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Gender-Related Vulnerability of Dopaminergic Neural Networks in Parkinson's Disease

In Parkinson's disease (PD) neurodegeneration of dopaminergic systems leads to motor and non-motor abnormalities. Sex might influence the clinical phenotypes and progression of PD. Molecular imaging data have only addressed nigro-striato-cortical dopamine system that appears more preserved in women. There is still a lack of evidence on gender/sex differences in the mesolimbic dopaminergic system. We aimed at assessing PD gender differences in both the dopaminergic pathways, by using a metabolic connectivity approach. This approach is based on the evidence of a significant coupling between neurotransmission impairment and the alteration of metabolic networks. We included 34 idiopathic PD patients and 34 healthy controls for comparison. The molecular architecture of both the dopaminergic networks was estimated throughout partial correlation analyses using FDG-PET metabolic data (threshold set at p<0.01, corrected for Bonferroni multiple comparisons). Male patients were characterized by a widespread altered connectivity of nigro-striato-cortical network and a spared reconfiguration of the mesolimbic pathway. On the other hand, PD females showed greater changes in the mesolimbic network and only a partial reconfiguration of the nigro-striato-cortical one. Our findings add remarkable knowledge on the neurobiology of gender differences in PD with the identification of selective neural vulnerabilities of the dopaminergic networks in male and female subjects. The gender differences here obtained exploring brain system metabolic connectivity, might be due to the combination of both biological and sociodemographic factors. Gender differences in PD should be considered for a more comprehensive overview that may influence treatments and the targeting of modifiable risk factors.