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.

项目概要 睡眠中断和白天嗜睡是最常见的非运动症状 (NMS) 帕金森病（PD）。这些症状背后的机制尚不清楚，并且治疗 选择仍然有限。内源性人体昼夜节律系统，最有效地同步 眼睛的光线照射，在调节睡眠和困倦方面具有关键作用。我们对患者的调查 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； (ii) 时钟基因表达的昼夜节律计时（“相位”）的变化； (iii) 强光的有益效果 治疗是一种基于昼夜节律的干预措施，针对睡眠和清醒巩固。在这个项目中，我们建议扩展 这一系列的研究和检查表达黑视蛋白的本质光敏视网膜神经节细胞 (ipRGC) 跨越 PD 的连续体。 ipRGC 起源于视网膜下丘脑束，通过该束 将光刺激投射到中央昼夜节律起搏器，并使昼夜节律与外部光同步，从而 影响昼夜节律和睡眠行为。最近提出的人类黑视蛋白功能的替代标记 是使用非侵入式彩色瞳孔测量法获得的照明后瞳孔反应 (PIPR)。 为了量化 ipRGC 功能、昼夜节律、睡眠和困倦之间的关系，我们将研究四个 参与者分组：(i) 晚期帕金森病 (n=20)，(ii) 初治药物帕金森病 (n=20)，(iii) 快速眼动睡眠行为 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)，以及 (iv) 健康对照 (HC) (n=20)。放映结束后，参与者将佩戴 actiwatch 进行持续活动 在 14 天的基线期内监测并记录每日睡眠日记。参与者将接受瞳孔测量 并完成有关睡眠和困倦的调查问卷，其中一部分将接受多巴胺转运蛋白治疗 SPECT 成像量化黑质纹状体去神经。参与者随后将入院住院 评估昼夜节律标记、睡眠和困倦，包括夜间多导睡眠图，然后 多次睡眠潜伏期测试和 24 小时昼夜节律协议，用于采血测量褪黑激素。 目标 1 将测试黑视蛋白依赖性视网膜光转导是否在 PD 连续体中发生改变 与HC相比。目标 2 和 3 将检验以下假设：黑视蛋白依赖性视网膜光转导 与 PD 连续体中的昼夜节律幅度以及睡眠和/或困倦相关 HC。探索性目标 4 将检查黑视蛋白依赖性视网膜光转导与 黑质纹状体多巴胺能系统的成像指标。 1-3年级注册的参与者将接受两次- 年随访瞳孔测量、体动记录仪和睡眠/困倦评估。短期内，该项目将提供 视网膜/黑视蛋白生理学在调节睡眠、困倦和其他 NMS 方面的研究基础 PD。从长远来看，这项工作将推动针对视网膜的新型昼夜节律干预措施的开发 PD 退化，例如光感受器特异性光疗法或黑视蛋白基因疗法。