Impact of sleep apnea and its treatment on memory and tau accumulation in the brain

项目摘要 阿尔茨海默病(AD)是最常见的神经退行性疾病，其特征是 Tau缠结和淀粉样斑块的堆积。目前的共识是AD的病理过程开始了 在出现明显的临床症状之前几十年。新出现的证据表明，睡眠障碍可能是一种 在导致阿尔茨海默病的早期认知退化以及淀粉样蛋白和tau的代谢中都是重要的因素。 阻塞性睡眠呼吸暂停(OSA)是美国最常见的睡眠障碍，估计患病率为 在认知正常的老年人中有40%-50%。我们之前已经表明，OSA的严重程度与 大脑淀粉样蛋白负荷的纵向增加，但OSA对tau及其受体的长期影响知之甚少。 过度磷酸化是缠结形成的关键步骤，以及OSA对空间分布的影响 导航记忆，可能是AD影响的最早的记忆形式。我们的初步横截面 数据表明，OSA严重程度越高，总tau(T-tau)和磷酸化水平越高 脑脊液中的tau(P-tau)和空间导航记忆的夜间加工能力较差。 认知正常的老年人。此外，自我报告的OSA的存在与更大的纵向 脑脊液T-tau和P-tau在3年内升高。尽管这些观察表明阻塞性睡眠呼吸暂停综合征与异常记忆有关 在大脑中处理和调节tau，OSA在这些过程中的因果作用将被加强 其他分析。通过测量空间编码和处理的行为读数 导航记忆，并通过添加tau PET通过精确的解剖分辨率来量化大脑tau负荷 60名无症状、认知正常的老年人在基线和2.5年后的脑成像 广泛的阻塞性睡眠呼吸暂停严重程度，他们已经接受多导睡眠图(PSG)、动作图和 结构脑MRI作为R01AG056031的一部分，我们可以测试隔夜空间加工的预期 记忆力纵向下降(目标1)，而大脑tau负担纵向增加(目标2) 这取决于测量的OSA严重程度。OSA在tau代谢中的作用也将是 通过正压(PAP)治疗阻塞性睡眠呼吸暂停综合征(OSA)得到加强。而脑脊液Aβ42水平可在 根据睡眠状况的不同，脑脊液tau水平可能会在几周内发生变化。 因此，我们的目标是在治疗前和8周后检测脑脊液中的T-tau和P-tau，以及血浆中的T-tau 在80名认知正常的老年阻塞性睡眠呼吸暂停伴主观嗜睡患者中，开出了PAP治疗 第一次来到西奈山综合睡眠中心(MSISC)。令人满意的PAP依从性通常发生在 50%的患者在MSISC，我们将通过从用户机器上下载来监测依从性。 测量脑脊液和血浆tau作为PAP粘附性的函数是目标3的基础。

Project Summary Alzheimer's disease (AD) is the most common neurodegenerative disease and is characterized by the accumulation of tau tangles and amyloid plaques. Current consensus is that the AD pathological process begins decades before overt clinical symptoms occur. Emerging evidence suggests that sleep disruption may be an important factor in both early cognitive deterioration leading to AD and in the metabolism of amyloid and tau. Obstructive sleep apnea (OSA) is the most common sleep disorder in the US with an estimated prevalence of 40-50% in the cognitively normal elderly. We have previously shown that OSA severity is associated with longitudinal increase in brain amyloid load, but less is known about the long-term effects of OSA on tau and its hyperphosphorylation, a crucial step in the formation of tangles, as well as the effects of OSA on spatial navigational memory, perhaps the earliest form of memory affected in AD. Our preliminary cross-sectional data suggest that higher OSA severity is associated with higher levels of total tau (T-tau) and phosphorylated tau (P-tau) in the cerebrospinal fluid (CSF) and poorer overnight processing of spatial navigational memory in cognitively normal elderly. Further, self-reported presence of OSA is associated with greater longitudinal increase in CSF T-tau and P-tau over 3 years. Although these observations implicate OSA in aberrant memory processing and regulation of tau in the brain, a causal role for OSA in these processes would be strengthened by additional analyses. By measuring behavioral readouts of both the encoding and processing of spatial navigation memory, and quantifying brain tau burden with precise anatomical resolution by adding tau PET brain imaging at baseline and 2.5 years later in 60 asymptomatic, cognitively normal older individuals with a wide range of OSA severity who are already being followed with polysomnography (PSG), actigraphy, and structural brain MRI as part of R01AG056031, we can test the expectations that overnight processing of spatial memory declines longitudinally (Aim 1) and that brain tau burden increases longitudinally (Aim 2) in a way that is dependent on measured OSA severity. A role for OSA in the metabolism of tau also would be strengthened by treating OSA with positive airway pressure (PAP). Whereas CSF Aβ42 levels can change in a matter of hours depending on sleep condition, CSF tau levels are thought to change over several weeks. Therefore, we aim to examine T-tau and P-tau in CSF and T-tau in plasma prior to treatment and 8 weeks later in 80 cognitively normal older individuals with OSA and subjective sleepiness prescribed PAP treatment for the first time at the Mount Sinai Integrative Sleep Center (MSISC). Satisfactory PAP adherence occurs in typically 50% of patients at the MSISC, and we will monitor adherence through downloads from users' machines. Measuring CSF and plasma tau as a function of PAP adherence serves as the basis for Aim 3.