A Dose Selection Trial of Light Therapy for Impaired Sleep in Parkinson's Disease

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。帕金森病的这些方面影响多达90% 导致生活质量下降，情绪和认知受损，增加事故风险；以及 导致发病率和死亡率增加。NMS的发病机制未得到很好的认识和治疗 选择仍然有限。内源性人体昼夜节律系统在睡眠和睡眠调节中起着关键作用 警觉性，并最有效地与环境光刺激同步。我们的试点临床试验建议 每天两次的强光疗法(LT)对帕金森病患者的睡眠和警觉性的有益影响。最近的其他几项研究 也显示了LT对帕金森病有类似的有益作用。虽然LT的这些结果令人鼓舞，但剂量方面 在转化为临床实践之前，还需要进一步研究。 本项目旨在研究LT剂量的一个核心方面：LT的频率。剂量频率将 影响LT的依从性和耐受性及临床疗效。在我们提议的工作中，144名帕金森病患者 自我报告睡眠受损的患者将随机接受(I)每天两次(上午)亮白LT(BWLT)治疗 和晚上)，(Ii)BWLT每天一次(仅晚上)，(Iii)BWLT每周一次(仅晚上)，以及(Iv)暗红色LT (DRLT)每天两次(上午和晚上)，每小时一块，为期八周，使用商业上可用的 灯箱。结果将包括安全性以及对睡眠、警觉、疲劳、运动和非运动的测量 症状和生活质量。在整个研究过程中，参与者将佩戴手腕活动记录仪进行连续 监测睡眠-觉醒模式，并保持每天的睡眠日记和LT暴露的记录。目标1将 采用对比选择设计，确定每天服用BWLT是否能改善帕金森病患者的睡眠 足以带入第三阶段疗效试验，如果是的话，带入的剂量频率是多少。目标2 将(I)评估每周一次的BWLT是否是一种适当的但相对于两次更低的负担控制条件- 每日DRLT；(Ii)评估每日BWLT对PD患者疲劳的影响；以及(Iii)确定患者是否坚持 致LT。探索性分析将评估每日BWLT对整体PD症状严重程度、运动和 非运动症状、睡眠的客观测量、生活质量、情绪和认知。 从长远来看，这个项目解决了为睡眠受损和其他NMS开发新疗法的需要 与帕金森病有关。短期内，该项目将为未来LT的第三阶段临床试验奠定基础， 确定了BWLT的最佳频率和合适的控制条件。该项目是对 在最新的(2014)NINDS PD研究中概述了几个最优先的临床研究领域 共识会议和2011年NIH睡眠障碍研究计划：(I)开发有效的治疗方法 帕金森病的非运动特征；(Ii)促进对睡眠和脑内昼夜节律功能的理解 改善睡眠和昼夜节律紊乱的预防、诊断和治疗。

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. These aspects of PD affect as many as 90% of patients; contribute to poor quality of life, impaired mood and cognition, and increased risk for accidents; and lead to increased morbidity and mortality. 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 and alertness and is most effectively synchronized by environmental light stimuli. Our pilot clinical trial suggested beneficial effects of twice-daily bright light therapy (LT) on sleep and alertness in PD. Several other recent studies have revealed similar beneficial effects of LT in PD. While these outcomes of LT are encouraging, dosing aspects of LT require further study before translation to clinical practice. This project aims to investigate one central aspect of dosing of LT: the frequency of LT. Dose frequency will influence adherence and tolerability as well as the clinical effect of LT. In our proposed work, 144 PD patients with impaired sleep by self-report will be randomized to receive (i) bright-white LT (BWLT) twice daily (morning and evening), (ii) BWLT once daily (evening only), (iii) BWLT once weekly (evening only), and (iv) dim-red LT (DRLT) twice daily (morning and evening) in one-hour blocks for eight weeks using a commercially available lightbox. Outcomes will include safety, and measures of sleep, alertness, fatigue, motor and non-motor symptoms, and quality of life. Throughout the study, participants will wear a wrist actigraph for continuous monitoring of sleep-wake patterns, and keep daily sleep diaries and records of their LT exposure. Aim 1 will utilize a comparative selection design to determine whether either daily dose of BWLT improves sleep in PD sufficiently to carry forward into a phase III efficacy trial and, if so, which dose frequency to carry forward. Aim 2 will (i) assess whether once-weekly BWLT is an appropriate but lower burden control condition relative to twice- daily DRLT; (ii) estimate the effect of daily BWLT on fatigue in PD; and (iii) determine whether patients adhere to LT. Exploratory analyses will estimate the effect of daily BWLT on overall PD symptom severity, motor and non-motor symptoms, objective measures of sleep, quality of life, mood, and cognition. Long-term, this project addresses the need to develop novel treatments for impaired sleep and other NMS associated with PD. Short-term, the project will provide a foundation for a future phase III clinical trial of LT by determining the optimal frequency of BWLT and the appropriate control condition. This project is responsive to several highest priority areas for clinical research outlined in the most recent (2014) NINDS PD Research Consensus Meeting and in the 2011 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.