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

Abstract

Background:

In Parkinson’s disease (PD), neurodegeneration of dopaminergic systems leads to motor and non-motor abnormalities. Sex might influence the clinical PD phenotypes and progression. Previous molecular imaging data focused only on the nigro-striato-cortical dopamine system that appeared 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 brain metabolic connectivity approach. This is based on the evidence of a significant coupling between the neurotransmission and metabolic impairments.

Methods:

We included 34 idiopathic PD patients (Female/Male: 16/18) and 34 healthy controls for comparison. The molecular architecture of both the dopaminergic networks was estimated throughout partial correlation analyses using brain metabolism data obtained by fluorine-18-fluorodeoxyglucose positron emission tomography (threshold set at p < 0.01, corrected for Bonferroni multiple comparisons).

Results:

Male patients were characterized by a widespread altered connectivity in the nigro-striato-cortical network and a sparing of the mesolimbic pathway. On the contrary, PD females showed a severe altered connectivity in the mesolimbic network and only a partial reconfiguration of the nigro-striato-cortical network.

Discussion:

Our findings add remarkable knowledge on the neurobiology of gender differences in PD, with the identification of specific neural vulnerabilities. The gender differences here revealed might be due to the combination of both biological and sociodemographic life factors. Gender differences in PD should be considered also for treatments and the targeting of modifiable risk factors.

Impact statement

Multivariate methods to fluorine-18-fluorodeoxyglucose positron emission tomography (FDG-PET) brain data enable to reconstruct brain connectivity patterns within and between neurotransmitter systems, thus providing an in vivo window to the functional architecture of these systems. We focused on the dopaminergic nigro-striato-cortical and mesolimbic networks to investigate gender differences in Parkinson's disease. We found specific neural vulnerabilities of the dopaminergic pathways in males and females by using a metabolic connectivity approach. Our study contributes to the knowledge of the biological basis of gender differences in PD, which may lead to different clinical phenotypes. Understanding how gender may influence pathology is critical for prevention and treatment strategies.