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

项目总结 阿尔茨海默病及相关痴呆(ADRD)和睡眠呼吸暂停是常见的衰老表型。沉睡 呼吸暂停也可能是AD的一种表型，因为ADRD的病理可能会扰乱辅助呼吸的神经回路 睡吧。然而，还没有研究检查“睡眠呼吸暂停”回路中的ADRD病理是否与睡眠呼吸暂停有关。 像其他ADRD表型，如认知或活动能力，睡眠呼吸暂停是多维的。三键缺陷 尺寸可导致睡眠呼吸暂停：a)未能维持呼吸道通畅，b)呼吸驱动效率低下，以及 C)通过觉醒终止异常呼吸暂停。在模式生物中，相互联系，神经化学和空间 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，因为收集中枢神经系统组织的多维睡眠呼吸暂停研究很少见，并且 ADRD分期不评估基础赛道的位置。在先导研究中，3个关键维度被测量为 使用新型传感器从社区中的老年人那里获得睡眠呼吸暂停表型。很少有老年人患有 Rush Memory and Aging Project(MAP，R01AG17917)中的睡眠呼吸暂停患者患有肥胖症，提示为未成年人 结构和重要的神经源性贡献。我们在尸检中记录了混合的ADRD病理 3个“睡眠-呼吸暂停”回路的脑干组织，它们服务于MAP中3个关键维度中的每一个 呼吸暂停。因此，测试ADRD退行性变化是否会导致老年睡眠呼吸暂停是可行的。 这一创新的临床-尸检方案将利用独特的临床、病理和生物显微镜 来自MAP的来自老年人的资源，MAP是一项基于社区的队列研究，大脑捐赠。这项研究将I) 使用新型传感器获得3个关键睡眠呼吸暂停维度的全面睡眠呼吸暂停表型 MRI对患有和不患有ADRD的老年人上呼吸道结构进行量化，以及ii)量化退行性变 病理标记物和细胞类型特异性染色显示脑干“睡眠呼吸暂停”回路结节的变化 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的假设 与睡眠呼吸暂停的三个关键生理维度存在差异。AIMS 2和3将测试 退行性改变即ADRD病理(AIM 2)和亚型特异性神经元丢失(AIM)的假说 3)在3个“睡眠呼吸暂停”回路中，与睡眠呼吸暂停的这些关键维度有关。目标4将测试 假设AD病理存在于无临床AD痴呆的老年人的“睡眠呼吸暂停”回路中， 而这些人的回路ADRD病理与睡眠呼吸暂停及其关键维度有关。 显示睡眠呼吸暂停是AD的一种常见的早期非认知表型，就像REM睡眠一样 行为障碍是帕金森病的早期标志，将推动我们观念上的范式转变 ADRD和睡眠呼吸暂停。睡眠呼吸暂停是阿尔茨海默病的结果可能被用来识别老年人 有患阿尔茨海默氏症风险的成年人，并促进其预防。特定细胞的数据将推动靶向药物的发现 患有ADRD的老年人的睡眠呼吸暂停治疗，以及对当前治疗无效的睡眠呼吸暂停。

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.