# Retinal Determinants of Circadian Function and Sleep-Wake Cycles in Parkinson's Disease

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2024 · $611,020

## Abstract

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 p...

## Key facts

- **NIH application ID:** 10912809
- **Project number:** 5R01NS129636-02
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Aleksandar Videnovic
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $611,020
- **Award type:** 5
- **Project period:** 2023-09-01 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10912809

## Citation

> US National Institutes of Health, RePORTER application 10912809, Retinal Determinants of Circadian Function and Sleep-Wake Cycles in Parkinson's Disease (5R01NS129636-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10912809. Licensed CC0.

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