MELATONIN AND COGNITION IN MILD COGNITIVE IMPAIRMENT (MCI)

这个子项目是许多利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 假设： 我们假设，在衰老过程中，褪黑激素分泌的减少和昼夜节律紊乱的出现将与认知能力下降的速度更快有关。 目标： 与年龄相关的认知能力下降是有据可查的，导致认知障碍，从年龄相关的记忆障碍（AAMI）到痴呆。最近的数据表明，褪黑激素可以防止认知能力下降和β-淀粉样蛋白的沉积，这与阿尔茨海默病（AD）的发展有关。然而，迄今为止，大多数研究都集中在使用外源性褪黑激素和内源性褪黑激素在促进认知能力下降和痴呆症的发病中的作用尚不清楚。 褪黑激素由松果体分泌，其产生具有明显的昼夜节律，其产生于下丘脑视交叉上核（SCN）（主昼夜节律钟）内。在人类中，褪黑激素表现出明显的日/夜变化，在黑暗期开始时升高，在黑暗期达到峰值，并随着晨光而降低。褪黑激素节律通过眼睛光同步到24小时，眼睛光通过视网膜-下丘脑束传递到SCN。 衰老过程的一个重要方面是昼夜节律系统的解体。因此，时钟输出信号，如褪黑激素，表现出与年龄相关的变化在幅度和定时。大量的报告描述了与年龄相关的褪黑激素节律的变化，其中大多数报告表明，随着年龄的增长，夜间褪黑激素峰值的幅度下降。 实验设计： 这项研究建立在一项正在进行的关于老年人压力、皮质醇和认知能力下降的纵向研究的基础上（PI O 'Hara博士）。从这项正在进行的调查中，我们将招募40名70岁以上的社区老年人，他们患有轻度认知障碍（MCI）。作为母研究的一部分，在基线和年度随访时，所有受试者都接受了广泛的认知成套测试，包括记忆力、注意力和处理速度的测量，因为这些认知领域显示出特别强烈的年龄相关性下降。将在年度认知评估后7天内评估自我报告的睡眠问卷以及通过体动记录仪进行的客观睡眠-觉醒周期测量。将以两种不同的方式评估褪黑激素水平：在受试者家中，即在自然条件下，24小时过程中的尿液中褪黑激素水平;以及在斯坦福大学GCRC，在受控条件下，24小时过程中的唾液和尿液中褪黑激素水平。在两年研究期间的一次年度随访时重复所有测量，与母研究中用于皮质醇采集的时间点相同。 1)昼夜睡眠-觉醒周期的评估：将使用体动记录仪和关于睡眠质量和时间以及时钟类型的自我报告问卷来评估昼夜睡眠-觉醒周期。这些测量将在基线和一次年度随访访视时进行。 2)几天内休息和活动的昼夜节律模式的稳定性（日间稳定性，IS），以及3）其碎片化水平（日内变异性，IV）。 结束点： 这是一项在社区居住的MCI老年人中进行的观察性纵向研究，而不是治疗研究或临床试验。研究将继续进行，直至所有受试者完成测试。我们相信，在本研究期间进行的测量将使我们能够确定：1）在一年的时间内，内源性褪黑激素水平的变化，即昼夜节律幅度，是否与认知能力的变化相关; 2）在一年的时间内，内源性褪黑激素变化对认知能力的影响是否由睡眠-觉醒周期的变化介导。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Hypothesis: We hypothesize that, during the aging process, a decrease in melatonin secretion and the appearance of a circadian rhythm disturbance will be associated with a more rapid rate of cognitive decline. Goals: Age-related cognitive decline is well documented, leading to cognitive impairment ranging from age-associated memory impairment (AAMI) to dementia. Recent data suggest that melatonin may protect against cognitive decline and the deposition of beta-amyloid that is associated with the development of Alzheimer's Disease (AD). However, most studies to date have focused on the use of exogenous melatonin and the role of endogenous melatonin in contributing to cognitive decline and the onset of dementia is unclear. Melatonin is secreted by the pineal gland and its production has a distinct circadian rhythm, which is generated within the hypothalamic suprachiasmatic nuclei (SCN), the master circadian clock. In humans melatonin exhibits a clear day/night variation with a rise at the beginning of the dark period, its peak during the dark phase, and a decrease with the morning light. The melatonin rhythm is synchronized to 24 hour by ocular light, which is conveyed via the retino-hypothalamic tract to the SCN. One significant aspect of the aging process is deconsolidation of the circadian system. As a result, clock-output signals, such as melatonin, exhibit age-related changes in both amplitude and timing. An extensive number of reports describe changes in melatonin rhythm related to age with most of them suggesting a decline in the magnitude of the nocturnal melatonin peak with age. Experimental Design: This study builds upon an ongoing NIA-funded longitudinal study on stress, cortisol and cognitive decline in older adults (PI Dr. O'Hara). From this ongoing investigation, we will recruit 40 community-dwelling older adults over 70 yrs of age, who have mild cognitive impairment (MCI). As a part of the parent study, at baseline and annual follow-ups all subjects undergo an extensive cognitive battery including measures of memory, attention, and processing speed since these cognitive domains display particularly robust age-related declines. Self-reported sleep questionnaires as well as objective sleep-wake cycle measures via actigraphy will be assessed over the course of 7 days following the annual cognitive assessment. Melatonin levels will be assessed in two different ways: in urine over the course of 24-hr at the subjects' homes, i.e. under naturalistic conditions; and in saliva and urine over the course of 24-hr under controlled conditions at the Stanford GCRC. All measurements will be repeated at one annual follow-up during the two-yr study period, at the same timepoints used for cortisol collection as part of the parent study. 1) Assessment of the Circadian Sleep-Wake Cycle: The circadian sleep-wake cycle will be assessed using actigraphy and self-report questionnaires on the quality and timing of sleep, as well as on chronotype. These measures will be performed at baseline and one annual follow-up visit. 2) The stability of the circadian patterning of rest and activity over several days (interdaily stability, IS), and 3) its level of fragmentation (intradaily variability, IV). Endpoints: This is an observational, longitudinal study in community-dwelling older adults with MCI, not a treatment study or a clinical trial. The study will proceed until all subjects have completed the testing. We believe that measurements taken during this study will allow us to determine: 1) if changes in levels of endogenous melatonin, i.e. the circadian amplitude, are correlated with changes in cognitive performance, over a one-yr period; and 2) if the impact of changes in endogenous melatonin on cognitive performance is mediated by changes in the sleep-wake cycle, over a one-year period.