Motor functional hierarchical organization of cerebrum and its underlying genetic architecture in Parkinson’s disease

Hierarchy has been identified as a principle underlying the organization of human brain networks. However, it remains unclear how the network hierarchy is disrupted in Parkinson's disease (PD) motor symptoms and, how it is modulated by the underlying genetic architecture. The aim of this study was to explore alterations in the motor functional hierarchical organization of the cerebrum and their underlying genetic mechanism. In this study, the brain network hierarchy of each group was described through a connectome gradient analysis among 68 healthy controls (HC), 70 postural instability and gait difficulty (PIGD) subtype, 69 tremor-dominant (TD) subtype, including both male and female participants, according to its motor symptoms. Furthermore, transcription-neuroimaging association analyses using gene expression data from Allen Human Brain Atlas and case-control gradient differences were performed to identify genes associated with gradient alterations. Different PD motor subtypes exhibited contracted principal and secondary functional gradients relative to HC. The identified genes in different PD motor subtypes enriched for shared biological processes like metal ion transport, inorganic ion transmembrane transport. In addition, these genes were overexpressed in Ntsr+ neurons cell, enriched in extensive cortical regions and wide developmental time windows. Aberrant cerebral functional gradients in PD related motor symptoms have been detected, and the motor-disturbed genes have shared biological functions. The present findings may contribute to a more comprehensive understanding of the molecular mechanisms underlying hierarchical alterations in PD.Significant statement The pattern of network hierarchy in different Parkinson's disease (PD) motor subtypes remains unclear. In our study, we used connectome gradient analysis to characterize alterations in the functional hierarchical organization of the cerebrum across PD motor subtypes. Additionally, transcription-neuroimaging association analyses were employed to investigate the genetic mechanisms underlying these gradient changes. Our findings suggest that distinct PD motor subtypes exhibit contracted functional gradients, with genes associated with these gradient alterations enriched in similar biological functions.