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Background/Objective: Idiopathic REM sleep behavior disorder (iRBD) often precedes Parkinson's disease (PD) and other alpha-synucleinopathies. The aim of the study is to investigate brain glucose metabolism of patients with RBD and PD by means of a multidimensional scaling approach, using18F-FDG-PET as a biomarker of synaptic function. Methods: Thirty-six iRBD patients (64.1±6.5 y, 32 M), 72 PD patients, and 79 controls (65.6±9.4 y, 53 M) underwent brain 18 F-FDG-PET. PD patients were divided according to the absence (PD, 32 subjects; 68.4±8.5 y, 15 M) or presence (PDRBD, 40 subjects; 71.8±6.6 y, 29 M) of RBD. 18F-FDG-PET scans were used to independently discriminate subjects belonging to four categories: Controls (RBD no, PD no), iRBD (RBD yes, PD no), PD (RBD no, PD yes) and PDRBD (RBD yes, PD yes). Results: The discriminant analysis was moderately accurate in identifying the correct category. This is because the model mostly confounds iRBD and PD, thus the intermediate classes. Indeed, iRBD, PD and PDRBD were progressively located at increasing distance from controls and are ordered along a single dimension (principal coordinate analysis) indicating the presence of a single flux of variation encompassing both RBD and PD conditions. Conclusion: Data-driven approach to brain 18 F-FDG-PET showed only moderate discrimination between iRBD and PD patients, highlighting brain glucose metabolism heterogeneity among such patients. iRBD should be considered as a marker of an ongoing condition that may be picked-up in different stages across patients and thus express different brain imaging features and likely different clinical trajectories.

Rationale: Idiopathic REM sleep behavior disorder (iRBD) is considered a prodromal stage of Parkinson's disease (PD) and other Lewy-body disorders. Spatial covariance analysis of [18F]-Fluorodeoxyglucose Positron Emission Tomography (18F-FDG-PET) data has disclosed a specific brain pattern of altered glucose metabolism in PD. In this study, we identify the metabolic pattern underlying iRBD and compare it to the known PD pattern. To understand the relevance of the iRBD pattern to disease progression, we study the expression of the iRBD pattern in de novo PD patients.Methods:The iRBD-related pattern was identified in18F-FDG-PET scans of 21 patients with polysomnographically-confirmed iRBD and 19 controls using spatial covariance analysis. Expression of the iRBD-related pattern was subsequently computed in18F-FDG-PET scans of 44 controls and 38 de novo, treatment-naïve PD patients. Of these 38 PD patients, 24 had probable RBD according to the Mayo Sleep Questionnaire. Neuropsychological evaluation showed mild cognitive impairment in 20 PD patients (PD-MCI), of whom sixteen also had concomitant RBD and roughly half (11/20) had bilateral motor symptoms.Results:The iRBD-related pattern was characterized by relative hypermetabolism in cerebellum, brainstem, thalamus, sensorimotor cortex, and hippocampus, and by relative hypometabolism in middle cingulate, temporal, occipital and parietal cortices. This topography partially overlapped with the PD-related pattern (PDRP). The iRBD-related pattern was significantly expressed in PD patients compared to controls (P