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Cholinergic dysfunction in isolated rapid eye movement sleep behaviour disorder links to impending phenoconversion

Lookup NU author(s): Emeritus Professor David Brooks, Professor Nicola PaveseORCiD

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This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).


Abstract

© 2024 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.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.


Publication metadata

Author(s): Terkelsen MH, Iranzo A, Serradell M, Baun AM, Stokholm MG, Danielsen EH, Ostergaard K, Otto M, Svendsen KB, Moller M, Johnsen EL, Garrido A, Vilas D, Santamaria J, Moller A, Gaig C, Brooks DJ, Borghammer P, Tolosa E, Pavese N

Publication type: Article

Publication status: Published

Journal: European Journal of Neurology

Year: 2024

Pages: epub ahead of print

Online publication date: 03/10/2024

Acceptance date: 16/09/2024

Date deposited: 15/10/2024

ISSN (print): 1351-5101

ISSN (electronic): 1468-1331

Publisher: John Wiley and Sons Inc

URL: https://doi.org/10.1111/ene.16503

DOI: 10.1111/ene.16503

Data Access Statement: The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical res

PubMed id: 39360592


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Funding

Funder referenceFunder name
Augustinus Fond (Denmark; 23-0916)
Danish Council for Independent Research (Denmark; 4004-00480B, 8020-00260B)
Danish Parkinson's Association (Denmark; R4-A104-B60)
Instituto de Salud Carlos III (Spain; CB06/05/0018)

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