This is an international multicentre study aimed at evaluating the combined value of dopaminergic neuroimaging and clinical features in predicting future phenoconversion of idiopathic REM sleep behaviour (iRBD) subjects to overt synucleinopathy. Nine centres sent 123I-FP-CIT-SPECT data of 344 iRBD patients and 256 controls for centralized analysis. 123I-FP-CIT-SPECT images were semiquantified using DaTQUANTTM, obtaining putamen and caudate specific to non-displaceable binding ratios (SBRs). The following clinical variables were also analysed: (i) Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale, motor section score; (ii) Mini-Mental State Examination score; (iii) constipation; and (iv) hyposmia. Kaplan-Meier survival analysis was performed to estimate conversion risk. Hazard ratios for each variable were calculated with Cox regression. A generalized logistic regression model was applied to identify the best combination of risk factors. Bayesian classifier was used to identify the baseline features predicting phenoconversion to parkinsonism or dementia. After quality check of the data, 263 iRBD patients (67.6 ± 7.3 years, 229 males) and 243 control subjects (67.2 ± 10.1 years, 110 males) were analysed. Fifty-two (20%) patients developed a synucleinopathy after average follow-up of 2 years. The best combination of risk factors was putamen dopaminergic dysfunction of the most affected hemisphere on imaging, defined as the lower value between either putamina (P < 0.000001), constipation, (P < 0.000001) and age over 70 years (P = 0.0002). Combined features obtained from the generalized logistic regression achieved a hazard ratio of 5.71 (95% confidence interval 2.85-11.43). Bayesian classifier suggested that patients with higher Mini-Mental State Examination score and lower caudate SBR asymmetry were more likely to develop parkinsonism, while patients with the opposite pattern were more likely to develop dementia. This study shows that iRBD patients older than 70 with constipation and reduced nigro-putaminal dopaminergic function are at high risk of short-term phenoconversion to an overt synucleinopathy, providing an effective stratification approach for future neuroprotective trials. Moreover, we provide cut-off values for the significant predictors of phenoconversion to be used in single subjects.

Centre of Sleep Medicine Dokkyo Medical University Hospital Tochigi Japan

Clinical Neurology Department of Neuroscience University of Genoa Italy

Department of Biomedical and Neuromotor Sciences University of Bologna Bologna Italy

Department of Brain and Behavioural Sciences University of Pavia Pavia Italy

Department of Neurology and Centre of Clinical Neuroscience 1st Faculty of Medicine Charles University and General University Hospital Prague Czech Republic

Department of Neurology Dokkyo Medical University Saitama Medical Centre Saitama Japan

Department of Neurology Mayo Clinic Rochester Minnesota USA

Department of Nuclear Medicine Mayo Clinic Rochester Minnesota USA

Department of Sleep and Neurology Beau Soleil Clinic and EuroMov Digital Health in Motion University of Montpellier Montpellier France

Division of Sleep Medicine Kansai Electric Power Medical Research Institute Osaka Japan

Institute of Clinical Neurosciences University of Bristol Bristol UK

Institute of Nuclear Medicine 1st Faculty of Medicine Charles University and General University Hospital Prague Czech Republic

IRCCS Istituto delle Scienze Neurologiche di Bologna Bologna Italy

IRCCS Ospedale Policlinico San Martino Genoa Italy

National Institute of Nuclear Physics Genoa section Genoa Italy

Neurology Unit Movement Disorders Division Department of Neurosciences Biomedicine and Movement Sciences University of Verona Verona Italy

Nuclear Medicine Department of Health Sciences University of Genoa Italy

Nuclear Medicine Unit Department of Medical Science and Public Health University of Cagliari Cagliari Italy

Nuclear Medicine Unit ICS Maugeri SpA SB IRCCS Pavia Italy

Nuclear Medicine Unit University hospital of Montpellier France

Oxford Parkinson's Disease Centre Nuffield Department of Clinical Neurosciences University of Oxford John Radcliffe Hospital Oxford UK

PETIC University Hospital of Wales Cardiff UK

Radiation Physics and Protection Department Churchill Hospital Oxford UK

Sleep Disorder Centre Department of Medical Sciences and Public Health University of Cagliari Italy

Unit of Sleep Medicine and Epilepsy IRCCS Mondino Foundation Pavia Italy

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