Distinct Longitudinal Clinical‐Neuroanatomical Trajectories in Parkinson's Disease Clinical Subtypes: Insight toward Precision Medicine

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BACKGROUND: Parkinson's disease (PD) varies widely across individuals in clinical manifestations and course of progression. Identification of distinct biological subtypes could explain this heterogeneity, identify its pathophysiology, and predict disease progression. OBJECTIVES: Our aim was to compare longitudinal clinical trajectories and brain atrophy patterns between clinical subtypes defined at the baseline de novo PD. METHODS: We analyzed data from 421 PD patients (mean follow-up: 8.2 years) in the Parkinson's Progression Markers Initiative (PPMI). Using multi-domain motor and non-motor criteria, de novo patients were classified into "mild motor-predominant" (n = 223), "intermediate" (n = 146), and "diffuse-malignant" (n = 52) subtypes. Deformation-based morphometry was performed on T1-weighted magnetic resonance imaging (MRIs) from 128 PD patients with at least two MRIs (71 mild motor-predominant, 42 intermediate, and 15 diffuse-malignant) and 60 controls, with an average MRI follow-up duration of 3.4 ± 1.1 in the PD cohort. Mixed-effects models compared clinical progression and longitudinal pattern of regional atrophy across subtypes. RESULTS: The diffuse-malignant subtype exhibited faster worsening of motor severity (P = 0.007), cognition (P < 0.0001), and activities of daily living (P < 0.0001) compared to mild motor-predominant subtype over 8 years. These findings remained statistically significant after an age-matched subgroup analysis and adjustment for the levodopa treatment. Accelerated atrophy was observed in the precuneus, temporal and fusiform gyri, cerebellum, and other regions (corrected-P < 0.05). CONCLUSIONS: Longitudinal analysis revealed distinct patterns of clinical progression and regional atrophy in PD subtypes, with the diffuse-malignant subtype showing more severe neurodegeneration and clinical deterioration suggesting existence of diverse pathophysiological mechanisms in PD. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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