Forgetting to sleep: metabolic consequences of sleep loss and associated neurocognitive deficits

忘记睡觉：睡眠不足和相关神经认知缺陷的代谢后果

• 批准号: 9245189
• 负责人: Aalim M Weljie
• 金额: $ 20.13万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9245189
• 关键词: Aging; Alzheimer' s Disease; Apolipoprotein E; Biological Markers; Blood; Brain; Characteristics; Circadian Rhythms; Clinical; Cognition; Cognitive; Data; Dementia; Disease; Elderly; Gene Expression; Genotype; Habits; Health; Heritability; Hour; Individual; Jet Lag Syndrome; Life; Link; Lipids; Measurement; Measures; Metabolic; Metabolic Marker; Metabolism; Methods; Modernization; NMR Spectroscopy; Neurocognition; Neurocognitive; Neurocognitive Deficit; Neurotransmitters; Oxidative Stress; Parkinson Disease; Pattern; Periodicity; Phenotype; Population; Predisposition; Publishing; Reporting; Resistance; Risk Factors; Sampling; Schedule; Series; Serum; Sleep; Sleep Deprivation; Sleep disturbances; Societies; Techniques; Technology; Testing; Transcend; Translations; Variant; Work; aged; cognitive process; cognitive testing; design; flexibility; forgetting; genetic signature; liquid chromatography mass spectrometry; metabolic phenotype; metabolome; metabolomics; middle age; neurobehavioral; novel; novel marker; pressure; response; social; trait; vigilance; young adult

Project Summary / Abstract: Sleep loss is increasingly recognized as a significant factor in aging-related dementias with widespread impact on health and cognition. The extent of sleep loss has increased consistently for several decades, with modern society suffering from shortened sleep due to factors such as work hours, `social jetlag', parental responsibilities and technology. Sleep loss has a demonstrated interaction with aging phenotypes, including in Alzheimer's and Parkinson's diseases, but is also suspected to be a risk factor for conversion of younger populations to dementias later in life. For example, sleep loss makes the `young seem old' with respect to cognition, while quality sleep in younger populations may be neuroprotective later in life. However, little is known about the distinct mechanisms by which sleep interacts with organismal metabolism and how this disruption overlaps with aging phenotypes. Furthermore, quantitative cognitive assessments have shown that individuals are differentially susceptible to sleep loss, and these sleep loss `resistant' or `susceptible' characteristics are trait-like in that they transcend temporal experimental boundaries and are heritable. Here we propose to profile metabolite changes in blood as a function of neurobehavioral response to sleep loss by leveraging data previously collected in a controlled total sleep deprivation (TSD) study. We hypothesize that the metabolite markers of TSD will be similar to those found previously in our studies of sleep restriction as well as published aging studies, and that the metabolite concentrations and rhythms will be sensitive to individual neurobehavioral response. We will test our overall hypothesis in three independent but overlapping aims designed to probe the relationship between neurocognitive response to TSD, changes in diurnal metabolite rhythms, and novel biomarkers of sleep loss.  Aim 1. To define the variation in known blood metabolic markers of sleep loss as function of neurobehavioral susceptibility to total sleep deprivation using a targeted metabolomics approach. Hypothesis: We expect to observe a blunted response in those metabolites indicative of sleep debt in a population of individuals who are resistant to sleep loss as defined by PVT response.  Aim 2. To use a comprehensive and untargeted metabolomics approach to elucidate novel indicators of sleep vulnerability and total sleep deprivation. Hypothesis: An increased number of metabolites responsive to TSD compared to previous markers of SR will be detected, and that these markers will overlap with existing markers in neurocognitive deficits such as Parkinson's and Alzheimer's disease.  Aim 3. To establish the impact of total sleep deprivation on diurnal rhythms of metabolite fluctuations, and the differential metabolite patterns with respect to neurobehavioral susceptibility. Hypothesis: Diurnal rhythms will be enhanced in amplitude in those with increased susceptibility, and that similar to observed changes in gene expression, the response will be reduced in individuals resistant to TSD.

项目摘要 /摘要： 越来越多地将睡眠损失视为与衰老相关痴呆症具有宽度影响的重要因素 关于健康和认知。几十年来，睡眠损失的程度一直持续增加，现代 由于工作时间，“社交lag”，父母等因素，社会患睡眠缩短 责任和技术。睡眠损失与衰老表型相互作用，包括 阿尔茨海默氏症和帕金森氏症的疾病，但也被怀疑是conversion依的危险因素 人群对痴呆症的后期生活。例如，睡眠损失使“年轻人看起来老” 认知，虽然年轻人群的质量睡眠可能会在以后的生活中具有神经保护作用。但是，几乎没有 知道睡眠与有机新陈代谢相互作用的不同机制以及如何 这种破坏与衰老表型重叠。此外，定量认知评估具有 表明个人对睡眠损失有所不同，并且这些睡眠损失“抗药性”或 “易感”特征是特质的，因为它们超越了暂时的实验边界，并且是 遗传。在这里，我们提议概述血液中的代谢物变化，这是神经行为反应的函数 通过利用先前在受控的总睡眠剥夺（TSD）研究中收集的数据来丧失睡眠损失。我们 假设TSD的代谢物标记将与我们研究中先前发现的代谢标记相似 睡眠限制以及已发表的衰老研究，以及代谢物浓度和 节奏将对个体的神经行为反应敏感。我们将检验我们的总体假设 三个独立但重叠的目的旨在探究神经认知反应之间的关系 对于TSD，昼夜代谢物节奏的变化以及睡眠损失的新型生物标志物。 目的1。定义已知血液丧失的血液代谢标记的变化作为功能 使用靶向代谢组学方法，神经行为对完全睡眠剥夺的敏感性。 假设：我们希望在那些指示睡眠甲板的代谢物中观察到钝的反应 抗PVT反应定义的耐睡眠损失的个体人群。 目的2。使用一种全面且无靶的代谢组学方法来阐明新型指标 睡眠脆弱性和完全睡眠剥夺。假设：代谢物数量增加 与先前的SR标记相比，对TSD的响应将被检测到，并且这些标记将重叠 神经认知中的现有标记定义了帕金森氏病和阿尔茨海默氏病。 目的3。建立全部睡眠剥夺对代谢产物的昼夜节奏的影响 波动和差异代谢物模式相对于神经行为敏感性。 假设：在易感性增加的人中，放大器的昼夜节奏将得到增强，并且 与观察到的基因表达变化相似，对TSD有抵抗力的个体将减少反应。