Understanding circadian responses to light in persons with Mild Cognitive Impairment and Alzheimer's disease

项目概要/摘要 严重的睡眠-觉醒和昼夜节律系统功能障碍在阿尔茨海默病患者中很常见 疾病及相关痴呆（ADRD）。在轻度认知障碍（MCI）患者中， 在痴呆的潜在前驱期，高达60%的患者存在明显的睡眠-觉醒障碍。 研究表明，适当的光照时间可以提高睡眠效率，减少躁动，甚至 限制ADRD人群的认知能力下降，但准确地指定人类的刺激 昼夜节律系统和开发有效的光传递方法已被确定为主要的 成功治疗的挑战。虽然现在已经确定， 人类的昼夜节律系统与人类的视觉系统相比有很大的不同，相对而言知之甚少 关于视网膜光分布和黄斑色素光密度（MPOD）的个体差异 影响褪黑激素的抑制，褪黑激素是一种昼夜节律生物标志物，特别是在老化的眼睛中。拟议的研究旨在 描述这两个因素在昼夜光传导中的作用，以使照明设备的开发成为可能 提供精确和定制的昼夜节律有效剂量。我们在健康年轻人中的初步数据 表明较高的MPOD与较低的褪黑激素抑制相关。在这项研究中，我们将扩展这些 MCI和年龄匹配的老年人的研究结果。具体而言，所有参与者将被视为4个创新 照明干预包括2个离散窄带光源（蓝色，λmax = 451 nm;绿色，λmax = 522 nm）在2个离散的光分布图案处：（1）“轴上”（即，沿着眼睛的视轴指向 中央凹）和（2）“离轴”（即，指向眼睛视轴的周边）。根据视网膜形态 和2°视场中光感受器的最高密度，我们假设，对于相同的光水平， 轴上传递的光在抑制褪黑激素方面比离轴传递的光更有效。球队 我们聚集在一起参加这个项目是独一无二的，包括一个研究人员谁专门研究人类 昼夜节律对光的反应，另一个具有昼夜节律光传导机制和建模的专业知识， 另一位视觉科学家提出了人类昼夜光传导的第一个模型（如何 视网膜将光信号转换为生物钟的电信号）。次要结果将是 更好地理解MPOD如何与认知能力下降相关，探索性结果将 研究MPOD是否可以用作光敏性的生物标志物。如果成功，拟议的研究 将“揭示”一个相对未开发的昼夜光传导和空间敏感性的途径， 了解这一点对于指定和实施昼夜节律有效的照明设计至关重要， 医疗机构、老年护理生活设施以及MCI和ADRD患者的住所。这些结果将 还帮助我们开发基于光的干预措施，旨在为MCI提供强大的明暗模式， ADRD患者，这将促进更好的睡眠和更好的认知。

PROJECT SUMMARY/ABSTRACT Severe sleep-wake and circadian system dysfunctions are common in patients afflicted with Alzheimer's disease and related dementias (ADRD). In people with mild cognitive impairment (MCI), an “at risk” or potential prodromal stage of dementia, sleep-wake disturbance is evident in up to 60% of patients. Appropriately timed light exposure has been shown to increase sleep efficiency, decrease agitation, and even limit cognitive decline in the ADRD population, but accurately specifying the stimulus for the human circadian system and developing effective light delivery methods have been identified as the primary challenges for successful treatment. While it is now established that the spectral and absolute sensitivity of the human circadian system is quite different compared to the human visual system, relatively little is known about how retinal light distribution and individual variations in macular pigment optical density (MPOD) affect suppression of melatonin, a circadian biomarker, especially in the aging eye. The proposed study aims to delineate the role of these 2 factors in circadian phototransduction, to enable development of lighting devices delivering precise and tailored circadian-effective doses. Our preliminary data in healthy young adults indicate a higher MPOD was associated with lower melatonin suppression. In this study, we will extend these findings to MCI and age-matched older adults. Specifically, all participants will be treated to 4 innovative lighting interventions consisting of 2 discrete narrowband light sources (blue, λmax = 451 nm; green, λmax = 522 nm) at 2 discrete light distribution patterns: (1) “on-axis”' (i.e., directed along the eye's visual axis to the fovea) and (2) “off-axis” (i.e., directed on the periphery of the eye's visual axis). Given the retinal morphology and the highest density of photoreceptors in the 2° field of view, we hypothesize that, for the same light level, light delivered on-axis will be more effective at suppressing melatonin than light delivered off-axis. The team we have assembled to participate in this project is unique, including a researcher who specializes in human circadian responses to light, another with expertise circadian phototransduction mechanisms and modeling, yet another who is a vision scientist and proposed the first model of human circadian phototransduction (how the retina converts light signals into electrical signals for the biological clock). A secondary outcome will be a better understanding of how MPOD may be associated with cognitive decline and an exploratory outcome will investigate whether MPOD can be used as a biomarker for light sensitivity. If successful, the proposed study will `shed light' on a relatively unexplored avenue of circadian phototransduction and spatial sensitivity, the understanding of which is essential for specifying and implementing a circadian-effective lighting design in healthcare facilities, senior care living facilities, and residences of MCI and ADRD patients. These results will also help us develop light-based interventions designed to deliver a robust light-dark pattern to MCI and ADRD patients, which will promote better sleep and better cognition.