Data-driven neurobiological subtyping of Parkinson’s disease using diffusion MRI-derived isotropic diffusion

Parkinson’s disease (PD) exhibits marked clinical and biological heterogeneity. This study aimed to identify neurobiologically defined PD subtypes using isotropic diffusion (ISO), a diffusion MRI-derived metric sensitive to changes in isotropic water diffusion associated with microstructural alterations, and to determine whether these subtypes differ in baseline motor profiles and longitudinal change in imaging and motor scores. Baseline ISO values were extracted from 12 subcortical motor regions in 156 de novo PD patients from the Parkinson’s Progression Markers Initiative. Hierarchical clustering was applied to ISO values to derive data-driven subtypes. Baseline differences in motor severity were assessed using independent two-sample t-tests. Longitudinal change in ISO and motor outcomes over four years was evaluated using baseline-adjusted change-score regression models in patients with complete follow-up data (n = 78). Two subtypes emerged: subtype 1 (n = 62) with lower ISO values and subtype 2 (n = 94) with higher ISO across all regions. Subtype 2 showed greater baseline rigidity and bradykinesia. In longitudinal analyses (subtype 1, n = 34; subtype 2, n = 44), no significant differences were observed between subtypes in change in ISO across subcortical regions or in progression of motor scores over four years. Our findings indicate that ISO-derived subtypes are associated with distinct baseline neurobiological and motor profiles in early PD, but do not show evidence of differential motor or imaging progression over a four-year follow-up. This pattern highlights the complexity of PD heterogeneity and underscores the need for further investigation in larger, long-term cohorts.