Objective: To determine whether resting-state pupil fluctuations reflect structural and functional impairment of monoaminergic brainstem nuclei and are associated with non-motor symptom burden in early Parkinson’s disease (PD).

Background: Early stages of PD are characterized by non-motor symptoms (NMS) that reduce quality of life. NMS are thought to arise from dysfunction of monoaminergic brainstem nuclei. Resting-state pupil fluctuations are considered a non-invasive proxy for central neuromodulatory activity, particularly noradrenergic signaling, but their relationship to brainstem alterations in early PD remains unclear.

Method: We studied 43 patients with early PD (Hoehn and Yahr ≤2) and 43 age- and sex-matched healthy controls. The multimodal protocol included neuromelanin-sensitive MRI (NM-MRI) and resting-state fMRI with simultaneous in-scanner pupillometry. The locus coeruleus (LC), substantia nigra (SN), and ventral tegmental area (VTA) were manually segmented based on relative intensity and predefined anatomical ROIs. Functional data were preprocessed using a brainstem-optimized pipeline in SPM12. Seed-based connectivity analyses were performed for these nuclei and an additional MNI-based dorsal raphe nucleus mask. Pupil fluctuation metrics were derived using an OpenCV-based pipeline. Coupling between BOLD fluctuations and pupil dynamics was assessed using general linear and cross-correlation models. NMS-related measures (BDI-II, PHQ-9, PDQ-39, MoCA) were correlated with imaging and pupillometric measures.

Results: Compared with controls, patients showed significantly reduced LC and SN volumes on NM-MRI (both p<0.0001) and altered seed-based functional connectivity. Resting-state pupil fluctuations correlated with structural integrity and functional connectivity of monoaminergic brainstem nuclei, most prominently the LC. Coupling between pupil dynamics and LC-BOLD activity was impaired in early PD. Imaging and pupillometric measures correlated with NMS-related measures.

Conclusion: Resting-state pupil fluctuations reflect structural and functional dysfunction of monoaminergic brainstem nuclei in early PD, particularly the LC, and are associated with non-motor symptom burden. Pupillometry may be a promising non-invasive biomarker of non-dopaminergic dysfunction underlying non-motor symptoms in early PD.

« Back to 2026 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/resting-state-pupil-fluctuations-reflect-monoaminergic-brainstem-dysfunction-associated-with-non-motor-symptoms-in-early-parkinsons-disease/