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.

FIGURE 1

Regions of interest analyses of baseline positron emission tomography ¹¹C‐donepezil distribution volume ratio (DVR) values. Phenoconverters (n = 6, purple), non‐phenoconverters (n = 9, green) and healthy controls (n = 9, blue), mean ± 1 standard deviation (SD). Purple circles: Parkinson's. Purple squares: dementia with Lewy bodies. Dot inside: below 2 SDs from the isolated rapid eye movement sleep behaviour disorder group mean (dotted line). *p < 0.05.

FIGURE 2

Regions of interest analyses of baseline postitron emission tomography 6‐Fluoro‐(¹⁸F)‐l‐3,4‐dihydroxyphenylalanine (¹⁸F‐DOPA) K _i values. Phenoconverters (n = 8, purple), non‐phenoconverters (n = 9, green) and healthy controls (n = 9, blue), mean ± 1 standard deviation (SD). Purple circles: Parkinson's disease. Purple squares: dementia with Lewy bodies. Dot inside: below 2 SDs from the isolated rapid eye movement sleep behaviour disorder group mean (dotted line). *p < 0.05.

FIGURE 3

Analyses of time from postitron emission tomography (PET) scan to recognise phenoconversion. Kaplan–Meier failure plots. PET uptake values lower (red) and equal to or higher (blue) than the group mean. (a) ¹¹C‐donepezil PET uptake in the parietal cortex. (b) 6‐Fluoro‐(¹⁸F)‐l‐3,4‐dihydroxyphenylalanine (¹⁸F‐DOPA) PET uptake in the most and least affected putamen.