Neuroanatomical heterogeneity drives divergent cognitive and motor trajectories in Parkinson's disease subtypes

Introduction: Cognitive symptoms of Parkinson's disease (PD) may initially present subtly, often overshadowed by more noticeable motor symptoms. However, as PD progresses, predicting which individuals will experience significant cognitive decline becomes challenging due to variability, suggesting distinct PD subtypes with varying cognitive trajectories. This study aimed to identify early PD subtypes based on patterns of gray matter atrophy in brain regions associated with cognition and assess their distinct patterns of cognitive change over time. Recognizing PD primarily as a movement disorder, we also evaluated their motor symptoms. Methods: We analyzed T1-weighted MRI data, cognitive, and motor scores from 114 de novo PD patients and 120 healthy controls. Multivariate gray matter volumetric distances (M_GMV) across frontal, subcortical, parietal, temporal, and occipital regions were computed, and K-means clustering was used to identify PD subtypes. Subsequently, cognitive assessments were compared between subtypes at baseline and 48 months using linear mixed-effects models and reliable change indices. Motor-symptom changes were assessed using linear mixed-effects models. Results: Two PD subtypes were identified from baseline MRI. Subtype 1 showed significantly higher M_GMV in frontal (p < 0.001) and subcortical (p < 0.001) regions, indicating atrophy. At 48 months, subtype 1 had poorer global cognitive performance than subtype 2 (p = 0.005) and faster progression of postural instability and gait disturbance (p = 0.04). Conclusions: PD subtypes identified early by distinct frontal and subcortical atrophy patterns exhibited divergent trajectories of cognitive decline and worsening motor symptoms over time, underscoring the neuroanatomical heterogeneity that drives clinical variability in PD.