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 睡眠中断和白天嗜睡是最常见的非运动症状（NMS）之一， 帕金森病（PD）。这些症状背后的机制还不清楚，治疗 选择仍然有限。内源性人类昼夜节律系统，其最有效地同步于 眼睛的光暴露，在调节睡眠和困倦中具有关键作用。我们在患者中的研究 PD显示：（i）褪黑激素的昼夜节律变钝，褪黑激素是一种公认的昼夜节律标志物; (ii)生物钟基因表达的昼夜节律定时（“相位”）的变化;以及（iii）强光的有益效果 治疗，一种基于昼夜节律的干预，对睡眠和觉醒的巩固。在这个项目中，我们建议扩大 这一系列的调查和检查黑视蛋白表达的内在感光视网膜神经节细胞 （ipRGC）跨越PD的连续体。ipRGC起源于视网膜下丘脑束， 将光刺激投射到中枢昼夜节律起搏器并使昼夜节律与外部光同步， 影响昼夜节律和睡眠行为。最近提出的人类黑视素功能的替代标志物 是使用非侵入式彩色瞳孔测量法获得的照明后瞳孔响应（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）晚期PD（n=20），（ii）新发、药物初治PD（n=20），（iii）REM睡眠行为 病症，其代表进展性突触核蛋白病的前驱期，例如PD（n=20），和（iv） 健康对照（HC）（n=20）。筛选结束后，参与者将佩戴actiwatch进行持续活动 在14天的基线期内监测并保持每日睡眠日记。参与者将接受瞳孔测量 并完成关于睡眠和嗜睡的问卷调查，一部分人将接受多巴胺转运蛋白治疗， SPECT成像以量化黑质纹状体去神经支配。受试者随后将住院 评估昼夜节律标志物、睡眠和嗜睡，包括夜间多导睡眠描记，然后 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。 目的1将测试黑视素依赖性视网膜光转导是否在PD的连续过程中发生改变， 与HC相比。目的2和3将检验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和睡眠和/或嗜睡相关， 嗯。探索性目标4将检查黑视蛋白依赖性视网膜光转导与视网膜光信号转导之间的关系。 黑质纹状体多巴胺能系统的成像指标。1-3年级的学生将接受两次- 年随访瞳孔测量、体动记录和睡眠/嗜睡评估。短期内，该项目将提供 研究视网膜/黑视素生理学在调节睡眠、嗜睡和其他NMS方面的基础， 警局从长远来看，这项工作将推动针对视网膜病变的新型基于昼夜节律的干预措施的发展。 在PD中的变性，例如光受体特异性光疗法或黑视素基因疗法。