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.
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