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Abstract Purpose 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 metric sensitive to extracellular water, and to determine whether these subtypes differ in baseline motor profiles and longitudinal progression. Methods 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. Group differences in baseline motor severity were evaluated using t-tests, and linear mixed-effects models assessed longitudinal changes in ISO and motor scores over four years. Results 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. Longitudinally, subtype 1 exhibited significant ISO increases, whereas subtype 2 remained stable at elevated levels. However, motor progression rates did not differ significantly between subtypes. Conclusion Diffusion MRI-derived ISO identified distinct neurobiological subtypes of PD with divergent trajectories of extracellular pathology but similar clinical progression. ISO may serve as a sensitive biomarker for PD heterogeneity, warranting further validation in larger, long-term cohorts.
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