Abstract Non-motor symptoms (NMS) are some of the most disabling manifestations of Parkinson’s disease (PD). Disrupted sleep and alertness are among the most common NMS. Mechanisms leading to NMS are not well understood and treatment options remain limited. The endogenous human circadian system has a critical role in the regulation of sleep-wake cycles and is mostly effectively synchronized by environmental light. The circadian system has not been systematically studied in the PD population. Our pilot studies in patients with PD revealed: (i) blunting of 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 (LT) on sleep-wake consolidation. This project aims to examine effects of LT on NMS with an emphasis on sleep, alertness, and circadian markers in a cohort of 54 PD participants with poor sleep over 14 weeks. Study participants will be randomized to either bright white LT or dim-red LT (control) condition. Participants will have inpatient assessments for circadian markers and sleep using polysomnography (PSG) before and after LT. Throughout the study, participants will wear an actigraph for continuous monitoring of sleep-wake patterns, keep daily sleep diaries and records of LT exposure, and complete visual analog scales (VAS) for alertness level. Questionnaires to assess sleep, alertness, and NMS will be performed at baseline, following 8 weeks of LT, and at the end of the study. Aim 1 will determine effects of LT on self-reported (Parkinson’s Disease Sleep Scale 2 and sleep diaries) and objective (PSG, actigraphy) measures of sleep. Aim 2 will determine effects of LT on circadian markers, specifically amplitude and phase of melatonin and clock genes Bmal1, Per1,2, and 3, as well as inter- daily stability of the rest-activity cycles (actigraphy). Aim 3 will determine effects of LT on alertness (Epworth Sleepiness Scale and VAS alertness scale). Aim 4 will determine effects of LT on NMS burden (The Non Motor Symptoms Assessment Scale for PD and Part I of the Movement Disorders Society Unified Parkinson’s Disease Rating Scale). The study design will quantify within each individual the relationships of LT, objective and subjective sleep, circadian markers, alertness, and NMS burden. Long-term, this project addresses the need to improve our understanding of the pathophysiology of NMS in PD and develop novel treatments. Short- term, the project will provide a foundation for a future clinical trial of LT through testing of a potential target (the circadian system), therapy (LT) and outcome measures in the PD population. This project is responsive to several highest priority areas for clinical research outlined in the most recent NINDS PD Research Consensus Meeting, and in the NIH Sleep Disorders Research Plan: (i) to develop effective treatments for non-motor features of PD; (ii) to advance the understanding of sleep and circadian functions in both the brain and body; and (iii) to improve prevention, diagnosis, and treatment of sleep and circadian disorders.

Project Narrative Non-motor symptoms (NMS), including poor sleep and alertness affect up to 90% of patients with Parkinson’s disease (PD) and contribute to poor quality of life, morbidity and mortality in the PD population. This project will examine effects of light therapy on sleep, alertness, circadian rhythms and other NMS in PD. Short-term outcomes include clinical recommendations for using light therapy to improve sleep-wake cycles and other NMS in PD, while in the long-term, results from this study will guide development of novel circadian-based treatments for PD.