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

Background 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. Methods 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. Findings 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. Interpretation 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. Funding This work was made possible by an Ignition grant from the University of Sydney and University College London (Global Engagement Fund). Research in context: Evidence before this study Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and isolated REM sleep behaviour disorder (iRBD), sit on a Lewy body disease spectrum with overlapping clinical features but marked heterogeneity in symptom profile, timing, and progression. Neuroimaging and neuropathological studies report diverse patterns of neurodegeneration within each syndrome, with partial overlap across the broader spectrum. Recent, large-scale subtyping work suggests at least two spatiotemporal neurodegeneration trajectories. However, in vivo imaging subtyping which has particularly strong translational relevance, has largely focused on a single syndrome or has included limited representation of the full Lewy body disease continuum. Added value of this study This study includes a large, balanced cohort spanning PD, DLB and prodromal iRBD with detailed clinical and neuropsychological phenotyping. Using MRI-derived atrophy, we identified four transdiagnostic subtypes that capture clinically meaningful variability beyond syndromic diagnosis. We found that stage, an indicator of accumulated atrophy better addresses the between-syndromic differences in disease duration. We also show that certain subtypes with early limbic degeneration are associated with visual hallucinations, and are linked to amygdalar atrophy, and that subtype plus stage improves prediction of hallucinations beyond amygdalar volume alone. Longitudinal analysis further identified a subset of patients with PD with earlier cortico-limbic degeneration as being at higher risk of cognitive impairment. Implications of all the available evidence The current field of LBD is moving towards a biologically grounded stratification and staging criteria that better reflects clinical heterogeneity. These transdiagnostic subtypes alongside stage, provide complementary information that can inform emerging LBD staging frameworks and enable more targeted clinical trial design through improved stratification and risk enrichment.