Background: Parkinson's disease (PD) varies widely across individuals in clinical manifestations and course of progression. Identification and characterization of distinct biological subtypes could help explain this heterogeneity, identify the underlying pathophysiology, and predict disease progression across the subgroups of PD. Objective: We aimed to compare long-term trajectories of various motor and non-motor clinical features, as well as patterns of brain atrophy between PD subtypes, using longitudinally acquired brain MRIs. Methods: Data on 421 individuals with early-stage PD was retrieved from the Parkinson's Progression Markers Initiative (PPMI), with an average follow-up time of 8.2 years until February 2024. Participants were classified into three clinical subtypes at the de novo stage using a previously validated subtyping criteria based on major motor and non-motor classifiers (early cognitive impairment, REM sleep behavior disorder (RBD), dysautonomia): "mild-motor predominant" (n=223), "intermediate" (n=146), and diffuse-malignant (n=52). To investigate the pattern of brain atrophy, we used T1-weighted MRIs from a subset of the PPMI population with at least two MRIs obtained, which consisted of 134 PD individuals and 60 healthy controls. Deformation-based morphometry (DBM) maps were calculated and mixed effect models were used to examine the interaction between PD subtypes and rate of atrophy across brain regions, controlling for sex and age at baseline. Results: Compared to the "mild motor-predominant" subtype, participants who were categorized as diffuse-malignant PD at baseline experienced greater worsening in motor severity (p=0.007), cognition (p<0.0001) and activities of daily living (ADL) (p<0.0001) after 8 years. Individuals with diffuse-malignant PD showed a significantly higher rate of atrophy across multiple brain regions, including precuneus, paracentral lobule, inferior temporal gyrus, fusiform gyrus, and lateral hemisphere of the cerebellum (corrected p<0.05). Conclusion: Our study revealed a distinct pattern of long-term progression in various motor and non-motor clinical outcomes between different subtypes of idiopathic PD. Furthermore, we demonstrated an accelerated atrophy pattern within several brain regions in the diffuse-malignant PD subtype. These findings suggest a more widespread and aggressive neurodegenerative process in a subgroup of people with PD, favoring the existence of diverse underlying pathophysiology with clinical relevance for future precision medicine in PD.

The authors have declared no competing interest.

SMF reports receiving Parkinson Canada Research Fellowship Award. YZ reports receiving research funding from the Healthy Brains for Healthy Lives (HBHL), Fonds de recherche du Quebec - Sante (FRQS) Chercheurs boursiers et chercheuses boursieres en Intelligence artificielle, as well as Natural Sciences and Engineering Research (NSERC) discovery grant. MD reports receiving research funding from the HBHL, Canadian Institutes of Health Research (CIHR), and FRQS.

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The study used ONLY openly available human data that were originally located at: https://www.ppmi-info.org/access-data-specimens/download-data

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