Establishing Sleep Apnea as a non-cognitive phenotype of brainstem ADRD pathologies in older adults

项目摘要 阿尔茨海默病和相关痴呆症（ADRD）和睡眠呼吸暂停是常见的衰老表型。睡眠 呼吸暂停也可能是一种AD表型，因为ADRD病理可能破坏辅助呼吸的神经回路 睡吧然而，没有研究检查是否ADRD病理在“睡眠呼吸暂停”电路与睡眠呼吸暂停。 与其他ADRD表型（如认知或移动性）一样，睡眠呼吸暂停是多维的。3键缺陷 尺寸可导致睡眠呼吸暂停：a）无法维持气道通畅，B）呼吸驱动效率低下，以及 c）由觉醒引起的异常呼吸暂停终止。在模式生物中，神经化学和空间上相互关联 不同的脑干回路控制着这些关键的维度。然而，ADRD病理在人类中的作用 睡眠呼吸暂停是未知的，因为收集CNS组织的多维睡眠呼吸暂停研究很少， ADRD分期不评估潜在回路的部位。在试点研究中，测量了3个关键方面， 使用新型传感器从社区中的老年人获得睡眠呼吸暂停表型。很少有老年人 拉什记忆和衰老项目（MAP，R 01 AG 17917）中的睡眠呼吸暂停者肥胖， 结构和重要的神经源性贡献。我们在尸检中记录了混合性ADRD病理 3个“睡眠-呼吸暂停”回路的脑干组织，分别服务于MAP睡眠成人的3个关键维度 呼吸暂停因此，测试ADRD退行性变化是否可能导致老年睡眠呼吸暂停是可行的。 这一创新的临床尸检提案将利用独特的临床，病理和生物标本 来自MAP的老年人资源，MAP是一项基于社区的大脑捐赠队列研究。本研究将（I） 使用新型传感器获得3个关键睡眠呼吸暂停维度的综合睡眠呼吸暂停表型， MRI量化有和无ADRD的老年人的上气道结构，和II）量化退行性 通过病理学标记物和细胞类型特异性染色的脑干“睡眠呼吸暂停”回路节点的变化 标记并整合这些新数据。目标1将检验人口统计学和临床预测因素 与睡眠呼吸暂停的三个关键生理维度有着不同的联系。目标2&3将测试 假设退行性变化，即ADRD病理（目的2）和亚型特异性神经元丢失（目的 3)在3个“睡眠呼吸暂停”回路中，与这些关键的睡眠呼吸暂停维度有关。目标4将测试 假设AD病理学存在于没有临床AD痴呆的老年人的“睡眠呼吸暂停”回路中， 并且这些个体中的回路ADRD病理与睡眠呼吸暂停及其关键维度相关。 表明睡眠呼吸暂停是AD的一种常见的早期非认知表型，与REM睡眠非常相似。 行为障碍是帕金森病的早期标志，将推动我们对帕金森病与精神分裂症之间关系的概念发生范式转变。 ADRD和睡眠呼吸暂停。显示睡眠呼吸暂停是AD的后果，可用于识别老年人， 老年痴呆症的风险，并促进其预防。细胞特异性数据将推动靶向药物的发现 睡眠呼吸暂停治疗老年人ADRD和睡眠呼吸暂停对目前的治疗无反应。

PROJECT SUMMARY Alzheimer’s disease and related dementias (ADRD) and sleep apnea are common aging phenotypes. Sleep apnea may also be an AD phenotype, as ADRD pathologies may disrupt neural circuits subserving breathing in sleep. Yet, no study has examined if ADRD pathologies in “sleep apnea” circuits are related to sleep apnea. Like other ADRD phenotypes such as cognition or mobility, sleep apnea is multi-dimensional. Defects in 3 key dimensions can lead to sleep apnea: a) failure to maintain airway patency, b) inefficient respiratory drive, and c) aberrant apnea termination by arousal. In model organisms, interconnected, neurochemically and spatially distinct brainstem circuits control these key dimensions. However, the role of ADRD pathologies in human sleep apnea is unknown, as multi-dimensional sleep apnea studies with collection of CNS tissues are rare, and ADRD staging does not assess sites of underlying circuits. In pilot studies, 3 key dimensions were measured to obtain sleep apnea phenotypes from older adults in the community using novel sensors. Few older adults with sleep apnea in the Rush Memory and Aging Project (MAP, R01AG17917) were obese, suggesting a minor structural and an important neurogenic contribution. We documented mixed ADRD pathologies in postmortem brainstem tissues of 3 “sleep-apnea” circuits that serve each of the 3 key dimensions in MAP adults with sleep apnea. Thus, testing if ADRD degenerative changes may lead to sleep apnea in old age is feasible. This innovative clinical-postmortem proposal will leverage unique clinical, pathological and biospecimen resources from older adults from MAP, a community-based cohort study with brain donation. This study will I) obtain comprehensive sleep apnea phenotyping of 3 key sleep apnea dimensions using a novel sensor and MRI to quantify upper airway structure in older adults with and without ADRD, and II) quantify degenerative changes in brainstem “sleep apnea” circuit nodes by staining for both pathology markers and cell type specific markers and integrate these novel data. Aim 1 will test the hypothesis that demographic and clinical predictors are differentially associated with three key physiological dimensions of sleep apnea. Aims 2&3 will test the hypotheses that degenerative changes i.e. ADRD pathologies (Aim 2) and subtype specific neuronal loss (Aim 3) within the 3 “sleep apnea” circuits are related to these key sleep apnea dimensions. Aim 4 will test the hypotheses that AD pathology is present in “sleep apnea” circuits of older adults without clinical AD dementia, and that circuit ADRD pathologies in these individuals is associated with sleep apnea and its key dimensions. Showing that sleep apnea is a common and early non-cognitive phenotype of AD, much as REM sleep behavior disorder is an early marker of PD, will drive a paradigm shift in our concept of the relation between ADRD and sleep apnea. Showing that sleep apnea is a consequence of AD may be used to identify older adults at risk of AD dementia and facilitate its prevention. Cell-specific data will drive drug discovery of targeted sleep apnea treatments for older adults with ADRD and sleep apnea unresponsive to current treatments.