The Role of Impaired Neurobehavioral Alertness in Cognitive Decline and Alzheimer’s Disease Pathology

项目总结/摘要 阿尔茨海默病（AD）是一种使人衰弱的神经系统疾病，并且很快将在美国达到流行病的比例。 在人口老龄化的背景下。明确需要识别处于AD病理学风险中的人，以便 可以制定和实施预防战略。多项新兴研究表明， 睡眠障碍，特别是白天过度嗜睡和阻塞性睡眠呼吸暂停（OSA）， 增加AD病理和痴呆的风险。白天过度嗜睡是一个重要的临床 OSA的表型，个体的警觉性受损-一种功能（和显著表现）， 过度嗜睡-经历更严重的后遗症。我们调查小组的初步研究 证明通过心理警觉任务（PVT）测量的日间警觉性降低， 特别是与AD病理学和认知有关，OSA调节受损 警觉性、AD病理学和神经认知功能。该项目将推进这一重要的研究领域， 利用新兴的阿尔茨海默病生物标志物，可以在血液中检测到丰富的独特的 威斯康星州睡眠队列研究（WSC）中的睡眠数据。自2000年以来，世界安全理事会一直在跟踪参与者。 20世纪80年代末，是唯一的纵向队列存储生物标本，睡眠，PVT，和神经认知数据 跨越几十年来阐明日间警觉性和OSA与AD病理学的关系， 认知能力下降本研究将前瞻性采集额外的血液标本、PVT和 神经认知数据的目标样本450 WSC参与者谁现在是老年人，以解决三个 具体的目标与初步数据支持的可测试的假设。首先，它将确定是否受损 神经行为警觉性与较高水平的病理性磷酸化tau蛋白相关。二是会 确定受损的神经行为警觉性是否与更严重的 神经变性第三，它将确定受损的神经行为警觉性是否与纵向 认知轨迹对于所有的目标，假设OSA调节白天和夜间之间的关系。 警觉性和AD病理和认知下降。详细的睡眠和健康历史数据可在WSC 重要的是，允许许多关键协变量被包括在用于假设检验的统计模型中。 解决这一应用的具体目标将对AD和睡眠研究产生相当大的影响， 将容易获得的神经行为警觉性的客观测量与AD病理学的纵向风险联系起来 和认知能力下降这样做，该项目将最终导致改善预防和治疗 针对睡眠和警觉性作为阿尔茨海默病可改变的风险因素的策略。

PROJECT SUMMARY/ABSTRACT Alzheimer's disease (AD) is a debilitating neurological disorder, and soon will reach epidemic proportions in the context of an aging population. There is a clear need to identify persons at risk for AD pathology, so that preventative strategies can be developed and implemented. Multiple emerging lines of research demonstrate that sleep disturbance, and particularly excessive daytime sleepiness and obstructive sleep apnea (OSA), both increase the risk for AD pathology and dementia. Excessive daytime sleepiness is an important clinical phenotype of OSA, with individuals with impaired alertness – a function (and salient manifestation) of excessive sleepiness – experiencing more severe sequelae. Preliminary studies from our investigative team demonstrate that diminished daytime alertness measured by the psychomotor vigilance task (PVT) is specifically related to AD pathology and cognition, and that OSA moderates relationships between impaired alertness, AD pathology, and neurocognitive function. This project will advance this vital research area by leveraging emerging Alzheimer's disease biomarkers that can be detected in blood with the wealth of unique sleep data available in the Wisconsin Sleep Cohort (WSC) Study. The WSC has followed participants since the late 1980s, and is the only longitudinal cohort with stored biospecimens, sleep, PVT, and neurocognitive data spanning decades to elucidate the relationships of daytime alertness and OSA with AD pathology and cognitive decline. This investigation will prospectively collect additional blood specimens, PVT, and neurocognitive data in a targeted sample of 450 WSC participants who are now older aged, to address three Specific Aims with testable hypotheses supported by preliminary data. First, it will determine if impaired neurobehavioral alertness is associated with higher levels of pathological phosphorylated tau. Second, it will determine whether impaired neurobehavioral alertness is associated with more severe markers of neurodegeneration. Third, it will determine if impaired neurobehavioral alertness is associated with longitudinal cognitive trajectory. For all Aims, it is hypothesized that OSA moderates relationships between daytime alertness and AD pathology and cognitive decline. Detailed sleep and health history data available in the WSC importantly allows for many key covariates to be included in statistical models used for hypothesis testing. Addressing the Specific Aims of this application will have a sizeable impact on AD and sleep research, by linking a readily obtained objective measure of neurobehavioral alertness to longitudinal risk of AD pathology and cognitive decline. In so doing, this project will ultimately lead to improved preventative and therapeutic strategies that target sleep and alertness as modifiable risk factors for Alzheimer's disease.