Retinal Determinants of Circadian Function and Sleep-Wake Cycles in Parkinson's Disease

帕金森病昼夜节律功能和睡眠-觉醒周期的视网膜决定因素

• 批准号: 10735341
• 负责人: Aleksandar Videnovic
• 金额: $ 63.37万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10735341
• 关键词: Acceleration; Admission activity; Advanced Development; Affect; Age; Anatomy; Area; Attenuated; Binding; Biological Markers; Biological Rhythm; Blood specimen; Brain; Cell physiology; Chronic; Circadian Dysregulation; Circadian Rhythms; Clinical Research; Companions; Consensus; Corpus striatum structure; Denervation; Development; Disease; Dopa; Drowsiness; Etiology; Eye; Foundations; Functional disorder; Gender; Gene Expression; Genes; Goals; Health; Hour; Human; Hypothalamic structure; Image; Impairment; Individual; Inpatients; Intervention; Investigation; Light; Lighting; Measurement; Measures; Melatonin; Modeling; Monitor; Morphology; National Institute of Neurological Disorders and Stroke; Nature; Parkinson Disease; Participant; Pathogenesis; Patient Self-Report; Patients; Pharmaceutical Preparations; Phase; Photoreceptors; Phototherapy; Phototransduction; Physiology; Pittsburgh Sleep Quality Index; Play; Polysomnography; Positioning Attribute; Protocols documentation; Pupil; Questionnaires; REM Sleep Behavior Disorder; Reporting; Research; Resistance; Retina; Retinal Degeneration; Retinal Ganglion Cells; Role; Sleep; Sleep Disorders; Sleep Wake Cycle; Sleep disturbances; Stimulus; Surrogate Markers; Symptoms; System; Testing; United States National Institutes of Health; Work; actigraphy; advanced disease; associated symptom; circadian; circadian pacemaker; clinical implementation; common symptom; constriction; density; diaries; disabling symptom; dopamine transporter; effective therapy; experimental study; follow-up; functional improvement; gene therapy; improved; insight; light effects; light transmission; meetings; melanopsin; neurophysiology; new therapeutic target; non-motor symptom; novel; novel marker; participant enrollment; poor sleep; response; screening; single photon emission computed tomography; sleep behavior; sleep quality; suprachiasmatic nucleus; synucleinopathy

Project Summary Disrupted sleep and daytime sleepiness are among the most common non-motor symptoms (NMS) of Parkinson’s disease (PD). Mechanisms underlying these symptoms are not well understood, and treatment options remain limited. The endogenous human circadian system, which is most effectively synchronized by ocular light exposure, has a critical role in regulating sleep and sleepiness. Our investigations in patients with PD revealed: (i) blunting of the 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, a circadian-based intervention, on sleep and wake consolidation. In this project, we propose to expand this line of investigation and examine melanopsin-expressing intrinsically photosensitive Retinal Ganglion Cells (ipRGC) across the continuum of PD. The ipRGC give origin to the retinohypothalamic tract through which they project light stimuli to the central circadian pacemaker and synchronize circadian rhythms to external light, thus affecting circadian and sleep behavior. A recently proposed surrogate marker of melanopsin function in humans is the post-illumination pupil response (PIPR) obtained using non-invasive chromatic pupillometry. To quantify the relationships among ipRGC function, circadian rhythms, sleep, and sleepiness, we will study four groups of participants: (i) advanced PD (n=20), (ii) de-novo, drug-naïve PD (n=20), (iii) REM Sleep Behavior Disorder, which represents a prodromal stage of an evolving synucleinopathy, such as PD (n=20), and (iv) healthy controls (HC) (n=20). After the screening, participants will wear an actiwatch for continuous activity monitoring and keep daily sleep diaries during a 14-day baseline period. Participants will undergo pupillometry and complete questionnaires about sleep and sleepiness, and a subset will undergo Dopamine Transporter SPECT Imaging to quantify nigrostriatal denervation. Participants will be subsequently admitted for inpatient assessment of circadian markers, sleep, and sleepiness, including overnight polysomnography, followed by multiple sleep latency testing and a 24-hour Circadian Protocol for blood sampling for melatonin measurements. Aim 1 will test if melanopsin-dependent retinal phototransduction is altered across the continuum of PD compared with HC. Aims 2 and 3 will test the hypothesis that melanopsin-dependent retinal phototransduction is correlated with circadian amplitude and sleep and/or sleepiness across the continuum of PD compared with HC. Exploratory Aim 4 will examine associations between melanopsin-dependent retinal phototransduction and imaging metrics of the nigrostriatal dopaminergic system. Participants enrolled in years 1-3 will undergo a two- year follow-up pupillometry, actigraphy, and sleep/sleepiness assessment. Short-term, the project will provide a foundation for investigations of retinal/melanopsin physiology in regulating sleep, sleepiness, and other NMS in PD. Long-term, the work will advance the development of novel circadian-based interventions aimed at retinal degeneration in PD, such as photoreceptor-specific light therapy or melanopsin gene therapy.

项目摘要 睡眠和白天嗜睡是最常见的非运动症状（NMS）之一 帕金森氏病（PD）。这些症状的基础机制尚不清楚，治疗 选项仍然有限。内源性人类昼夜节律系统，最有效地同步 眼光暴露，在调节睡眠和嗜睡中起关键作用。我们对患者的调查 PD透露：（i）淡化褪黑激素的昼夜节律，这是昼夜节律的标志； （ii）时钟基因表达的昼夜节律时间（“相”）的变化； （iii）明亮光的有益效果 治疗是一种基于昼夜节律的干预措施，就睡眠和唤醒整合。在这个项目中，我们建议扩展 这种调查和检查黑素蛋白表达本质上光敏性的视网膜神经节细胞 （IPRGC）在PD的连续体中。 IPRGC起源于视网膜丘脑的道路 向中央昼夜节奏起搏器进行灯光刺激，并将昼夜节律同步到外部光线 影响昼夜节律和睡眠行为。最近提出的黑色素蛋白功能的替代标记在人类中 是使用非侵入性色体化学法获得的刷子后瞳孔反应（PIPR）。 为了量化IPRGC功能，昼夜节律，睡眠和嗜睡之间的关系，我们将研究四个 参与者组：（i）高级pd（n = 20），（ii）de-novo，药物不pd（n = 20），（iii）rem睡眠行为 疾病，代表不断发展的突触核蛋白病的前驱阶段，例如PD（n = 20），（iv） 健康对照（HC）（n = 20）。筛选后，参与者将佩戴Actiwatch进行连续活动 在14天的基准期内监视并保留每日睡眠日记。参与者将进行成绩计量法 有关睡眠和嗜睡的完整问卷，子集将经历多巴胺转运蛋白 SPECT成像以量化黑质纹状体神经保护。参与者随后将被接纳为住院 评估昼夜节律标记，睡眠和嗜睡，包括隔夜多摄影术，其次是 多次睡眠潜伏期测试和用于褪黑激素测量的血液采样的24小​​时昼夜节律方案。 AIM 1将测试黑色素蛋白依赖性视网膜光转导在PD的连续体中 与HC相比。目标2和3将检验以下假设，即黑色素蛋白依赖性视网膜光转导 与PD连续的昼夜节律放大器和/或嗜睡相比，与 HC。探索性目标4将检查黑色素蛋白依赖性视网膜光转导和 黑质多巴胺能系统的成像指标。参加1 - 3年的参与者将经历两次 - 年后随访的成绩，行动学和睡眠/嗜睡评估。短期，该项目将提供 在调节睡眠，嗜睡和其他NMS中研究视网膜/黑色素蛋白生理的研究基金会 PD。长期，这项工作将推动旨在视网膜的新型基于昼夜节律的干预措施的发展 PD的变性，例如感光特异性光治疗或黑色素蛋白基因疗法。