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

项目摘要 尽管越来越多的证据表明，体内的24小时生物钟在这两种诊断中都起着关键作用 许多疾病的有效治疗，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战略的重大障碍。我们的主要关注点是 建议是关于缺乏准确和有效的工具来实时测量昼夜节律 研究背景。当前的黄金标准方法需要测量稳健的输出标记 昼夜节律系统(例如，褪黑激素或皮质醇)从采集的血液、唾液或尿液的频繁序列样本中提取 在高度受控的条件下8-48小时，这在患者群体中是不切实际的。此外，一个 这种方法的主要局限性是不能立即获得结果，因为必须发送样品 用于化验和分析，然后才能得到结果。这一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扰乱或不稳定，那么结果可能不再有用， 例如在它们被接收时用于有效治疗的定时。目前还不存在护理点方法来 用我们最强大的昼夜节律标记物--褪黑素来测量昼夜节律。然而，最近，我们已经 识别在基于现场的非研究环境中保持稳健节律的昼夜节律的其他标记， 这些标记可以使用现有的护理点设备进行实时测量。我们正在进行一项研究 在26岁至55岁的健康参与者中验证基于现场的昼夜节律测量 这些新奇的记号笔的节奏。然而，在这种方法可以扩展到患者群体之前，我们需要 为了在55-70岁的老年人(目标1)中验证我们的发现，他们将是预期的目标人群 用于基于昼夜节律的诊断和治疗策略的后续研究。我们还需要了解 到目前为止，某些类型的药物对我们在这些标志物中检测节律的能力的影响(目标2) 这些方法仅在未服用药物的个人中进行了测试。我们研究的参与者将被要求测量 并在48小时内记录家中护理设备的读数，同时记录他们的睡眠- 唤醒活动、进餐时间和用药情况。Cosinor分析将应用于每个48小时的配置文件 量化一个重要的昼夜节律的存在。这项研究的发现是关键的一步 基于昼夜节律的老年病治疗的发展，包括阿尔茨海默病，其中 昼夜节律紊乱非常普遍，对昼夜节律紊乱的治疗可以缓解这种情况 症状，甚至可能延缓疾病的发展。因此，这项初步研究将提供重要的初步 未来R01的数据，用于在更广泛的人群中测量家庭或门诊/PCP中的昼夜节律 临床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机 节奏。

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.