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

帕金森病非运动症状的亮光调节

• 批准号: 10054198
• 负责人: Aleksandar Videnovic
• 金额: $ 55.07万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10054198
• 关键词: ARNTL gene; Activity Cycles; Address; Affect; Area; Biological Rhythm; Brain; Chronic; Circadian Dysregulation; Circadian Rhythms; Clinical; Clinical Research; Clinical Trials; Consensus; Coupled; Development; Diagnosis; Disease; Dopa; Drowsiness; Etiology; Foundations; Functional disorder; Future; Gene Expression; Genes; Goals; Hormonal; Hour; Human; Hypothalamic structure; Impairment; Individual; Inpatients; Intervention; Life; Light; Measures; Medical; Medicine; Melatonin; Morbidity - disease rate; Movement Disorder Society Unified Parkinson' s Disease Rating Scale; National Institute of Neurological Disorders and Stroke; Nature; Neurodegenerative Disorders; Outcome; Outcome Measure; Parkinson Disease; Participant; Patient Self-Report; Patients; Pattern; Phase; Phototherapy; Pilot Projects; Polysomnography; Population; Prevention; Psyche structure; Quality of life; Questionnaires; Randomized; Recommendation; Records; Reporting; Research; Research Design; Resistance; Rest; Role; Severities; Signal Transduction; Sleep; Sleep Disorders; Sleep Wake Cycle; Sleep disturbances; System; Testing; United States National Institutes of Health; Visual; Work; actigraphy; alertness; analog; associated symptom; base; circadian; cohort; diaries; effective therapy; experience; improved; improved functioning; insight; light effects; meetings; molecular marker; mortality; non-motor symptom; novel; poor sleep; sleep regulation; suprachiasmatic nucleus; therapeutic target; therapy outcome

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.

抽象的 非运动症状（NMS）是帕金森病（PD）最严重的一些表现。 睡眠障碍和警觉性是导致 NMS 的最常见机制。 内源性人体昼夜节律系统发挥着关键作用。 调节睡眠-觉醒周期，并且主要通过环境光有效地同步。 我们尚未对 PD 患者的昼夜节律系统进行过系统研究。 PD 揭示：(i) 褪黑激素的昼夜节律减弱，褪黑激素是昼夜节律的公认标志物 (ii) 时钟基因表达的昼夜节律时间（“阶段”）的变化；以及（iii）强光疗法的有益效果； （LT）关于睡眠-觉醒巩固。 该项目旨在研究 LT 对 NMS 的影响，重点是睡眠、警觉性和昼夜节律 研究参与者将被随机分组​​，该队列由 54 名睡眠质量不佳的 PD 参与者组成。 参与者将接受亮白色 LT 或暗红色 LT（对照）条件的住院评估。 在整个研究过程中，使用多导睡眠图 (PSG) 测量昼夜节律标记和睡眠。 参与者将佩戴活动记录仪来持续监测睡眠-觉醒模式，记录每日睡眠日记 LT 暴露记录，以及完整的警觉水平问卷视觉模拟量表 (VAS)。 评估睡眠、警觉性和 NMS 将在基线、LT 8 周后以及治疗结束时进行 研究目标 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。 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 Bmal1、Per1、2 和 3 的振幅和相位，以及间 每日休息活动周期的稳定性（体动记录仪）将确定 LT 对警觉性的影响 (Epworth)。 目标 4 将确定 LT 对 NMS 负担的影响（非电机 PD 症状评估量表和运动障碍协会统一帕金森病第一部分 研究设计将量化每个个体内 LT、客观的关系。 从长远来看，该项目解决了主观睡眠、昼夜节律标记、警觉性和 NMS 负担。 需要提高我们对 PD 中 NMS 病理生理学的理解并开发新的治疗方法。 短期内，该项目将通过测试潜在目标（即 PD 人群中的昼夜节律系统）、治疗 (LT) 和结果测量。 最新的 NINDS PD 研究共识中概述了临床研究的几个最优先领域 会议以及 NIH 睡眠障碍研究计划：(i) 开发非运动障碍的有效治疗方法 PD 的特征；(ii) 增进对大脑和身体睡眠和昼夜节律功能的了解； (iii) 改善睡眠和昼夜节律紊乱的预防、诊断和治疗。

项目成果

Chronotype, sleep, and sleepiness in Parkinson's disease.

帕金森病的睡眠时间型、睡眠和嗜睡。

• DOI: 10.1016/j.parkreldis.2022.10.011
• 发表时间: 2023
• 期刊: Parkinsonism & related disorders
• 影响因子: 4.1
• 作者: Murphy,Samantha;Chibnik,LoriB;Videnovic,Aleksandar
• 通讯作者: Videnovic,Aleksandar

SLEEP AND CIRCADIAN RHYTHM DISORDERS IN PARKINSON'S DISEASE.

• DOI: 10.1007/s40675-017-0079-y
• 发表时间: 2017-09
• 期刊: Current sleep medicine reports
• 影响因子: 1.8
• 作者: Gros P;Videnovic A
• 通讯作者: Videnovic A

Management of sleep disorders in Parkinson's disease and multiple system atrophy.

• DOI: 10.1002/mds.26918
• 发表时间: 2017-05
• 期刊: Movement disorders : official journal of the Movement Disorder Society
• 作者: Videnovic A

Light Therapy in Parkinson's Disease: Towards Mechanism-Based Protocols.

• DOI: 10.1016/j.tins.2018.03.002
• 发表时间: 2018-05
• 期刊: Trends in neurosciences
• 影响因子: 15.9
• 作者: Fifel K;Videnovic A
• 通讯作者: Videnovic A

Clinical trials in REM sleep behavioural disorder: challenges and opportunities.

• DOI: 10.1136/jnnp-2020-322875
• 发表时间: 2020-07
• 期刊: Journal of neurology, neurosurgery, and psychiatry
• 作者: Videnovic A;Ju YS;Arnulf I;Cochen-De Cock V;Högl B;Kunz D;Provini F;Ratti PL;Schiess MC;Schenck CH;Trenkwalder C;Treatment and Trials Working Group of the International RBD Study Group
• 通讯作者: Treatment and Trials Working Group of the International RBD Study Group