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 睡眠障碍和白天嗜睡是最常见的非运动症状(NMS)之一 帕金森氏病(PD)。这些症状的潜在机制尚不清楚，治疗 选择仍然有限。内源性的人类昼夜节律系统，最有效的同步方式是 眼部光线暴露，在调节睡眠和困倦方面起着至关重要的作用。我们对慢性阻塞性肺疾病患者的调查 PD显示：(I)褪黑素的昼夜节律减弱，褪黑素是昼夜节律的公认标记物； (Ii)时钟基因表达的昼夜节律(“阶段”)的变化；及。(Iii)强光的有益影响。 治疗，一种基于昼夜节律的干预，对睡眠和清醒的巩固。在这个项目中，我们建议扩展 这一系列研究和检测黑素表达本质上是光敏性视网膜神经节细胞 (IpRGC)跨越PD的连续体。IpRGC起源于视网膜下丘脑束，它们通过该束 将光刺激投射到中央昼夜节律起搏器，使昼夜节律与外部光同步，从而 影响昼夜节律和睡眠行为的。最近提出的人类黑素功能的替代标记物 是使用非侵入性彩色瞳孔测量法获得的照明后的瞳孔反应(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 参与者组：(I)晚期帕金森病(n=20)，(Ii)去新生，药物-幼稚帕金森病(n=20)，(Iii)快速眼动睡眠行为 紊乱，代表进行性联核病的前驱阶段，如帕金森病(n=20)，以及(Iv) 健康对照组(HC)(n=20)。筛选结束后，参与者将佩戴Actiwatch进行持续活动 在14天的基准期内监测并记录每日睡眠日记。参与者将接受斜视测量 并完成关于睡眠和困倦的问卷，其中一部分将接受多巴胺转运蛋白的测试 SPECT成像定量测定黑质纹状体失神经。参与者随后将因住院而入院。 评估昼夜节律标记物、睡眠和困倦，包括夜间多导睡眠图，随后进行 多重睡眠潜伏期测试和24小时昼夜节律血样测量褪黑激素。 Aim 1将测试依赖于黑素蛋白的视网膜光转导是否在整个PD的连续体中发生改变 与HC相比。目标2和目标3将检验黑素依赖的视网膜光转导的假设 与昼夜节律幅度以及睡眠和/或嗜睡程度在整个PD连续体中的相关性 啊哈。探索性目标4将研究依赖于黑素的视网膜光转导和 黑质纹状体多巴胺能系统的成像测量。在1-3年级注册的学员将经历两次- 一年随访的斜视测量、活动描记和睡眠/嗜睡评估。短期内，该项目将提供 视网膜/黑素蛋白生理学在调节睡眠、嗜睡和其他NMS中的研究基础 警察。从长远来看，这项工作将推动以昼夜节律为基础的针对视网膜的新型干预措施的发展 帕金森病的变性，如光感受器特异光疗法或黑素基因疗法。