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

 描述(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，其特征是淀粉样斑块和神经纤维缠结的堆积。最近的研究支持这一假说，即大脑中的淀粉样β蛋白(A？)动态受到睡眠-觉醒周期的影响，在清醒时，可溶性A？的产生增加，而在慢波睡眠(SWS)时减少。在这个模型中，在淀粉样蛋白沉积之前，老年人脑中可溶性Aü水平可能相对增加，这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，如晚年常见的睡眠障碍(SDB)或失眠。我们有初步证据表明：a)SDB可促进正常老年人的认知衰退；b)SDB可增加中年成年人的脑脊液(CSF)A？42水平；c)在正常老年人中，脑脊液A？42的增加与SWS的减少有关。我们的目标是在20名认知正常的没有SDB或脑淀粉样蛋白的老年人(目标1)和22名患有严重SDB的中年成年人中测试这一假设，这些患者接受了治疗性持续正压(CPAP)治疗和良好的治疗依从性(目标2)。在老年组，我们将评估在没有SDB或淀粉样蛋白负荷(用18F-florbetaben PET扫描测量)的情况下，SWS与脑脊液A？42/A？40比值的关系。在中年组，我们将在一晚取消CPAP来扰乱睡眠，并允许参与者在第二晚使用治疗性CPAP睡觉。两次探视均在早晨进行腰椎穿刺术，以评估急性CPAP停药扰乱睡眠对脑脊液Aü42水平的影响。该项目将首次探索SWS对A？42动态变化的保护作用。 一组老年受试者，以及在一个具有良好特征的严重中年阻塞性SDB患者的临床样本中，CPAP停用造成的急性睡眠障碍对脑脊液Aç42水平的影响。这一建议可能确认：1)与年龄相关的SWS丢失对脑脊液A？42动力学影响的证据；2)高度普遍的睡眠障碍可能导致AD病理的机制；以及3)SWS作为预防AD的新的治疗靶点。

 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.