Pupillary response to light progressively declines from healthy aging to REM sleep behavior disorder to Parkinson’s disease
The melanopsin-mediated pupillary light response shows a graded reduction from healthy controls to patients with isolated REM sleep behavior disorder (iRBD) to those with Parkinson’s disease (PD), making it a potential non-invasive biomarker for early synucleinopathy, according to a study in Movement Disorders.
The post-illumination pupillary response (PIPR) was also positively associated with circadian rest-activity rhythm amplitude and cognitive performance, linking melanopsin dysfunction to the non-motor features of these conditions.
What they found
Chan and colleagues from the Chinese University of Hong Kong and the University of Pittsburgh measured the PIPR at 6 seconds after light offset in 135 participants, 45 per group, matched for age (mean 64.4 years) and sex (56% male). The net PIPR was calculated by subtracting the red-light response from the blue-light response, isolating the melanopsin-driven component from cone and rod contributions.
The results showed a clear progressive gradient:
- Healthy controls: 23.8% net PIPR-6s
- iRBD (prodromal synucleinopathy): 18.6%
- Parkinson’s disease: 13.3%
The differences were highly significant (p < 0.001), with a stepwise reduction across groups.
Net PIPR-6s was also positively associated with circadian rest-activity rhythm amplitude and mesor (measured by 1-week actigraphy), as well as with scores on the Hong Kong Montreal Cognitive Assessment. This suggests that melanopsin dysfunction is linked not only to neurodegeneration but also to the circadian disruption and cognitive decline common in PD and its prodromal stages.
Why it matters
Idiopathic RBD is the strongest known predictor of prodromal synucleinopathy, over 80% of iRBD patients will eventually develop Parkinson’s disease or dementia with Lewy bodies. However, reliable, non-invasive biomarkers to track disease progression from the prodromal stage are lacking.
The PIPR is quick, non-invasive, and requires only standard pupillometry equipment. The graded reduction across the healthy-iRBD-PD continuum suggests it could serve as a progression marker in clinical trials of disease-modifying therapies, or as a screening tool to identify iRBD patients at highest risk of imminent conversion.
The associations with circadian amplitude and cognition also implicate melanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs) in the broader non-motor symptom burden of synucleinopathies, which may open new targets for circadian-based interventions.
Limits
The study is cross-sectional. Longitudinal data are needed to determine whether PIPR declines over time within individuals and whether the rate of decline predicts conversion from iRBD to PD. The findings also require replication in more diverse populations beyond the Hong Kong cohort.
Bottom line
Melanopsin-mediated pupillary response is progressively reduced across the healthy-iRBD-PD continuum and correlates with circadian rhythm strength and cognitive performance, supporting its development as a non-invasive biomarker for synucleinopathy progression.
Source: Chan JWY, Huang B, Gong S, et al. Melanopsin-Mediated Post-Illumination Pupillary Response in Idiopathic REM Sleep Behavior Disorder and Parkinson’s Disease. Movement Disorders. 2026 Jun 29. DOI: 10.1002/mds.70412