Data-driven trajectories of atrophy explain clinical heterogeneity across Lewy body diseases.
Authors
Affiliations (25)
Affiliations (25)
- Central 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.
- UCL 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.
- Division of Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society (NVS), Center for Alzheimer Research, Karolinska Institutet, Blickagången 16, Huddinge, Stockholm 141 52, Sweden.
- Division 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.
- Centre for Age-Related Medicine (SESAM), Stavanger University Hospital, Postboks 8100, Stavanger 4068, Norway.
- Translational and Clinical Research Institute, Campus for Ageing and Vitality, Newcastle Upon Tyne NE4 5PL, UK.
- Sant 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.
- Neurology and Geriatrics Department, Brugmann University Hospital, Université Libre De Bruxelles, Place Arthur Van Gehuchten 4, Brussels 1020, Belgium.
- Unit for Brain Aging and Dementia, Department of Geriatric Medicine, Dokuz Eylul University, School of Medicine, Balcova, Izmir 35340, Turkey.
- Behavioral Neurology and Movement Disorders Unit, Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, Topkapı, Turgut Özal Millet Cd, Istanbul 34093, Turkey.
- Instituto de Investigación Sanitaria La Fe, Avenida Fernando Abril Martorell, 106, Valencia 46026, Spain.
- Oxford Parkinson's Disease Centre, University of Oxford, Oxford, UK.
- UCL 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.
- Dementia Research Centre, University College London, 8-11 Queen Square, London WC1N 3AR, UK.
- Division 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.
- Translational 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.
- Division 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.
- Division 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.
- Brain 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.
- Parkinson's Disease Research Centre, Macquarie Medical School, Macquarie University, Australia.
- Division 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.
- Brain 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.
- Functional Imaging Laboratory, Department of Imaging Neuroscience, Institute of Neurology, University College London, 12 Queen Square, London WC1N 3AR, UK.
- UCL 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: [email protected].
- Central 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: [email protected].
Abstract
Lewy 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. To 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. Four 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. These 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. This work was made possible by an Ignition grant from the University of Sydney and University College London (Global Engagement Fund).