SNRI-driven recovery of impaired pupil dynamics in Progressive Supranuclear Palsy

BackgroundProgressive supranuclear palsy (PSP) is a tauopathy marked by early degeneration of brainstem nuclei such as the locus coeruleus (LC), a central player of the ascending reticular activating system (ARAS). ARAS dysfunction contributes to cognitive and arousal disturbances and is increasingly recognized as a therapeutic target. Methods14 PSP patients (eight females, age 70.81 {+/-} 6.32 years, disease duration 4.69 {+/-} 3.24 years) were assessed before and after [≥]4 weeks of SNRI (serotonin-norepinephrine reuptake inhibitor) treatment. Participants were assessed by non-invasive neurophysiological measures as pupillometry, performed at rest and during an auditory oddball paradigm, and clinically, using PSP-specific clinical scales and quantitative gait analysis. Pupil, cognitive, and gait parameters were compared with age-matched healthy controls. ResultsAt baseline, pupil size, pupil dilation responses and surprise pupil responses were reduced in PSP patients compared to controls, accompanied by impaired executive functions, reduced phonemic verbal fluency and depressive symptoms in PSP patients. SNRI treatment selectively rescued certain impaired pupil metrics in PSP, leading to a significant improvement of the surprise pupil response and partial normalization of pupil fluctuations at rest. Pupil metric changes were associated with notable improvement in executive functions and quality of life at follow-up. ConclusionIn summary, our findings reveal altered pupil-linked arousal regulation in PSP and its modulation by SNRI therapy, suggesting pupillometric indices as promising biomarkers of therapeutic response.