BACKGROUND: Synucleinopathies include a spectrum of disorders varying in features and severity, including idiopathic/isolated REM sleep behaviour disorder (iRBD), Parkinson's disease (PD), and dementia with Lewy bodies (DLB). Distinct brain atrophy patterns may already be seen in iRBD; however, how brain atrophy begins and progresses remains unclear. METHODS: A multicentric cohort of 1276 participants (451 polysomnography-confirmed iRBD, 142 PD with probable RBD, 87 DLB, and 596 controls) underwent T1-weighted MRI and longitudinal clinical assessments. Brain atrophy was quantified using vertex-based cortical surface reconstruction and volumetric segmentation. The unsupervised machine learning algorithm, Subtype and Stage Inference (SuStaIn), was used to reconstruct spatiotemporal patterns of brain atrophy progression. FINDINGS: SuStaIn identified two distinct subtypes of brain atrophy progression: 1) a "cortical-first" subtype, with atrophy beginning in the frontal lobes and involving the subcortical structures at later stages; and 2) a "subcortical-first" subtype, with atrophy beginning in the limbic areas and involving cortical structures at later stages. Both cortical- and subcortical-first subtypes were associated with a higher rate of increase in MDS-UPDRS-III scores over time, but cognitive decline was subtype-specific, being associated with advancing stages in patients classified as cortical-first but not subcortical-first. Classified patients were more likely to phenoconvert over time compared to stage 0/non-classified patients. Among the 88 patients with iRBD who phenoconverted during follow-up, those classified within the cortical-first subtype had a significantly increased likelihood of developing DLB compared to PD, unlike those classified within the subcortical-first subtype. INTERPRETATION: There are two distinct atrophy progression subtypes in iRBD, with the cortical-first subtype linked to an increased likelihood of developing DLB, while both subtypes were associated with worsening parkinsonian motor features. This underscores the potential utility of subtype identification and staging for monitoring disease progression and patient selection for trials. FUNDING: This study was supported by grants to S.R. from Alzheimer Society Canada (0000000082) and by Parkinson Canada (PPG-2023-0000000122). The work performed in Montreal was supported by the Canadian Institutes of Health Research (CIHR), the Fonds de recherche du Québec - Santé (FRQS), and the W. Garfield Weston Foundation. The work performed in Oxford was funded by Parkinson's UK (J-2101) and the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC). The work performed in Prague was funded by the Czech Health Research Council (grant NU21-04-00535) and by The National Institute for Neurological Research (project number LX22NPO5107), financed by the European Union - Next Generation EU. The work performed in Newcastle was funded by the NIHR Newcastle BRC based at Newcastle upon Tyne Hospitals NHS Foundation Trust and Newcastle University. The work performed in Paris was funded by grants from the Programme d'investissements d'avenir (ANR-10-IAIHU-06), the Paris Institute of Neurosciences - IHU (IAIHU-06), the Agence Nationale de la Recherche (ANR-11-INBS-0006), Électricité de France (Fondation d'Entreprise EDF), the EU Joint Programme-Neurodegenerative Disease Research (JPND) for the Control-PD Project (Cognitive Propagation in Prodromal Parkinson's disease), the Fondation Thérèse et René Planiol, the Fonds Saint-Michel; by unrestricted support for research on Parkinson's disease from Energipole (M. Mallart) and the Société Française de Médecine Esthétique (M. Legrand); and by a grant from the Institut de France to Isabelle Arnulf (for the ALICE Study). The work performed in Sydney was supported by a Dementia Team Grant from the National Health and Medical Research Council (#1095127). The work performed in Cologne was funded by the Else Kröner-Fresenius-Stiftung (grant number 2019_EKES.02), the Köln Fortune Program, Faculty of Medicine, University of Cologne, and the "Netzwerke 2021 Program (Ministry of Culture and Science of Northrhine Westphalia State). The work performed in Aarhus was supported by funding from the Lundbeck Foundation, Parkinsonforeningen (The Danish Parkinson Association), and the Jascha Foundation.

Centre for Advanced Research in Sleep Medicine CIUSSS NÎM Hôpital du Sacré Cœur de Montréal Montreal H4J 1C5 Canada

Centre for Advanced Research in Sleep Medicine CIUSSS NÎM Hôpital du Sacré Cœur de Montréal Montreal H4J 1C5 Canada; Department of Medicine University of Montreal Montreal H3T 1A4 Canada

Centre for Advanced Research in Sleep Medicine CIUSSS NÎM Hôpital du Sacré Cœur de Montréal Montreal H4J 1C5 Canada; Department of Psychology Université du Québec à Montréal Montreal H2X 3P2 Canada; Research Centre Institut universitaire de gériatrie de Montréal Montreal H3W 1W5 Canada

Centre of Neurology Department of Parkinson Sleep and Movement Disorders University Hospital Bonn Bonn Germany; German Centre for Neurodegenerative Diseases Forschungszentrum Jülich Jülich Germany

Department of Medicine University of Toronto Toronto Ontario Canada; Rotman Research Institute Baycrest Health Services Toronto Ontario Canada

Department of Neurology and Centre of Clinical Neurosciences 1st Faculty of Medicine Charles University and General University Hospital Prague Czechia

Department of Neurology University Hospital Cologne Faculty of Medicine University of Cologne Cologne Germany; Cognitive Neuroscience Institute of Neuroscience and Medicine Forschungszentrum Jülich Jülich Germany

Department of Neuroscience Rehabilitation Ophthalmology Genetics Maternal and Child Health Clinical Neurology University of Genoa Genoa 16132 Italy

Department of Neuroscience Rehabilitation Ophthalmology Genetics Maternal and Child Health Clinical Neurology University of Genoa Genoa 16132 Italy; IRCCS Ospedale Policlinico San Martino Genoa 16132 Italy

Department of Nuclear Medicine and PET Aarhus University Hospital Aarhus DK 8200 Denmark

Department of Psychiatry University of Cambridge School of Clinical Medicine Cambridge UK

Division of Neurology Department of Medicine and Neuroscience and Mental Health Institute University of Alberta Edmonton Canada

Institut du Cerveau Paris Brain Institute ICM Sorbonne Université INSERM UMR 1127 CNRS 7225 Clinical Investigation Centre Paris 75013 France

Oxford Parkinson's Disease Centre and Division of Neurology Nuffield Department of Clinical Neurosciences University of Oxford Oxford UK

Parkinson's Disease Research Clinic Macquarie Medical School Macquarie University Sydney Australia

Parkinson's Disease Research Clinic Macquarie Medical School Macquarie University Sydney Australia; Department of Kinesiology and Health Sciences University of Waterloo Waterloo N2L 3G1 Canada

Parkinson's Disease Research Clinic Macquarie Medical School Macquarie University Sydney Australia; Parkinson's Disease Research Clinic Brain and Mind Centre University of Sydney Camperdown NSW 2050 Australia

Research Centre Institut universitaire de gériatrie de Montréal Montreal H3W 1W5 Canada; Department of Radiology Radio Oncology and Nuclear Medicine University of Montreal Montreal H3T 1A4 Canada

The Neuro McGill University Montreal H3A 2B4 Canada

The Neuro McGill University Montreal H3A 2B4 Canada; Centre for Advanced Research in Sleep Medicine CIUSSS NÎM Hôpital du Sacré Cœur de Montréal Montreal H4J 1C5 Canada

The Neuro McGill University Montreal H3A 2B4 Canada; Centre for Advanced Research in Sleep Medicine CIUSSS NÎM Hôpital du Sacré Cœur de Montréal Montreal H4J 1C5 Canada; Department of Neurology Montreal General Hospital Montreal H3G 1A4 Canada

The Neuro McGill University Montreal H3A 2B4 Canada; Division of Neurology Department of Medicine and Neuroscience and Mental Health Institute University of Alberta Edmonton Canada

Translational and Clinical Research Institute Newcastle University Newcastle UK

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