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Data-driven trajectories of atrophy explain clinical heterogeneity across Lewy body diseases

Lookup NU author(s): Professor John-Paul TaylorORCiD, Dr Michael FirbankORCiD, Dr Dag Aarsland

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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.

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Author(s): Konuri A, Leal GC, Zebarjadi N, Habich A, Castellanos-Perilla N, Gonzalez MC, Taylor J-P, Firbank M, Alcolea D, Bejanin A, Segers K, Benoit F, Isik AT, Samanci B, Cháfer-Pericás C, Wade-Martins R, Hu MTM, Bhome R, Dobreva I, Walker Z, Aarsland D, Westman E, Ferreira D, Halliday G, Lewis SJG, Weil RS, Landin-Romero R, Lambert C, Oxtoby NP, Matar E

Publication type: Article

Publication status: Published

Journal: eBioMedicine

Year: 2026

Volume: 131

Print publication date: 01/09/2026

Online publication date: 05/08/2026

Acceptance date: 06/07/2026

Date deposited: 26/08/2026

ISSN (electronic): 2352-3964

Publisher: The Lancet Publishing Group

URL: https://doi.org/10.1016/j.ebiom.2026.106400

DOI: 10.1016/j.ebiom.2026.106400

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