Objective: Since easily accessible (bio-) markers are needed to predict progression and outcome in prodromal stages of neurodegenerative diseases this study was designed to evaluate PLR in iRBD compared to PD patients and healthy controls.

Background: Visual and retinal dysfunction including impairment of the pupillary light reflex (PLR) have already been described in Parkinson’s disease (PD) [1]. However, recent studies strongly indicated PLR abnormalities even in clinically isolated REM Sleep Behavior Disorder (iRBD) as a prodromal stage of α-synuncleinopathies [2].

Method: We included 16 iRBD patients (age 69.1±6.9years), 14 matched PD patients (n =14, age 69.1±7.5years, UPDRS III 20.8±12.9; H&Y 2.2±0.4) as well as 13 matched controls (age 68.8±6.3years). iRBD patients and control groups underwent extensive neuro-ophthalmological evaluation including standardized infrared pupillometry using the Compact Integrated Pupillograph (CIP, AmTech, Weinheim, Germany).  RBD patients were re-evaluated longitudinally in standardized intervals of 1 and 2 years after baseline, PLR metrics were associated with clinical variables at baseline and follow-up visits. Exclusion criteria included ophthalmological conditions interfering with PLR, e.g. glaucoma.

Results: PLR amplitude was decreased in PD patients compared to iRBD and controls (ANOVA/Bonferroni P=0.003 and P=0.026, respectively). Furthermore, PLR latency was increased in PD compared to the control group (ANOVA/Bonferroni, P=0.031). Pupil amplitude was negatively associated with UPDRS II and UPDRS total scores (Pearson test r=-0.499; P=0.001; r=-0.338; P=0.030, respectively). Furthermore, constriction velocity was negatively associated with RBDSQ scores and hyposmia at baseline (Sniffin sticks SDI, r=0.573, P=0.016). After 2 years the differential increase of UPDRS I score (2±0) was closely associated with PLR latency (r=0.789, P=0.002).

Conclusion: Evaluation of PLR showed autonomic and retinal dysfunction in PD and iRBD confirming early involvement of retinal and brainstem structures within the neurodegenerative process. Our results are in line with recent studies indicating more widespread α-synunclein pathology in patients with iRBD as compared to the supposed amygdala/brain first subtype [3]. Further research is needed to evaluate these potential markers in neurodegenerative diseases and to confirm our results.

References: 1. Wang CA, McInnis H, Brien DC, Pari G, Munoz DP. Disruption of pupil size modulation correlates with voluntary motor preparation deficits in Parkinson’s disease. Neuropsychologia. 2016 Jan 8;80:176-184. doi:10.1016/ j.neuropsychologia.2015.11.019. Epub 2015 Nov 26.PMID: 26631540

2. Perkins JE, Janzen A, Bernhard FP, Wilhelm K, Brien DC, Huang J, Coe BC, Vadasz D, Mayer G, Munoz DP, Oertel WH. Saccade, Pupil, and Blink Responses in Rapid Eye Movement Sleep Behavior Disorder. Mov Disord. 2021 Jul;36(7):1720-1726. doi: 10.1002/mds.28585. Epub 2021 Mar 22.PMID: 33754406

3. Borghammer P, Just MK, Horsager J, Skjærbæk C, Raunio A, Kok EH, Savola S, Murayama S, Saito Y, Myllykangas L, Van Den Berge N. A postmortem study suggests a revision of the dual-hit hypothesis of Parkinson’s disease. NPJ Parkinsons Dis. 2022 Nov 30;8(1):166. doi: 10.1038/s41531-022-00436-2.PMID: 36450732

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MDS Abstracts - https://www.mdsabstracts.org/abstract/pupil-response-is-impaired-in-clinically-isolated-rem-sleep-behavior-disorder-and-parkinsons-disease/