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Disease progression modelling reveals heterogeneity in trajectories of Lewy-type α-synuclein pathology

Author

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  • Sophie E. Mastenbroek

    (Vrije Universiteit Amsterdam, Amsterdam University Medical Center, location VUmc
    Brain imaging
    Faculty of Medicine, Lund University)

  • Jacob W. Vogel

    (Faculty of Medicine, SciLifeLab, Lund University)

  • Lyduine E. Collij

    (Vrije Universiteit Amsterdam, Amsterdam University Medical Center, location VUmc
    Brain imaging
    Faculty of Medicine, Lund University)

  • Geidy E. Serrano

    (Banner Sun Health Research Institute)

  • Cécilia Tremblay

    (Banner Sun Health Research Institute)

  • Alexandra L. Young

    (Institute of Psychiatry, Psychology and Neuroscience, King’s College London
    University College London)

  • Richard A. Arce

    (Banner Sun Health Research Institute)

  • Holly A. Shill

    (Barrow Neurological Institute)

  • Erika D. Driver-Dunckley

    (Parkinson’s Disease and Movement Disorders Center, Mayo Clinic)

  • Shyamal H. Mehta

    (Parkinson’s Disease and Movement Disorders Center, Mayo Clinic)

  • Christine M. Belden

    (Banner Sun Health Research Institute)

  • Alireza Atri

    (Banner Sun Health Research Institute
    Center for Mind/Brain Medicine, Brigham & Women’s Hospital & Harvard Medical School)

  • Parichita Choudhury

    (Banner Sun Health Research Institute)

  • Frederik Barkhof

    (Vrije Universiteit Amsterdam, Amsterdam University Medical Center, location VUmc
    Brain imaging
    University College London)

  • Charles H. Adler

    (Parkinson’s Disease and Movement Disorders Center, Mayo Clinic)

  • Rik Ossenkoppele

    (Faculty of Medicine, Lund University
    Neurology, Vrije Universiteit Amsterdam, Amsterdam University Medical Center location VUmc
    Amsterdam Neuroscience, Neurodegeneration)

  • Thomas G. Beach

    (Banner Sun Health Research Institute)

  • Oskar Hansson

    (Faculty of Medicine, Lund University
    Skåne University Hospital)

Abstract

Lewy body (LB) diseases, characterized by the aggregation of misfolded α-synuclein proteins, exhibit notable clinical heterogeneity. This may be due to variations in accumulation patterns of LB neuropathology. Here we apply a data-driven disease progression model to regional neuropathological LB density scores from 814 brain donors with Lewy pathology. We describe three inferred trajectories of LB pathology that are characterized by differing clinicopathological presentation and longitudinal antemortem clinical progression. Most donors (81.9%) show earliest pathology in the olfactory bulb, followed by accumulation in either limbic (60.8%) or brainstem (21.1%) regions. The remaining donors (18.1%) initially exhibit abnormalities in brainstem regions. Early limbic pathology is associated with Alzheimer’s disease-associated characteristics while early brainstem pathology is associated with progressive motor impairment and substantial LB pathology outside of the brain. Our data provides evidence for heterogeneity in the temporal spread of LB pathology, possibly explaining some of the clinical disparities observed in Lewy body disease.

Suggested Citation

  • Sophie E. Mastenbroek & Jacob W. Vogel & Lyduine E. Collij & Geidy E. Serrano & Cécilia Tremblay & Alexandra L. Young & Richard A. Arce & Holly A. Shill & Erika D. Driver-Dunckley & Shyamal H. Mehta &, 2024. "Disease progression modelling reveals heterogeneity in trajectories of Lewy-type α-synuclein pathology," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-49402-x
    DOI: 10.1038/s41467-024-49402-x
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    References listed on IDEAS

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    1. Ruben Smith & Francesca Capotosti & Martin Schain & Tomas Ohlsson & Efthymia Vokali & Jerome Molette & Tanja Touilloux & Valerie Hliva & Ioannis K. Dimitrakopoulos & Andreas Puschmann & Jonas Jögi & P, 2023. "The α-synuclein PET tracer [18F] ACI-12589 distinguishes multiple system atrophy from other neurodegenerative diseases," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    2. Lukas Frontzkowski & Michael Ewers & Matthias Brendel & Davina Biel & Rik Ossenkoppele & Paul Hager & Anna Steward & Anna Dewenter & Sebastian Römer & Anna Rubinski & Katharina Buerger & Daniel Janowi, 2022. "Earlier Alzheimer’s disease onset is associated with tau pathology in brain hub regions and facilitated tau spreading," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    3. Alexandra L Young & Razvan V Marinescu & Neil P Oxtoby & Martina Bocchetta & Keir Yong & Nicholas C Firth & David M Cash & David L Thomas & Katrina M Dick & Jorge Cardoso & John Swieten & Barbara Borr, 2018. "Uncovering the heterogeneity and temporal complexity of neurodegenerative diseases with Subtype and Stage Inference," Nature Communications, Nature, vol. 9(1), pages 1-16, December.
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