3D-迷宫)和细微认知障碍测试(SCIT)；这两种测试对睡眠中断都很敏感 在标准神经心理测试中认知正常或轻微受损的受试者。我们将测试 假设OSA在基线时的严重程度预测空间导航记忆的纵向下降和 斯希特。OSA、AD生物标记物与认知功能障碍之间关系的证明提示 AD的风险因素可以非侵入性地评估(例如，通过迷宫/SCIT或通过发现OSA或睡眠特异性 生物标志物)。这些数据将指导未来针对睡眠障碍的干预性研究(例如 OSA，增加睡眠时间)和结果(例如，认知改善)，并以改善为长期目标 世界旅游中心响应者队列中的生活质量和健康结果。

Project Summary Cognitive decline is the hallmark of Alzheimer’s disease (AD) and biomarkers to measure amyloid beta (Aβ) or tau burden are increasingly being used to identify early (pre-clinical) AD risk prior to emergence of cognitive impairment. Disturbances of sleep are common in AD, mild cognitive impairment and also in normal elderly with Aβ positive biomarkers. This suggests that: i) disturbed sleep contributes to AD-neurodegeneration (i.e. sleep disturbances such as from obstructive sleep apnea (OSA) are modifiable risk factors for AD); or, ii) sleep is particularly sensitive to Aβ and neurofibrillary tangle pathology (i.e. sleep disturbance is an early biomarker of AD), impacting quality of life. Our published data show that increased OSA severity in cognitively normal older subjects is associated with increased Aβ burden. Our preliminary data also show that OSA is associated with elevated cerebrospinal fluid (CSF) tau, a finding that may have a stronger link to cognitive decline. We have recently confirmed an increased prevalence (75%) of new-onset OSA in World Trade Center (WTC) dust- exposed subjects (i.e. responders) compared to the general population. The WTC responder cohort is aging and there is evidence of early cognitive impairment and high incidence of cognitive decline compared to age matched norms. This cohort is unique for its high prevalence of OSA, the availability of longitudinal data on presence and duration of OSA as well as information on other relevant risk factors for AD such as depression and post- traumatic stress disorder (PTSD), and provides a unique opportunity to evaluate the relationship between sleep disruption, biomarkers for AD risk and cognition. The purpose of the present proposal is to examine the impact of OSA severity and sleep related changes on AD plasma biomarkers, tau burden and cognition in WTC subjects using novel methodology and adjusting for potential confounders. Aim 1 will examine longitudinal changes in plasma tau and tau burden in 64 subjects with and without OSA to test the hypothesis that OSA severity is correlated with (i) changes in plasma tau and (ii) with greater longitudinal tau burden using PET-MR imaging using 18F-PI2620. Aim 2 will examine the relationship between OSA and cognition using a visual-spatial memory test (3D-maze) and the subtle cognitive impairment test (SCIT); both tests are sensitive to sleep disruption in subjects who are cognitively normal or minimally impaired by standard neuropsychological testing. We will test the hypothesis that OSA severity at baseline predicts longitudinal decline in spatial navigational memory and SCIT. Demonstration of a relationship between OSA, AD biomarkers and cognitive impairment suggests specific risk factors for AD might be assessed non-invasively (e.g. by maze/SCIT or by finding OSA or sleep specific biomarkers). These data will guide future interventional studies targeting sleep disruption (e.g. treatment of OSA, increase sleep duration) and outcomes (e.g. improvement in cognition) with the long-term goal of improving the quality of life and health outcomes in the WTC responder cohort.