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Multicenter Study
. 2025 Jul:117:105753.
doi: 10.1016/j.ebiom.2025.105753. Epub 2025 May 29.

Distinct brain atrophy progression subtypes underlie phenoconversion in isolated REM sleep behaviour disorder

Stephen Joza  1 , Aline Delva  2 , Christina Tremblay  3 , Andrew Vo  2 , Marie Filiatrault  4 , Max Tweedale  2 , Jean-François Gagnon  5 , Ronald B Postuma  6 , Alain Dagher  2 , Johannes Klein  7 , Michele Hu  7 , Petr Dusek  8 , Stanislav Marecek  8 , Zsoka Varga  8 , John-Paul Taylor  9 , John T O'Brien  10 , Michael Firbank  9 , Alan Thomas  9 , Paul C Donaghy  9 , Stéphane Lehéricy  11 ; Isabelle Arnulf  11 ; Marie Vidailhet  11 , Jean-Christophe Corvol  11 , Iceberg Study Group  11 , Richard Camicioli  12 , Howard Chertkow  13 , Simon Lewis  14 , Elie Matar  15 , Kaylena A Ehgoetz Martens  16 , Lachlan Churchill  15 , Michael Sommerauer  17 , Sinah Röttgen  18 , Per Borghammer  19 , Karoline Knudsen  19 , Allan K Hansen  19 , Dario Arnaldi  20 , Beatrice Orso  21 , Pietro Mattioli  20 , Luca Roccatagliata  20 , Oury Monchi  22 , Shady Rahayel  23
Collaborators, Affiliations
Multicenter Study

Distinct brain atrophy progression subtypes underlie phenoconversion in isolated REM sleep behaviour disorder

Stephen Joza et al. EBioMedicine. 2025 Jul.

Abstract

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.

Keywords: Dementia with Lewy bodies; MRI; Machine learning; Parkinson's disease; REM sleep behaviour disorder; Subtyping.

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Conflict of interest statement

Declaration of interests Outside the submitted work, Stephen Joza received support for attending meetings and/or travel from the American Academy of Neurology and Parkinson's Canada. Jean-François Gagnon received funding from the NIH/NIA. Ronald B. Postuma received grants from the CIHR, Michael J. Fox Foundation, NIH, Roche Diagnostics, and the Weston Foundation. He received consulting fees from Novartis, Eisai, Merck, Vaxxinity, BMS, Ventus, Korro, Vanqua, Roche, Regeneron, Helicon, Epic, and Clinilabs. He holds leadership roles with Parkinson Canada, the Michael J. Fox Foundation, MDS, Movement Disorders journal, and the RBD Study Group. Alain Dagher received travel support from the Michael J. Fox Foundation. Johannes C. Klein receives salary support from the NIHR Oxford Health Clinical Research Facility and the NIHR Oxford BRC, speaker honoraria from Merz, Ipsen, and AbbVie, and travel reimbursement from Merz and Ipsen. Michele Hu received consulting fees from Lundbeck, ESCAPE Bio, Evidera, Manus Neurodynamica, Biogen MA, CuraSen Therapeutics, Roche, JAZZ Pharma, and Aventis Pharma. She received honoraria and support for attending meetings from the International Movement Disorders Society, the 10th Singapore International Parkinson Disease and Movement Disorder Symposium, and the World Parkinson Congress. She holds a patent for predicting striatal dopamine levels via smartphone, serves on advisory boards and DSMBs including the Exenatide-PD3 Trial and ISAP Trial Steering Committee, is Treasurer of the ABN MDSIG, a shareholder and advisory founder of NeuHealth Digital Ltd. John T. O'Brien received consulting fees from Biogen and acted as a consultant for Roche, GE Healthcare, and Okwin. He received honoraria for lectures from GE Healthcare, serves on advisory boards or DSMBs for TauRx and Novo Nordisk, chairs the Research Strategy Council of the UK Alzheimer's Society, and received research support from Avid/Lilly, Merck, UCB, and Alliance Medical. Paul C. Donaghy received grants or contracts, paid to his institution, from Alzheimer's Research UK, the Michael J. Fox Foundation, the Alzheimer's Society, and GE Healthcare, and received an honorarium for a lecture at the Lewy Body Masterclass (paid to his institution). Jean-Christophe Corvol received grants/contracts from the Paris Brain Institute, ANR, and AXA Foundation (paid to institution), consulting fees from Roche, Servier, UCB, Ferrer, Alzprotect, iRegene, and Bayer, and serves on the Servier advisory board. Richard Camicioli serves (unpaid) on the Research and Scientific Advisory Board of Parkinson Canada. Howard Chertkow is the Scientific Director of CCNA (unpaid) and principal investigator or co-investigator on major research grants including from CIHR ($20.3M, 2024–29), Alzheimer's Society of Canada, BrightFocus, and NIH. He has also received funding for multi-site clinical trials sponsored by IntelGenX, Alector, Eli Lilly, Biogen, Hoffman LaRoche, and Anavex. He serves on advisory boards for Lilly and Eisai (personal payment). Simon Lewis received travel support from the International Parkinson's and Movement Disorder Society as a member of their Congress Scientific Program Committee (2022–2025). He holds leadership roles on editorial boards (Translational Neurodegeneration, Journal of Parkinson's Disease, Movement Disorders, Parkinsonism and Related Disorders, Journal of Neurology) and various international MDS working groups. Elie Matar received honoraria from CSL Seqirus and the International Parkinson's and Movement Disorders Society for presentations on non-motor and cognitive symptoms in Parkinson's. Dario Arnaldi received honoraria for lectures from Idorsia, Italfarmaco, PIAM, and Bruno. Beatrice Orso received a research grant from GE Healthcare. Shady Rahayel received grant support and travel reimbursement from the Michael J. Fox Foundation. Aline Delva, Christina Tremblay, Andrew Vo, Marie Filiatrault, Max Tweedale, John-Paul Taylor, Michael Firbank, Alan Thomas, Petr Dusek, Stanislav Marecek, Zsoka Varga, Stephane Lehericy, Isabelle Arnulf, Marie Vidailhet, Kaylena A. Ehgoetz Martens, Lachlan Churchill, Michael Sommerauer, Sinah Röttgen, Per Borghammer, Karoline Knudsen, Allan K. Hansen, Pietro Mattioli, Luca Roccatagliata, and Oury Monchi report no conflicts of interest.

Figures

Fig. 1
Fig. 1
Overview of study design, data processing, and subtype modelling. (a) 1276 participants were recruited, with 203 participants excluded after quality control. (b) T1-weighted MRI scans underwent cortical reconstruction, volumetric segmentation, multi-centre harmonisation, z-score normalisation, and disease progression modelling using the SuStaIn algorithm. (c) SuStaIn identified two distinct subtypes of brain atrophy progression, each with unique spatiotemporal patterns and stages of disease. DLB = dementia with Lewy bodies; iRBD = idiopathic/isolated REM sleep behaviour disorder; PD-pRBD = Parkinson's disease with probable RBD; QC = quality control; ROI = region of interest.
Fig. 2
Fig. 2
SuStaIn identified a two-subtype model as being the best representation of brain atrophy progression in patients. (a) CVIC across 10-fold cross-validation of left-out individuals; lower CVIC represents better model fit. (b) Distribution of subtypes across SuStaIn stages. (c) The assignability of disease subtype, operationalised as the distance from the top or bottom axis, which represents the maximum probability (100%) of that subtype. (d) SuStaIn identified two unique subtypes of brain atrophy progression. At each stage, the colour in each region indicates the level of severity of atrophy, with grey representing unaffected regions, red mildly affected regions (z-score of −1), magenta moderately affected regions (z-score of −2), and blue severely affected regions (z-score of −3 or more). Brainstem atrophy begins at approximately stage 6 in the subcortical-first subtype (not shown). CVIC = cross-validation information criterion; CVS = cross-validation similarity; iRBD = idiopathic/isolated REM sleep behaviour disorder; SuStaIn = Subtype and Staging Inference.
Fig. 3
Fig. 3
Progression of cortical and subcortical atrophy by subtype and stage in iRBD. The progression of atrophy in cortical regions (a) and subcortical regions (b) used in the SuStaIn modelling in classifiable patients with iRBD. iRBD = idiopathic/isolated REM sleep behaviour disorder; SuStaIn = Subtype and Staging Inference.
Fig. 4
Fig. 4
Progression of clinical variables by SuStaIn stage. Higher SuStaIn stages was associated with worse clinical scores on MDS-UPDRS-III and MoCA in patients. MoCA = Montreal Cognitive Assessment; MDS-UPDRS-III = Movement Disorders Society – Unified Parkinson's Disease Rating Scale, Part III; SuStaIn = Subtype and Staging Inference.
Fig. 5
Fig. 5
Phenoconversion risk (calculated from the logistic regression predicting phenoconversion) differs in patients with iRBD based on classifiability and stage. Patients with iRBD classified in the cortical-first subtype had a stronger likelihood of DLB compared to PD as disease severity (atrophy) increases. iRBD = idiopathic/isolated REM sleep behaviour disorder; SuStaIn = Subtype and Staging Inference.
Fig. 6
Fig. 6
Hypothetical schematic representing the pathways of evolution of brain atrophy progression in iRBD, as simulated by SuStaIn. In this model, the subcortical-first subtype is associated with increased phenoconversion compared to non-classified patients, possibly due to initial involvement of the basal ganglia structures. By contrast, the cortical-first subtype is associated with specific phenoconversion to DLB compared to PD as disease severity (atrophy) progresses. This model suggests that the cortical-first subtype is more closely related to what is classically known as DLB (i.e., initial cortical involvement followed by subcortical involvement, with a long-term risk of dementia), whereas the subcortical-first subtype is more closely related to PD (i.e., initial subcortical involvement followed by cortical involvement, with earlier phenoconversion to PD and an increased long-term risk of dementia under the label of PD dementia). DLB = dementia with Lewy bodies; iRBD = idiopathic/isolated REM sleep behaviour disorder; PD = Parkinson's disease.
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