Cortical Morphometric Similarity Network Gradient in Parkinson's Disease and its Association with Gene Expression Profiles

BACKGROUND: Recent studies have shown that Parkinson's disease (PD) is accompanied by alterations in functional and structural network gradients. However, whether changes are present in the cortical morphometric similarity network (MSN) gradient, and the relationship between alterations of the gradient and gene expression, remain largely unknown. This study aimed to examine potential differences in the principal MSN gradient between patients with PD and healthy controls (HCs), and to explore how these differences relate to gene expression profiles and clinical phenomenology. METHODS: The MSN was constructed in this study, and its gradient of the network was computed in 66 patients with PD and 100 HCs. Group comparisons were performed to assess alterations in the MSN gradient, and partial least squares regression was applied to explore the association between gene expression profiles and gradient-related changes in PD. RESULTS: In contrast to HCs, PD patients exhibited reconfiguration of the principal MSN gradient, with association cortices shifting upward, motor cortices shifting downward, and sensory cortices remaining low. These alterations showed uneven distribution across functional networks and a positive correlation with cognitive performance in the dorsal attention network. Additionally, case-control differences aligned spatially with cortical gene expression, with implicated genes enriched in neurobiological pathways related to synaptic function and ion transport. CONCLUSIONS: These findings revealed alterations in the principal MSN gradient in PD and provide potential molecular insights into the structural changes underlying the neurobiological mechanisms of PD. © 2026 International Parkinson and Movement Disorder Society.