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.

项目概要/摘要： 睡眠不足越来越被认为是与年龄相关的痴呆症的一个重要因素，具有广泛的影响 关于健康和认知。几十年来，睡眠不足的程度一直在增加， 由于工作时间、“社会时差”、父母的 责任和技术。睡眠不足与衰老表型有明显的相互作用，包括 阿尔茨海默氏症和帕金森氏症，但也被怀疑是一个危险因素，转换年轻 老年痴呆症的发病率。例如，睡眠不足使“年轻人看起来老了”， 高质量的睡眠在年轻人中可能对以后的生活有神经保护作用。然而， 了解睡眠与有机体新陈代谢相互作用的独特机制，以及如何 这种破坏与老化表型重叠。此外，定量认知评估 研究表明，个体对睡眠不足的敏感性不同，这些睡眠不足是“抵抗”的， “易受影响的”特征是类似于特质的，因为它们超越了时间实验的界限， 遗传的在这里，我们建议将血液中的代谢物变化作为神经行为反应的函数， 睡眠损失利用以前收集的数据在一个受控的总睡眠剥夺（TSD）的研究。我们 假设TSD的代谢物标志物与我们先前研究中发现的相似 睡眠限制以及已发表的衰老研究，代谢物浓度和 节律将对个体神经行为反应敏感。我们将测试我们的整体假设， 三个独立但重叠的目的，旨在探讨神经认知反应之间的关系， 到TSD，昼夜代谢节律的变化，以及睡眠丧失的新生物标志物。 1.确定已知的睡眠不足的血液代谢标志物的变化， 神经行为对完全睡眠剥夺的易感性，使用靶向代谢组学方法。 假设：我们预计会观察到这些代谢物的迟钝反应，表明睡眠不足。 根据PVT反应定义的对睡眠丧失有抵抗力的个体人群。 第二章.使用全面的非靶向代谢组学方法阐明新指标 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标记物相比，将检测到对TSD有响应的标记物，并且这些标记物将重叠 与神经认知缺陷如帕金森氏症和阿尔茨海默氏症的现有标志物。 第三章.确定完全睡眠剥夺对代谢物昼夜节律的影响 波动，以及关于神经行为易感性的差异代谢物模式。 假设：在易感性增加的人中，昼夜节律的振幅会增强， 与观察到的基因表达变化相似，在对TSD有抗性的个体中，反应将降低。