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

Abstract

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.

Keywords: REM sleep behavior disorder; cholinergic neurons/abnormalities; dopaminergic imaging; positron emission tomography.