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Abstract Parkinson’s disease (PD) is characterized by marked clinical heterogeneity. We applied Subtype and Stage Inference (SuStaIn), an unsupervised machine-learning algorithm, identifies distinct subtypes and their hypothesized progression from cross-sectional imaging, to identify MRI-based subtypes in PD. A total of 183 patients with PD and 107 healthy controls underwent T1-weighted MRI and clinical assessments covering motor, cognitive, psychiatric, sleep, autonomic, and olfactory functions, quality of life, and DAT-SPECT. SuStaIn identified three distinct PD subtypes with unique atrophy trajectories and clinical profiles. Subtype 0 showed early brainstem and frontal atrophy with executive dysfunction. Subtype 1 began with subcortical and temporal atrophy and was associated with hallucinations and sleep, autonomic, and DAT-SPECT dysfunction. Subtype 2 exhibited early parietal-occipital atrophy with later brainstem involvement and progressive cognitive and psychiatric symptoms. These findings highlight the utility of MRI-based subtyping to characterize clinical variability and may inform personalized disease management in PD.
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