Mapping the distribution of neurotransmitters to resting-state functional connectivity in patients with Parkinson’s disease

Abstract

Dopamine and serotonin are major monoamine neurotransmitters associated with Parkinson’s disease (PD), but the spatial distribution of these neurotransmitters and their relationship to underlying functional brain architecture are not fully understood. Here, estimates of functional connectivity were derived using resting-state functional MRI (rs-fMRI), while 11C-PE2I and 11C-DASB PET were used to evaluate interregional homogeneity of dopamine and serotonin levels, referred to as PET covariance, in 30 PD patients at baseline. Of these, 15 PD patients were followed up for 19 months. A region-of-interest (ROI)-based approach was adopted using 138 ROIs from the Automated Anatomical Labelling 3 (AAL3) atlas, excluding cerebellar regions, which were further grouped into canonical networks: visual, sensorimotor, attention, limbic, frontoparietal, default mode, subcortical, and brainstem. At baseline, linear regression revealed that FC was positively related to both 11C-PE2I covariance (β-values ranging from 0.478 to 0.800, p < 0.001)and 11C-DASB covariance (β-values ranging from 0.486 to 0.819, p < 0.001) across all networks. Notably, a stronger correlation was observed between FC and 11C-PE2I covariance within the subcortical network, while the correlation between FC and 11C-DASB covariance was more pronounced in the visual network. Longitudinally, we found positive correlations between baseline FC and both 11C-PE2I change covariance and 11C-DASB change covariance (β-values ranging from 0.252 to 0.654 and 0.280 to 0.690, respectively, p < 0.001) across all networks. The correlation with 11C-PE2I change covariance was significantly stronger than with 11C-DASB change covariance in the brainstem network but significantly weaker in the limbic and default mode networks. These correlations remained significant after controlling for the Euclidean distance between ROIs, indicating that the association is independent of spatial proximity. For both tracers, absolute PET uptake across seed ROIs was positively associated with correspondent regression-derived FC-PET β-weights, representing the relationship between PET uptake in target ROIs and their FC to the seed. This association was correlated with PD motor and non-motor severity across different brain regions that was dependent on the neurotransmitter system evaluated. For example, the total UPDRS-III score correlated with the FC-PET β-weights in 21/138 ROIs for 11C-PE2I, and in 16/138 ROIs for 11C-DASB. Our findings suggest that in patients with PD, dopamine and serotonin levels covary among brain regions that are highly functionally connected. This implies that the spatial distribution of these neurotransmitters follows the organizational principles of the brain’s functional connectomes, which are associated with features of the disease.