Excessive Sleepiness in Preclinical Alzheimer's Disease

项目总结/摘要 阿尔茨海默病（Alzheimer's Disease，AD）是一种严重的神经系统疾病，目前正逐渐成为一种流行病 在美国人口老龄化的背景下。目前的治疗策略影响甚微， 只会在认知缺陷形成后减缓疾病的发展因此，显然需要 在疾病的临床前阶段识别处于AD病理学风险中的人， 可以制定战略。多项新的研究表明，白天过度嗜睡是一种 与阿尔茨海默氏症相关的关键性脑卒中症状然而，白天嗜睡是 大部分普通人群都经历过，并且是一种非特异性症状，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，该项目将阐明如何具体 嗜睡的客观测量与疾病临床前阶段的AD生物标志物相关。 本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， 查询首先，它将验证与大脑中β-淀粉样蛋白增加相关的嗜睡的具体客观测量方法 在临床前AD中易受早期沉积影响的区域。具体而言，它将以初步调查结果为基础， 表明红外瞳孔测量，蓝斑去甲肾上腺素能张力的测量，是反映 边缘上回β淀粉样蛋白负荷增加。此外，它将测试假设，一个特定的 白天嗜睡的测量，在最慢的10%的反应的平均反应时间， 心理警戒任务，这是以前连接到活动的默认模式网络，将 与楔前叶/后扣带回皮质中的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，本研究将阐明是否磷酸化和总tau蛋白在脑脊液中， 液体与红外瞳孔测量的结果相关，因为假设蓝斑是 在AD中观察到的异常tau沉积的最早位点。该研究将在75井- 参加威斯康星州阿尔茨海默病研究中心的中老年人 研究，并将利用以前收集的神经成像和生物标本数据，结合前瞻性 评估日间嗜睡、纵向睡眠-觉醒模式和睡眠相关呼吸障碍， 进行稳健且受控良好的分析。解决这个应用程序的具体目标将有一个 对AD和睡眠研究产生了相当大的影响，通过将可测量的嗜睡表型与 在临床前AD的大脑中的病理过程。通过这样做，该项目将推动这一重要领域的发展， 在临床前AD的调查，这可能会导致改善筛选和预防性治疗的发展 疾病的战略。

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.