Validation of real-time field-based markers of circadian phase

验证基于现场的实时昼夜节律阶段标记

• 批准号: 10460919
• 负责人: Shadab A Rahman
• 金额: $ 8.95万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10460919
• 关键词: Acute; Address; Adult; Age; Aging; Alzheimer' s Disease; Biological Assay; Biological Clocks; Blood; Blood specimen; Cholesterol; Chronic Disease; Circadian Dysregulation; Circadian Rhythms; Clinic; Data; Development; Devices; Diagnosis; Disease; Disease Progression; Effectiveness; Enrollment; Exhibits; Female; Funding; Future; Gold; Home; Hormones; Hour; Hydrocortisone; Individual; Liver; Measurement; Measures; Melatonin; Methods; Older Population; Outpatients; Output; Participant; Patients; Pharmaceutical Preparations; Phase; Pilot Projects; Play; Population; Production; Protocols documentation; Reading; Reporting; Saliva; Sampling; Sleep; System; Target Populations; Testing; Time; Urine; Validation; base; circadian; circadian pacemaker; cohort; diagnostic strategy; effective therapy; inter-individual variation; male; meter; minimally invasive; novel marker; patient population; point of care; prospective test; reduce symptoms; time use; tool; treatment strategy

Project Summary Despite mounting evidence that the body’s internal 24-hour circadian clock plays key roles in both the diagnosis and effective treatment of many diseases, including diseases of aging such as Alzheimer’s disease, there remain significant barriers to implementing circadian-based diagnostic and treatment strategies. Our major focus in this proposal is on the lack of accurate and validated tools to measure circadian rhythms in real-time in a non- research setting. The current gold-standard approaches require measurement of a robust output marker of the circadian system (e.g., melatonin or cortisol) from frequent serial samples of blood, saliva, or urine collected over an 8-48 hour period under highly controlled conditions, which is impractical in patient populations. Moreover, a significant limitation of this approach is that results cannot be obtained immediately, as samples must be sent for assay and analyzed before results can be obtained. This delay, which can be several days or weeks, is problematic, because if the circadian system is disrupted or unstable, then the results may no longer be useful, e.g., for timing of effective treatment, by the time they are received. No point-of-care methods currently exist to measure circadian rhythms in our most robust circadian marker, melatonin. Recently, however, we have identified other markers of the circadian clock that maintain robust rhythms in field-based non-research settings, and these markers can be measured in real-time using existing point-of-care devices. We have an ongoing study in healthy participants between the ages of 26 and 55 years old to validate field-based measures of circadian rhythms in these novel markers. Before this approach can be extended to patient populations, however, we need to validate our findings in older individuals 55-70 years old (Aim 1), who would be the expected target population for subsequent studies of circadian-based diagnostic and treatment strategies. We also need to understand the impact of certain types of medications on our ability to detect rhythms in these markers (Aim 2), as to date these methods have been tested in non-medicated individuals only. Participants in our study will be asked to measure and record readings from point-of-care devices at home for a 48-hour period while also recording their sleep- wake activity, meal timing, and medication usage. Cosinor analyses will be applied to each 48-hour profile to quantify the presence of a significant circadian rhythm. The findings from this study are a critical step in the development of circadian-based treatment for diseases of aging, including Alzheimer’s disease, in which disruption of circadian rhythms is highly prevalent and for which treatment of circadian disruption can alleviate symptoms and may even slow the progression of disease. This pilot study thus will provide important preliminary data for a future R01 to measure circadian rhythms in a broader population at home or in the outpatient/PCP clinic as well as to prospectively test circadian-based timing of treatment using real-time assessment of circadian rhythms.

项目摘要 尽管越来越多的证据表明，人体内部的24小时生物钟在诊断中起着关键作用， 和有效治疗许多疾病，包括老年性疾病，如阿尔茨海默病，仍然存在 实施基于昼夜节律的诊断和治疗策略的重大障碍。我们在这方面的主要重点 建议是缺乏准确和有效的工具，以测量昼夜节律实时在非 研究设置。目前的金本位方法需要测量一个强大的产出指标， 昼夜节律系统（例如，褪黑激素或皮质醇）从血液，唾液或尿液中收集的频繁系列样品中， 在高度受控的条件下持续8-48小时，这在患者群体中是不切实际的。而且 这种方法的重要局限性是不能立即获得结果，因为必须发送样品 用于测定和分析，然后才能获得结果。这种延迟可能是几天或几周， 这是有问题的，因为如果昼夜节律系统被破坏或不稳定，那么结果可能不再有用， 例如，在一个实施方式中，有效治疗的时间，在他们收到的时候。目前没有即时护理方法， 测量我们最强大的昼夜节律标记物褪黑激素的昼夜节律。然而，最近， 确定了生物钟的其他标志物，这些标志物在基于实地的非研究环境中保持稳健的节奏， 并且这些标记可以使用现有的现场护理设备实时测量。我们有一项正在进行的研究 在26至55岁的健康参与者中，验证基于场的昼夜节律测量， 这些新奇的标记中的节奏。然而，在将这种方法推广到患者群体之前，我们需要 在55-70岁的老年人中验证我们的发现（目标1），他们将是预期的目标人群 用于后续基于昼夜节律的诊断和治疗策略的研究。我们还需要了解 某些类型的药物对我们检测这些标记物中的节律的能力的影响（目标2）， 这些方法仅在未服药的个体中进行了测试。我们研究的参与者将被要求测量 并在家中记录48小时的即时护理设备读数，同时记录他们的睡眠情况- 唤醒活动、进餐时间和药物使用。将对每个48小时曲线进行余弦分析， 量化一个重要的昼夜节律的存在。这项研究的结果是在这方面的关键一步。 开发基于昼夜节律的老年疾病治疗，包括阿尔茨海默病，其中 昼夜节律的破坏是非常普遍的， 症状，甚至可能减缓疾病的进展。因此，这项试点研究将提供重要的初步 未来R 01的数据，用于测量更广泛人群的昼夜节律，包括家庭或门诊/PCP 诊所以及使用昼夜节律的实时评估来前瞻性地测试基于昼夜节律的治疗时间 节奏