Global network and local vulnerabilities underlie brain atrophy across Parkinson's disease stages.

Parkinson's disease (PD) is associated with extensive structural brain changes. Recent work has proposed that the spatial pattern of disease pathology is shaped by both network spread and local vulnerability. However, only few studies assessed these biological frameworks in large patient samples across disease stages. Analyzing the largest imaging cohort in PD to date (n = 3,096 patients), we investigated the roles of network architecture and local brain features by relating regional abnormality maps to normative profiles of connectivity, intrinsic networks, cytoarchitectonics, neurotransmitter receptor densities, and gene expression. We found widespread cortical and subcortical atrophy in PD to be associated with advancing disease stage, longer time since diagnosis, and poorer global cognition. Structural brain connectivity best explained cortical atrophy patterns in PD and across disease stages. These patterns were robust among individual patients. The precuneus, lateral temporal cortex, and amygdala were identified as likely network-based epicentres, with high convergence across disease stages. Individual epicentres varied significantly among patients, yet they consistently localized to the default mode and limbic networks. Furthermore, we showed that regional overexpression of genes implicated in synaptic structure and signalling conferred increased susceptibility to brain atrophy in PD. In summary, this study demonstrates in a well-powered sample that structural brain abnormalities in PD across disease stages and within individual patients are influenced by both network spread and local vulnerability.