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

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 (PD), dementia with Lewy bodies (DLB), and prodromal idiopathic REM sleep behaviour disorder (iRBD) using the Subtype and Stage Inference (SuStaIn) algorithm. Four transdiagnostic subtypes 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 potential to refine prognosis, improve clinical trial stratification, and guide precision therapeutic approaches. Teaser Data-driven analysis reveals transdiagnostic brain atrophy subtypes in LBD explaining clinical heterogeneity and disease progression.