MELATONIN AND COGNITION IN MILD COGNITIVE IMPAIRMENT (MCI)

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。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更快速度有关。目标：与年龄相关的认知能力下降是有据可证的，导致认知障碍，从与年龄相关的记忆障碍（AAMI）到痴呆。最近的数据表明，褪黑素可以防止认知能力下降和β -淀粉样蛋白沉积，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外源性褪黑激素的使用上，而内源性褪黑激素在认知能力下降和痴呆发病中的作用尚不清楚。褪黑素是由松果体分泌的，它的产生有一个独特的昼夜节律，这是在下丘脑视交叉上核（SCN）中产生的，这是主昼夜节律钟。在人类中，褪黑素表现出明显的昼夜变化，在黑暗期开始时上升，在黑暗期达到峰值，随着早晨的光线下降。褪黑激素的节律由眼光同步到24小时，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，如褪黑素，在振幅和时间上都表现出与年龄相关的变化。大量的报告描述了与年龄相关的褪黑激素节律的变化，其中大多数表明夜间褪黑激素峰值的幅度随着年龄的增长而下降。实验设计：本研究建立在一项正在进行的nia资助的关于老年人压力、皮质醇和认知能力下降的纵向研究（PI DR. O'Hara）。从这项正在进行的调查中，我们将招募40名年龄在70岁以上、患有轻度认知障碍（MCI）的社区老年人。作为父母研究的一部分，在基线和年度随访中，所有受试者都要接受广泛的认知测试，包括记忆力、注意力和处理速度，因为这些认知领域表现出与年龄相关的强烈衰退。在年度认知评估后的7天内，将对自我报告的睡眠问卷以及通过活动记录仪测量的客观睡眠-觉醒周期进行评估。褪黑素水平将以两种不同的方式进行评估：在受试者家中24小时的尿液中，即在自然条件下；在斯坦福大学GCRC的控制条件下进行24小时的唾液和尿液测试。在为期两年的研究期间，所有的测量将在每年一次的随访中重复，在与父母研究相同的时间点用于皮质醇收集。1)昼夜睡眠-觉醒周期的评估：使用活动记录仪和自我报告问卷评估昼夜睡眠-觉醒周期的睡眠质量和时间，以及睡眠时型。这些措施将在基线和每年一次随访时进行。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）。终点：这是一项针对社区居住的轻度认知障碍老年人的观察性纵向研究，不是治疗研究或临床试验。研究将继续进行，直到所有受试者完成测试。我们相信，在这项研究中采取的测量将使我们能够确定：1)内源性褪黑激素水平的变化，即昼夜节律振幅，是否与认知表现的变化相关，为期一年；2)如果内源性褪黑激素的变化对认知表现的影响是由睡眠-觉醒周期的变化介导的，在一年的时间内。

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-yr period.