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

睡眠呼吸暂停在 WTC 应急人员认知和阿尔茨海默病生物标志物中的作用

• 批准号: 10314853
• 负责人: INDU A AYAPPA
• 金额: $ 59.38万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10314853
• 关键词: Role; Sleep; Apnea; Cognition; Alzheimer

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.

项目摘要 认知能力下降是阿尔茨海默病（AD）的标志，也是测量淀粉样蛋白β（Aβ）或 tau蛋白负荷越来越多地用于在认知障碍出现之前识别早期（临床前）AD风险 损伤睡眠障碍常见于AD、轻度认知障碍以及患有抑郁症的正常老年人。 Aβ阳性生物标志物。这表明：i）睡眠紊乱有助于AD神经变性（即睡眠障碍）， 障碍，如阻塞性睡眠呼吸暂停（OSA）是AD的可改变的危险因素）;或，ii）睡眠， 对Aβ和神经系统缠结病理学特别敏感（即睡眠障碍是A β的早期生物标志物， AD），影响生活质量。我们发表的数据显示，认知正常的老年人中， 受试者与Aβ负荷增加相关。我们的初步数据还显示，OSA与以下因素有关： 脑脊液（CSF）tau蛋白升高，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，世界贸易中心（WTC）灰尘中新发OSA的患病率增加（75%）- 与一般人群相比，暴露受试者（即应答者）。WTC响应者队列正在老化， 有证据表明，与年龄匹配的人相比， 规范高效该队列的独特之处在于其OSA的高患病率，关于存在和发展的纵向数据的可用性， OSA的持续时间以及关于AD的其他相关风险因素的信息，如抑郁症和 创伤后应激障碍（PTSD），并提供了一个独特的机会，以评估睡眠之间的关系， 干扰、AD风险和认知的生物标志物。本提案的目的是审查 OSA严重程度和睡眠相关变化对AD血浆生物标志物、tau蛋白负荷和WTC受试者认知的影响 使用新的方法并调整潜在的混杂因素。目标1将研究以下方面的纵向变化： 在64名患有和不患有OSA的受试者中检测血浆tau和tau负荷，以检验OSA严重程度是 与（i）血浆tau的变化和（ii）使用PET-MR成像的更大纵向tau负荷相关 使用18F-PI 2620。目的2将使用视觉-空间记忆检查OSA和认知之间的关系 测试（3D迷宫）和微妙的认知障碍测试（SCIT）;这两种测试都对睡眠中断敏感， 通过标准神经心理学测试认知正常或最低限度受损的受试者。我们将测试 假设OSA的严重程度在基线预测纵向下降的空间导航记忆， SCIT。证实OSA、AD生物标志物和认知障碍之间的关系表明， 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中断的干预性研究（例如， OSA，增加睡眠时间）和结果（例如认知改善），长期目标是改善 WTC应答者队列的生活质量和健康结果。