Excessive Sleepiness in Preclinical Alzheimer's Disease

项目摘要/摘要 阿尔茨海默病(AD)是最具破坏性的神经系统疾病之一，并正在蔓延 在美国人口老龄化的背景下，比例。目前的治疗策略影响很小， 只有在认知缺陷确定后，才能减缓疾病的进展。因此，显然有必要 在疾病的临床前阶段识别AD病理风险人群，以便采取预防措施 战略是可以制定的。多项新兴研究表明，白天过度嗜睡是一种 与阿尔茨海默氏症连续体相关的关键先兆症状。然而，白天的嗜睡是 大多数普通人群都会经历，是一种非特异性的症状，可以反映 大脑功能的无数变化。为了进一步推进这一领域的研究，这个项目将阐明具体到什么程度 在疾病的临床前阶段，嗜睡的客观测量与AD生物标记物有关。 这项研究将针对这一重要领域提出两个具体目标和三个相关假设 问询。首先，它将验证特定的客观嗜睡指标，这些指标映射到大脑中β-淀粉样蛋白的增加 临床前阿尔茨海默病的早期沉积易感区域。具体地说，它将建立在初步发现的基础上 提示红外线瞳孔测量法，一种测量蓝斑去甲肾上腺素能张力的方法，反映了 缘上回β-淀粉样蛋白负荷增加。此外，它还将检验一个特定的假设 白天昏昏欲睡的衡量标准是在最慢的10%的反应中的平均反应时间 先前已连接到默认模式网络中的活动的精神运动警戒任务将 与楔前/扣带后皮质的β淀粉样蛋白沉积有关，这是这一过程的关键组成部分 网络。最后，这项研究将澄清脑脊液中是否存在磷酸化和总tau蛋白。 液体与红外线瞳孔测量法的发现有关，假设蓝斑是 在AD中观察到异常tau沉积的最早部位。这项研究将在75口井-- 参加威斯康星州阿尔茨海默病研究中心的中老年特征 研究，并将利用之前收集的神经成像和生物成像数据，结合预期 评估白天嗜睡、纵向睡眠-觉醒模式和睡眠相关的呼吸障碍，以 执行可靠且受控良好的分析。解决此应用程序的特定目标将具有 通过将可测量的嗜睡表型与相关的 临床前阿尔茨海默病的脑内病理过程。通过这样做，该项目将推进这一至关重要的领域 探讨临床前AD，这可能导致改进的筛查和预防性治疗的发展 针对这种疾病的策略。

PROJECT SUMMARY/ABSTRACT Alzheimer's Disease (AD) is one of the most devastating neurological disorders, and is reaching epidemic proportions in the context of an aging U.S. population. Current treatment strategies have minimal impact and only slow the progression of the disorder once cognitive deficits are established. Thus, there is a clear need to identify persons at risk for AD pathology during the preclinical phase of the disorder, so that preventative strategies can be developed. Multiple emerging lines of research suggest excessive daytime sleepiness is a key precognitive symptom related to the Alzheimer's continuum. However, daytime somnolence is experienced by a large proportion of the general population, and is a non-specific symptom that can reflect myriad changes in brain function. To further advance this area of research, this project will clarify how specific objective measures of sleepiness are associated with AD biomarkers in the preclinical phase of the disorder. This study will address two Specific Aims and three related hypotheses targeted towards this vital area of inquiry. First, it will verify specific objective measures of sleepiness that map to increased β-amyloid in brain regions susceptible to early deposition in preclinical AD. Specifically, it will build on preliminary findings that suggest infrared pupillometry, a measure of noradrenergic tone in the locus coeruleus, is reflective of increased β-amyloid burden in the supramarginal gyrus. Additionally, it will test the hypothesis that a specific measure of daytime somnolence, the mean reaction time during the slowest 10% of responses on the psychomotor vigilance task, which has been previously connected to activity in the default mode network, will be associated with β-amyloid deposition in the precuneus/posterior cingulate cortex, a key constituent of this network. Finally, this investigation will clarify whether phosphorylated and total tau protein in the cerebrospinal fluid are associated with findings from infrared pupillometry as hypothesized, given the locus coeruleus is the earliest site of abnormal tau deposition observed in AD. This research will be conducted in 75 well- characterized middle to older-aged adults participating in Wisconsin Alzheimer's Disease Research Center studies, and will leverage previously collected neuroimaging and biospecimen data, combined with prospective assessment of daytime sleepiness, longitudinal sleep-wake patterns, and sleep-related breathing disorders, to perform robust and well-controlled analyses. Addressing the Specific Aims of this application will have a sizeable impact on AD and sleep research, by linking measureable sleepiness phenotypes to associated pathological processes in the brain in preclinical AD. In so doing, this project will advance this vital area of inquiry in preclinical AD, that may lead to the development of improved screening and preventative therapeutic strategies for the disease.