ArticleEBioMedicine2026
Data-driven trajectories of atrophy explain clinical heterogeneity across Lewy body diseases.
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30 authors.
Ajay KonuriCentral Clinical School, Faculty of Medicine and Health, University of Sydney, Australia; Brain and Mind Centre, Faculty of Medicine and Health, University of Sydney, Australia; Parkinson's Disease Research Centre, Macquarie Medical School, Macquarie University, Australia.
Gonzalo Castro LealUCL Hawkes Institute, University College London, 90 High Holborn, London WC1V 6LJ, UK; UCL Department of Computer Science, University College London, 66-72 Gower Street, London WC1E 6EA, UK.
Niloufar ZebarjadiDivision of Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society (NVS), Center for Alzheimer Research, Karolinska Institutet, Blickagången 16, Huddinge, Stockholm 141 52, Sweden.
Annegret HabichDivision of Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society (NVS), Center for Alzheimer Research, Karolinska Institutet, Blickagången 16, Huddinge, Stockholm 141 52, Sweden.
Nicolás Castellanos-PerillaDivision of Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society (NVS), Center for Alzheimer Research, Karolinska Institutet, Blickagången 16, Huddinge, Stockholm 141 52, Sweden; Department of Clinical Medicine, University of Bergen, Postboks 7804, Bergen 5020, Norway; Centre for Age-Related Medicine (SESAM), Stavanger University Hospital, Postboks 8100, Stavanger 4068, Norway.
María Camila GonzalezCentre for Age-Related Medicine (SESAM), Stavanger University Hospital, Postboks 8100, Stavanger 4068, Norway.
John-Paul TaylorTranslational and Clinical Research Institute, Campus for Ageing and Vitality, Newcastle Upon Tyne NE4 5PL, UK.
Michael FirbankTranslational and Clinical Research Institute, Campus for Ageing and Vitality, Newcastle Upon Tyne NE4 5PL, UK.
Daniel AlcoleaSant Pau Memory Unit, IR SANT PAU, Hospital de la Santa Creu i Sant Pau, 167 Sant Antoni Maria Clare, Barcelona 08025, Spain; Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED), 5 Valderrebollo Street, Madrid 28031, Spain.
Alexandre BejaninSant Pau Memory Unit, IR SANT PAU, Hospital de la Santa Creu i Sant Pau, 167 Sant Antoni Maria Clare, Barcelona 08025, Spain; Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED), 5 Valderrebollo Street, Madrid 28031, Spain.
Kurt SegersNeurology and Geriatrics Department, Brugmann University Hospital, Université Libre De Bruxelles, Place Arthur Van Gehuchten 4, Brussels 1020, Belgium.
Florence BenoitNeurology and Geriatrics Department, Brugmann University Hospital, Université Libre De Bruxelles, Place Arthur Van Gehuchten 4, Brussels 1020, Belgium.
Ahmet Turan IsikUnit for Brain Aging and Dementia, Department of Geriatric Medicine, Dokuz Eylul University, School of Medicine, Balcova, Izmir 35340, Turkey.
Bedia SamanciBehavioral Neurology and Movement Disorders Unit, Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, Topkapı, Turgut Özal Millet Cd, Istanbul 34093, Turkey.
Consuelo Cháfer-PericásInstituto de Investigación Sanitaria La Fe, Avenida Fernando Abril Martorell, 106, Valencia 46026, Spain.
Richard Wade-MartinsOxford Parkinson's Disease Centre, University of Oxford, Oxford, UK.
Michele T M HuOxford Parkinson's Disease Centre, University of Oxford, Oxford, UK.
Rohan BhomeUCL Hawkes Institute, University College London, 90 High Holborn, London WC1V 6LJ, UK; Dementia Research Centre, University College London, 8-11 Queen Square, London WC1N 3AR, UK.
Ivelina DobrevaDementia Research Centre, University College London, 8-11 Queen Square, London WC1N 3AR, UK.
Zuzana WalkerDivision of Psychiatry, University College London, 6th Floor, Wings A and B, Maple House, 149 Tottenham Ct Rd, London W1T 7NF, UK; Essex Partnership University NHS Foundation Trust, Sankey House, 81 High Rd, Pitsea, Basildon SS13 3BB, UK.
Dag AarslandTranslational and Clinical Research Institute, Campus for Ageing and Vitality, Newcastle Upon Tyne NE4 5PL, UK; Centre for Healthy Brain Ageing, Institute of Psychiatry, Psychology, and Neuroscience, King's College London, 16 De Crespigny Park, London SE5 8AB, UK.
Eric WestmanDivision of Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society (NVS), Center for Alzheimer Research, Karolinska Institutet, Blickagången 16, Huddinge, Stockholm 141 52, Sweden; The Ageing Epidemiology Research Unit, School of Public Health, Imperial College London, White City Campus, 90 Wood Lane, London W12 0BZ, UK.
Daniel FerreiraDivision of Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society (NVS), Center for Alzheimer Research, Karolinska Institutet, Blickagången 16, Huddinge, Stockholm 141 52, Sweden; Facultad de Ciencias de La Salud, Universidad Fernando Pessoa Canarias, Calle Alcalde Francisco Hernández González, 28, Las Palmas 35001, Spain.
Glenda HallidayBrain and Mind Centre, Faculty of Medicine and Health, University of Sydney, Australia; School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Australia.
Simon J G LewisParkinson's Disease Research Centre, Macquarie Medical School, Macquarie University, Australia.
Rimona S WeilDivision of Psychiatry, University College London, 6th Floor, Wings A and B, Maple House, 149 Tottenham Ct Rd, London W1T 7NF, UK; National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, Queen Square, London WC1N 3BG, UK.
Ramon Landin-RomeroBrain and Mind Centre, Faculty of Medicine and Health, University of Sydney, Australia; School of Health Sciences, Faculty of Medicine and Health, University of Sydney, Australia.
Christian LambertFunctional Imaging Laboratory, Department of Imaging Neuroscience, Institute of Neurology, University College London, 12 Queen Square, London WC1N 3AR, UK.
Neil P OxtobyUCL Hawkes Institute, University College London, 90 High Holborn, London WC1V 6LJ, UK; UCL Department of Computer Science, University College London, 66-72 Gower Street, London WC1E 6EA, UK. Electronic address: n.oxtoby@ucl.ac.uk.
Elie MatarCentral Clinical School, Faculty of Medicine and Health, University of Sydney, Australia; Brain and Mind Centre, Faculty of Medicine and Health, University of Sydney, Australia; Department of Neurology, Royal Prince Alfred Hospital, Camperdown, NSW 2050, Australia. Electronic address: elie.matar@sydney.edu.au.
Funding
Technology and Remote Assessment CoreU19AG063911 · NIA · MAYO CLINIC ROCHESTER · PI ADAM L. BOXER · 2019 to 2026
$120.9MWU INSTITUTE OF CLINICAL AND TRANSLATIONAL SCIENCESUL1TR002345 · NCATS · WASHINGTON UNIVERSITY · PI William G. Powderly · 2017 to 2026
$97.8MEarly Onset AD Consortium - the LEAD Study (LEADS)U01AG057195 · NIA · INDIANA UNIVERSITY INDIANAPOLIS · PI APOSTOLOVA, LIANA G, CARRILLO, MARIA C · 2018 to 2023
$70.3MSmartphone-Based "Burst" Cognitive AssessmentsP01AG003991 · NIA · WASHINGTON UNIVERSITY · PI JOHN MORRIS · 1985 to 2026
$69.5MThe Clinical Significance of Incidental White Matter Lesions on MRI Amongst a Diverse Population with Cognitive Complaints (INDEED)U19NS120384 · NINDS · UNIVERSITY OF CALIFORNIA AT DAVIS · PI Kumar B. Rajan · 2020 to 2026
$61.9MTHERAPEUTIC EFFECTS OF INTRA-NASAL INSULIN DETEMIRP50AG005136 · NIA · UNIVERSITY OF WASHINGTON · PI GRABOWSKI, THOMAS J. · 1985 to 2019
$57.2MThe natural history of AB accumulation in preclinical ADP01AG026276 · NIA · WASHINGTON UNIVERSITY · PI MORRIS, JOHN · 2005 to 2025
$49.5MSUPPLEMENT TO RUSH ALZHEIMERS DISEASE CENTER COREP30AG010161 · NIA · RUSH UNIVERSITY MEDICAL CENTER · PI BENNETT, DAVID ALAN · 1991 to 2020
$49.1MSatellite Diagnostic and Treatment Clinic CoreP50AG008702 · NIA · COLUMBIA UNIV NEW YORK MORNINGSIDE · PI DE JAGER, PHILIP L · 1989 to 2019
$46.3MNational Alzheimer's Coordinating CenterU24AG072122 · NIA · UNIVERSITY OF WASHINGTON · PI STEPHENS, KARI A · 2021 to 2025
$45.8MTREATMENT OF DEPRESSION IN ALZHEIMER'S DISEASEP50AG005133 · NIA · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI SWEET, ROBERT A · 1985 to 2019
$43.0MWashington University Institute of Clinical and Translational SciencesUL1TR000448 · NCATS · WASHINGTON UNIVERSITY · PI EVANOFF, BRADLEY A · 2012 to 2016
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Abstract
backgroundLewy body diseases (LBD) collectively share α-synuclein Lewy pathology, yet present wide clinical heterogeneity, with overlapping motor and non-motor features and progression patterns that challenge traditional diagnostic boundaries.
methodsTo resolve this spatiotemporal heterogeneity at the biological level, we applied a data-driven atrophy progression framework to MRI data from 833 individuals across Parkinson's disease, dementia with Lewy bodies, and prodromal isolated REM sleep behaviour disorder using the Subtype and Stage Inference algorithm.
findingsFour transdiagnostic subtypes (A: Early cortico-limbic/late basal ganglia, B: Early basal ganglia/late limbic, C: Early temporo-limbic/late basal ganglia, and D: Early basal ganglia-cingulate/late cortex) emerged, each defined by a distinct spatiotemporal progression of atrophy that explained cognitive, motor, and psychiatric variability. An early cortico-limbic/late basal ganglia subtype represented a dementia-prone subtype across clinical diagnoses, with limbic involvement associating with the emergence of visual hallucinations.
interpretationThese biologically relevant spatiotemporal atrophy subtypes provide an interpretable stratification of patients with LBD, with the potential to refine prognosis, improve clinical trial stratification, and guide precision therapeutic approaches.
fundingThis work was made possible by an Ignition grant from the University of Sydney and University College London (Global Engagement Fund).
Indexed as
Lewy Body DiseaseAgedAtrophyBrainDisease ProgressionFemaleHumansMagnetic Resonance ImagingMaleMiddle AgedParkinson DiseaseDementiaHeterogeneityLewy body diseasesMachine learningNeurodegenerationSubtypes
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