Bright light modulation of non-motor symptoms in Parkinson's disease

摘要 非运动症状(NMS)是帕金森病(PD)最具致残性的表现之一。 睡眠障碍和警觉性是最常见的NMS之一。导致NMS的机制不好 了解和治疗选择仍然有限。内源性的人体昼夜节律系统起着至关重要的作用 在睡眠-觉醒周期的调节中，大多数情况下是由环境光有效地同步。这个 帕金森病患者的昼夜节律系统尚未得到系统的研究。我们对慢性阻塞性肺疾病患者的先导性研究 PD显示：(I)褪黑素的昼夜节律变钝，这是一个公认的昼夜节律的标志； 时钟基因表达的昼夜节律变化(“时相”)；和(Iii)强光治疗的有益影响 (Lt)睡眠-清醒巩固。 该项目旨在检查LT对NMS的影响，重点是睡眠、警觉性和昼夜节律 在54名睡眠不佳的帕金森病患者超过14周的队列中进行标记。研究参与者将被随机分配 设置为亮白色LT或暗红色LT(对照)。参与者将接受住院评估，以 采用多导睡眠图(PSG)监测LT前后的昼夜节律指标和睡眠情况。在整个研究过程中， 参与者将佩戴活动记录仪，持续监测睡眠-觉醒模式，记录每日睡眠日记 和LT暴露记录，以及用于警觉级别的完整视觉模拟评分(VAS)。调查问卷至 评估睡眠、警觉性和NMS将在基线、LT后8周和在LT结束时执行 学习。目标1将确定LT对自我报告(帕金森氏病睡眠量表2和睡眠)的影响 日记)和客观(PSG，活动记录仪)测量睡眠。目标2将确定LT对昼夜节律的影响 标记，特别是褪黑素和时钟基因BMal1、Per1、2和3的幅度和相位，以及 休息-活动周期的每日稳定性(动作图)。目标3将确定LT对警觉性的影响(Epworth 嗜睡量表和VAS警觉量表)。目标4将确定LT对NMS负荷(非马达)的影响 帕金森病症状评定量表和帕金森氏症统一运动障碍协会第一部分 疾病分级量表)。研究设计将量化每个个体内部LT、目标之间的关系 主观睡眠、昼夜节律、警觉性和NMS负担。从长远来看，这个项目解决了 需要提高对帕金森病NMS病理生理学的认识，开发新的治疗方法。短小的- 该项目将通过测试一个潜在的靶点(即 帕金森病患者的生理系统)、治疗(LT)和结果测量。该项目是对 在最新的NINDS PD研究共识中概述的几个最优先的临床研究领域 会议，并在NIH睡眠障碍研究计划中：(I)开发有效的非运动疗法 帕金森病的特征；(Ii)促进对大脑和身体的睡眠和昼夜节律功能的了解； 以及(3)改进睡眠和昼夜节律紊乱的预防、诊断和治疗。

Abstract Non-motor symptoms (NMS) are some of the most disabling manifestations of Parkinson’s disease (PD). Disrupted sleep and alertness are among the most common NMS. Mechanisms leading to NMS are not well understood and treatment options remain limited. The endogenous human circadian system has a critical role in the regulation of sleep-wake cycles and is mostly effectively synchronized by environmental light. The circadian system has not been systematically studied in the PD population. Our pilot studies in patients with PD revealed: (i) blunting of circadian rhythm of melatonin, a well established marker of circadian rhythms; (ii) changes in circadian timing (“phase”) of clock gene expression; and (iii) beneficial effects of bright light therapy (LT) on sleep-wake consolidation. This project aims to examine effects of LT on NMS with an emphasis on sleep, alertness, and circadian markers in a cohort of 54 PD participants with poor sleep over 14 weeks. Study participants will be randomized to either bright white LT or dim-red LT (control) condition. Participants will have inpatient assessments for circadian markers and sleep using polysomnography (PSG) before and after LT. Throughout the study, participants will wear an actigraph for continuous monitoring of sleep-wake patterns, keep daily sleep diaries and records of LT exposure, and complete visual analog scales (VAS) for alertness level. Questionnaires to assess sleep, alertness, and NMS will be performed at baseline, following 8 weeks of LT, and at the end of the study. Aim 1 will determine effects of LT on self-reported (Parkinson’s Disease Sleep Scale 2 and sleep diaries) and objective (PSG, actigraphy) measures of sleep. Aim 2 will determine effects of LT on circadian markers, specifically amplitude and phase of melatonin and clock genes Bmal1, Per1,2, and 3, as well as inter- daily stability of the rest-activity cycles (actigraphy). Aim 3 will determine effects of LT on alertness (Epworth Sleepiness Scale and VAS alertness scale). Aim 4 will determine effects of LT on NMS burden (The Non Motor Symptoms Assessment Scale for PD and Part I of the Movement Disorders Society Unified Parkinson’s Disease Rating Scale). The study design will quantify within each individual the relationships of LT, objective and subjective sleep, circadian markers, alertness, and NMS burden. Long-term, this project addresses the need to improve our understanding of the pathophysiology of NMS in PD and develop novel treatments. Short- term, the project will provide a foundation for a future clinical trial of LT through testing of a potential target (the circadian system), therapy (LT) and outcome measures in the PD population. This project is responsive to several highest priority areas for clinical research outlined in the most recent NINDS PD Research Consensus Meeting, and in the NIH Sleep Disorders Research Plan: (i) to develop effective treatments for non-motor features of PD; (ii) to advance the understanding of sleep and circadian functions in both the brain and body; and (iii) to improve prevention, diagnosis, and treatment of sleep and circadian disorders.