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.

项目总结