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）的一些最致残的表现。 睡眠中断和警觉性是最常见的NMS。导致NMS的机制不完善 了解和治疗选择仍然有限。内源性的人类昼夜节律系统具有关键作用 在睡眠-觉醒周期的调节中，并且主要通过环境光有效地同步。的 PD人群的昼夜节律系统尚未得到系统研究。我们在患有 PD显示：（i）褪黑激素的昼夜节律变钝，褪黑激素是一种公认的昼夜节律标志物;（ii） 生物钟基因表达的昼夜节律定时（“相位”）的变化;以及（iii）明亮的光疗法的有益效果 (LT)关于睡眠-清醒巩固的研究 本项目旨在研究LT对NMS的影响，重点是睡眠，警觉性和昼夜节律 在14周内，54名睡眠不佳的PD参与者的队列中进行了标记。研究受试者将被随机分组 亮白色LT或暗红LT（对照）条件。参与者将接受住院评估， 在LT之前和之后使用多导睡眠图（PSG）的昼夜节律标记和睡眠。在整个研究中， 参与者将佩戴活动记录仪，持续监测睡眠-觉醒模式， 记录LT暴露情况，并完成警觉水平的视觉模拟量表（VAS）。问卷 评估睡眠、警觉性和NMS将在基线时、LT 8周后和治疗结束时进行。 study.目的1将确定LT对自我报告（帕金森病睡眠量表2和睡眠）的影响。 日记）和客观（PSG，活动记录）睡眠测量。目标2将确定LT对昼夜节律的影响 标记，特别是褪黑激素和时钟基因Bmal 1，Per 1，2和3的幅度和相位，以及间- 休息-活动周期的每日稳定性（活动记录）。目标3将确定LT对警觉性的影响（埃普沃思 嗜睡量表和VAS警觉量表）。目标4将确定LT对NMS负担的影响（非运动性 帕金森病症状评估量表和运动障碍协会统一帕金森病第一部分 疾病等级量表）。研究设计将在每个个体中量化LT、目标 以及主观睡眠、昼夜节律标记、警觉性和NMS负担。从长远来看，该项目解决了 需要提高我们对帕金森病中NMS病理生理学的理解，并开发新的治疗方法。短- 长期而言，该项目将通过测试潜在靶点（ 昼夜节律系统）、治疗（LT）和PD人群的结局指标。该项目是响应 在最近的NINDS PD研究共识中概述了临床研究的几个最高优先级领域 会议，并在美国国立卫生研究院睡眠障碍研究计划：（一）开发有效的治疗非运动性 PD的特征;（ii）促进对大脑和身体的睡眠和昼夜节律功能的理解; 以及（iii）改善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.