Interplay of age-sensitive cortical vulnerability and dopaminergic degeneration in clinical manifestations of Parkinson's disease

To identify the pattern of cortical atrophy variation in Parkinson's disease (PD) and its contribution to clinical manifestations beyond dopaminergic dysfunction, 45 healthy controls (HCs) underwent MRI, and 222 participants with PD additionally underwent dopamine transporter (DAT)-PET, Unified PD Rating Scale (UPDRS), and neuropsychological tests. Using principal component analysis in PD, a single pattern in cortical thickness (PC1PD) was identified. Linear regressions models were applied to investigate the effects of PC1PD and putaminal DAT (DAT-P) on parkinsonism, and PC1PD and caudate DAT (DAT-C) on cognition. PC1PD accounted for more than 80% of total cortical variance and showed a strong negative correlation with age. The spatial pattern of PC1PD was similar to that of PC1 derived from HCs, but its age-related association was more pronounced in PD. Independent of DAT-P, lower PC1PD was associated with higher UPDRS motor score and showed a synergistic significant interaction with DAT-P on the axial subscore. Independent of DAT-C, lower PC1PD was associated with worse performance in global cognition, language, and executive functions, with synergistic interaction with DAT-C on global cognition and executive function. The associations of PC1PD with UPDRS motor scores, general cognition, and executive function were stronger in older participants, indicating that aging amplifies the clinical effect of PC1PD. PC1PD represents an age-sensitive cortical vulnerability axis whose expression is amplified in PD, and its interplay with dopaminergic depletion and aging contributes to axial motor symptoms and executive dysfunction in PD.