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

将睡眠呼吸暂停确定为老年人脑干 ADRD 病理的非认知表型

• 批准号: 10602556
• 负责人: ARON S BUCHMAN
• 金额: $ 120.27万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10602556
• 关键词: Adult; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; Animal Model; Apnea; Arousal; Autopsy; Brain; Brain Stem; Breathing; Cell Count; Cells; Cessation of life; Clinical; Cognition; Cohort Studies; Collection; Communities; Data; Defect; Dementia; Dilator; Dimensions; Elderly; Event; Failure; Frequencies; Health; High Prevalence; Human; Immunohistochemistry; Impaired cognition; Individual; Legal patent; Magnetic Resonance Imaging; Measures; Memory; Minor; Nature; Neurons; Obesity; Pathologic; Pathology; Phenotype; Physiological; Pilot Projects; Population; Prevention; Protocols documentation; REM Sleep Behavior Disorder; Resources; Risk; Risk Factors; Role; Severities; Site; Sleep; Sleep Apnea Syndromes; Spinal Cord; Staging; Stains; Structure; Testing; Tissues; aging brain; brain cell; cell type; clinical predictors; drug discovery; feasibility testing; human old age (65+); indexing; innovation; middle age; model organism; neural circuit; neurochemistry; neuron loss; neuroregulation; novel; predictive tools; respiratory; sensor; sleep difficulty; wearable device; wearable sensor technology; young adult

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.

项目概要 阿尔茨海默病及相关痴呆症 (ADRD) 和睡眠呼吸暂停是常见的衰老表型。睡觉 呼吸暂停也可能是 AD 表型，因为 ADRD 病理可能会扰乱促进呼吸的神经回路 睡觉。然而，尚无研究检验“睡眠呼吸暂停”回路中的 ADRD 病理是否与睡眠呼吸暂停有关。 与认知或活动能力等其他 ADRD 表型一样，睡眠呼吸暂停是多维的。 3个关键缺陷 尺寸可导致睡眠呼吸暂停：a) 无法保持呼吸道通畅，b) 呼吸驱动效率低下，以及 c) 通过唤醒异常呼吸暂停终止。在模型生物体中，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维度。然而，ADRD 病理学在人类中的作用 睡眠呼吸暂停尚不清楚，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，并且 ADRD 分期不评估底层电路的位点。在试点研究中，测量了 3 个关键维度 使用新型传感器获取社区老年人的睡眠呼吸暂停表型。很少有老年人有 Rush Memory and Aging Project（MAP，R01AG17917）中的睡眠呼吸暂停患者患有肥胖症，表明患有轻微 结构和重要的神经源性贡献。我们在尸检中记录了混合 ADRD 病理 3 个“睡眠呼吸暂停”回路的脑干组织，服务于睡眠 MAP 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。 这项创新的临床尸检提案将利用独特的临床、病理和生物样本 来自 MAP 的老年人的资源，MAP 是一项基于社区的脑捐赠队列研究。这项研究将我） 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 可量化患有或不患有 ADRD 的老年人的上呼吸道结构，以及 II) 量化退行性病变 通过病理标记物和细胞类型特异性染色来改变脑干“睡眠呼吸暂停”回路节点 标记并整合这些新数据。目标 1 将检验以下假设：人口统计和临床预测因素 与睡眠呼吸暂停的三个关键生理​​维度有不同的相关性。目标 2 和 3 将测试 假设退行性变化，即 ADRD 病理（目标 2）和亚型特异性神经元损失（目标 3) 3 个“睡眠呼吸暂停”回路与这些关键的睡眠呼吸暂停维度相关。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， 这些个体的循环 ADRD 病理与睡眠呼吸暂停及其关键维度有关。 表明睡眠呼吸暂停是 AD 的一种常见且早期的非认知表型，就像快速眼动睡眠一样 行为障碍是帕金森病的早期标志，将推动我们对两者之间关系的概念发生范式转变 ADRD 和睡眠呼吸暂停。表明睡眠呼吸暂停是 AD 的后果，可用于识别老年人 有患 AD 痴呆症风险的成年人并促进其预防。细胞特异性数据将推动靶向药物的发现 针对患有 ADRD 和对当前治疗无反应的睡眠呼吸暂停的老年人的睡眠呼吸暂停治疗。