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: 10459199
• 负责人: INDU A AYAPPA
• 金额: $ 59.35万
• 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/10459199
• 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 认知下降是阿尔茨海默氏病（AD）和生物标志物的标志，以测量淀粉样蛋白β（Aβ）或 在出现在认知之前 损害。睡眠障碍在AD，轻度认知障碍中很常见，并且在正常情况下也很常见 Aβ阳性生物标志物。这表明：i）睡眠不足有助于ad神经变性（即睡眠 诸如阻塞性睡眠呼吸暂停（OSA）之类的干扰是AD的可修改风险因素）；或，ii）睡眠是 对Aβ和神经纤维缠结病理学特别敏感（即睡眠障碍是早期的生物标志物 广告），影响生活质量。我们发表的数据表明，认知正常老年人的OSA严重程度增加 受试者与Aβ负担增加有关。我们的初步数据还表明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 最近确认，世界贸易中心（WTC）尘埃中新发行的OSA的患病率增加（75％） 与一般人群相比，暴露的受试者（即响应者）。 WTC响应者队列正在衰老， 与年龄相比 规范。该队列对于OSA的高流行率是独一无二的，在存在和 OSA的持续时间以及有关AD的其他相关风险因素的信息，例如抑郁症和后 创伤性应激障碍（PTSD），并提供了一个独特的机会来评估睡眠之间的关系 破坏，广告风险和认知的生物标志物。本提案的目的是检查影响 OSA严重性和睡眠与AD等离子生物标志物，Tau Burnen和WTC受试者认知的变化有关 使用新颖的方法并调整潜在混杂因素。 AIM 1将检查纵向变化 在有或没有OSA的64名受试者中，血浆Tau和Tau Burnen测试了OSA严重程度的假设 与（i）使用PET-MR成像更大的纵向Tau Burnen的等离子体Tau和（ii）的变化相关 使用18F-PI2620。 AIM 2将使用视觉空间内存检查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）；这两种测试对睡眠中断敏感 认知正常或受到标准神经心理学测试损害的受试者。我们将测试 基线预测的OSA严重程度在空间导航记忆和 Scit。 OSA，AD生物标志物和认知障碍之间关系的演示表明了特定 AD的危险因素可能是非侵入性评估的（例如，通过迷宫/SCIT或查找OSA或睡眠特定 生物标志物）。这些数据将指导针对睡眠中断的未来介入研究（例如 OSA，增加睡眠持续时间）和结果（例如认知的改善），其长期目标是改善 WTC响应者队列中的生活质量和健康成果。