Brain Sleep Clearance of Amyloid-Beta Peptides Study (Brain SCRAPS)

大脑睡眠清除β-淀粉样肽研究（脑 SCRAPS）

• 批准号: 8970025
• 负责人: Ricardo S Osorio
• 金额: $ 24.92万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8970025
• 关键词: Abeta clearance; Acute; Adult; Age; Alzheimer disease prevention; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Amyloid deposition; Arousal; Biological Markers; Brain; Brain region; Cerebrospinal Fluid; Clinical; Cognitive; Collection; Continuous Positive Airway Pressure; Data; Deposition; Elderly; Enrollment; Epidemiologic Studies; Event; Goals; Home environment; Hour; Human; Impaired cognition; Laboratory Finding; Liquid substance; Longitudinal Studies; Measures; Modeling; Monitor; Neurodegenerative Disorders; Neurofibrillary Tangles; Participant; Pathology; Patients; Pattern; Physiological; Polysomnography; Positron-Emission Tomography; Production; Randomized; Reporting; Risk Factors; Sampling; Schedule; Senile Plaques; Sleep; Sleep Apnea Syndromes; Sleep Deprivation; Sleep Disorders; Sleep Fragmentations; Sleep Wake Cycle; Sleep disturbances; Sleeplessness; Slow-Wave Sleep; Spinal Puncture; Synapses; Testing; Therapeutic; Time; Transgenic Mice; Visit; Wakefulness; Withdrawal; actigraphy; age group; age related; cohort; compliance behavior; design; familial Alzheimer disease; interstitial; male; middle age; new therapeutic target; normal aging; protective effect; public health relevance

 DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a common neurodegenerative disease characterized by the accumulation of amyloid plaques and neurofibrillary tangles. Recent studies support the hypothesis that amyloid beta (Aß) dynamics in the brain are influenced by the sleep-wake cycle, with increases in the production of soluble Aß during wakefulness and decreases during slow wave sleep (SWS). In this model, prior to amyloid deposition, brain soluble Aß levels may be relatively increased in the elderly primarily due to loss of total sleep time and slow wave sleep (SWS) that occur with normal aging and/or secondarily, due to sleep disturbances such as Sleep Disordered Breathing (SDB) or insomnia that are common in late life. We have preliminary evidence showing that: a) SDB advances cognitive decline in normal elderly; b) SDB increases cerebrospinal fluid (CSF) Aß42 levels in middle age adults; and, c) increased CSF Aß42 is associated with reduced SWS in normal elderly. Our goal is to test this hypothesis in 20 cognitively normal elderly with no SDB or brain amyloid (Aim 1), and a group of 22 middle age adults with severe SDB treated with therapeutic continuous positive airway pressure (CPAP) and good treatment compliance (Aim 2). In the elderly group, we will evaluate the relationship between SWS and CSF Aß42/Aß40 ratio in the absence of SDB or amyloid burden (measured with a 18F-florbetaben PET scan). In the middle age group, we will disrupt sleep by withdrawing CPAP on one night and allow participants to sleep with therapeutic CPAP on a second night. A morning lumbar puncture will be performed in both visits to evaluate the effect of disrupting sleep by acute CPAP withdrawal on CSF Aß42 levels. This project will be the first to explore the protective effect of SWS on Aß42 dynamics in a group of elderly subjects as well as the effect of acute sleep disruption by CPAP withdrawal on CSF Aß42 levels in a well- characterized clinical sample of severe middle age obstructive SDB patients. This proposal may identify: 1) evidence of age-related SWS loss effects on CSF Aß42 dynamics; 2) a mechanism by which a highly prevalent sleep disorder may contribute to AD pathology; and, 3) SWS as new therapeutic target for AD prevention.

 描述（由申请人提供）：阿尔茨海默病（AD）是一种常见的神经退行性疾病，其特征在于淀粉样斑块和神经纤维缠结的积累。最近的研究支持这一假设，即大脑中的淀粉样蛋白β（A β）动力学受睡眠-觉醒周期的影响，在清醒期间可溶性A β的产生增加，在慢波睡眠（SWS）期间减少。在该模型中，在淀粉样蛋白沉积之前，老年人的脑可溶性腺苷酸水平可能相对增加，主要是由于正常衰老时发生的总睡眠时间和慢波睡眠（SWS）的损失，和/或其次是由于睡眠障碍，如睡眠呼吸障碍（SDB）或老年常见的失眠。我们有初步证据表明：a）SDB促进正常老年人的认知能力下降; B）SDB增加中年成人的脑脊液（CSF）A β 42水平;和c）CSF A β 42增加与正常老年人的SWS减少相关。我们的目标是在20名无SDB或脑淀粉样蛋白的认知正常老年人（目标1）和一组22名接受治疗性持续气道正压通气（CPAP）和良好治疗依从性的重度SDB中年人（目标2）中验证这一假设。在老年组中，我们将在不存在SDB或淀粉样蛋白负荷的情况下评价SWS和CSF A β 42/A β 40比值之间的关系（用18 F-氟倍他滨PET扫描测量）。在中年组中，我们将通过在一个晚上取消CPAP来扰乱睡眠，并允许参与者在第二个晚上使用治疗性CPAP睡眠。在两次访视中进行早晨腰椎穿刺，以评价急性CPAP停药对CSF A β 42水平的影响。该项目将首次探索SWS对Aß 42动力学的保护作用， 一组老年受试者，以及在严重的中年阻塞性SDB患者的充分表征的临床样本中，CPAP撤除引起的急性睡眠中断对CSF A β 42水平的影响。该提案可确定：1）年龄相关的SWS损失对CSF A β 42动力学影响的证据; 2）高度流行的睡眠障碍可能导致AD病理学的机制;和3）SWS作为AD预防的新治疗靶点。