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Cholinergic dysfunction in isolated rapid eye movement sleep behaviour disorder links to impending phenoconversion Terkelsen, Miriam H. Iranzo, Alex Serradell, Mónica Baun, Andreas M. Stokholm, Morten G. Danielsen, Erik Hvid Østergaard, Karen Otto, Maritt Svendsen, Kristina B. Møller, Mette Johnsen, Erik L. Garrido Pla, Alicia Vilas Rolán, Dolores Santamaria Cano, Joan Møller, Arne Gaig Ventura, Carles Brooks, David J. Borghammer, Per Tolosa, Eduardo Pavese, Nicola Dopamina Tomografia per emissió de positrons Receptors colinèrgics Trastorns del son Malaltia de Parkinson Dopamine Positron emission tomography Acetylcholine receptors Sleep disorders Parkinson's disease Background and purpose: Most patients with isolated rapid eye movement sleep behaviour disorder (iRBD) progress to a parkinsonian alpha-synucleinopathy. However, time to phenoconversion shows great variation. The aim of this study was to investigate whether cholinergic and dopaminergic dysfunction in iRBD patients was associated with impending phenoconversion. Methods: Twenty-one polysomnography-confirmed iRBD patients underwent baseline 11C-donepezil and 6-Fluoro-(18F)-l-3,4-dihydroxyphenylalanine (18F-DOPA) positron emission tomography (PET). Potential phenoconversion was monitored for up to 8 years. PET images were analysed according to patients' diagnoses after 3 and 8 years using linear regression. Time-to-event analysis was made with Cox regression, dividing patients into low and high tracer uptake groups. Results: Follow-up was accomplished in 17 patients. Eight patients progressed to either Parkinson's disease (n = 4) or dementia with Lewy bodies (n = 4), while nine remained non-phenoconverters. Compared with non-phenoconverters, 8-year phenoconverters had lower mean 11C-donepezil uptake in the parietal (p = 0.032) and frontal cortex (p = 0.042), whereas mean 11C-donepezil uptake in 3-year phenoconverters was lower in the parietal cortex (p = 0.005), frontal cortex (p = 0.025), thalamus (p = 0.043) and putamen (p = 0.049). Phenoconverters within 3 years and 8 years had lower 18F-DOPA uptake in the putamen (p < 0.001). iRBD patients with low parietal 11C-donepezil uptake had a 13.46 (95% confidence interval 1.42;127.21) times higher rate of phenoconversion compared with those with higher uptake (p = 0.023). iRBD patients with low 18F-DOPA uptake in the most affected putamen were all phenoconverters with higher rate of phenoconversion (p = 0.0002). Conclusions: These findings suggest that cortical cholinergic dysfunction, particularly within the parietal cortex, could be a biomarker candidate for predicting short-term phenoconversion in iRBD patients. This study aligns with previous reports suggesting dopaminergic dysfunction is associated with forthcoming phenoconversion. 2025-05-20T17:48:01Z 2025-05-20T17:48:01Z 2024-10-03 2025-05-20T17:48:01Z info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion Reproducció del document publicat a: https://doi.org/10.1111/ene.16503 European Journal of Neurology, 2024, vol. 31, num.12 https://doi.org/10.1111/ene.16503 cc-by-nc-nd (c) Terkelsen, Miriam H. et al., 2024 http://creativecommons.org/licenses/by-nc-nd/4.0/ info:eu-repo/semantics/openAccess Wiley Articles publicats en revistes (Medicina)