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

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, Christine M. Belden, Alireza Atri, Parichita Choudhury, Frederik Barkhof, Charles H. Adler, Rik Ossenkoppele, Thomas G. Beach and Oskar Hansson ()
Additional contact information
Sophie E. Mastenbroek: Vrije Universiteit Amsterdam, Amsterdam University Medical Center, location VUmc
Jacob W. Vogel: Faculty of Medicine, SciLifeLab, Lund University
Lyduine E. Collij: Vrije Universiteit Amsterdam, Amsterdam University Medical Center, location VUmc
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
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
Parichita Choudhury: Banner Sun Health Research Institute
Frederik Barkhof: Vrije Universiteit Amsterdam, Amsterdam University Medical Center, location VUmc
Charles H. Adler: Parkinson’s Disease and Movement Disorders Center, Mayo Clinic
Rik Ossenkoppele: Faculty of Medicine, Lund University
Thomas G. Beach: Banner Sun Health Research Institute
Oskar Hansson: Faculty of Medicine, Lund University

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-49402-x

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