Monoamine Loss and Functional Connectivity Alterations in Patients With Parkinson's Disease and Depression

The pathophysiology and neural substrates of depression in Parkinson's disease remain unclear. It has been associated with dysregulation of the monoaminergic systems. Furthermore, functional abnormalities within the mesolimbic-basal ganglia reward circuit may be involved in the pathogenesis of Parkinson's disease-related depression.

We aimed to investigate monoaminergic deficits and the corresponding changes within the striatum-mesolimbic circuitry in patients with Parkinson's disease and depression.

This study included eight depressed and 18 non-depressed patients with Parkinson's disease and 28 matched healthy controls. We simultaneously obtained ¹⁸F-fluoropropyl-dihydrotetrabenazine positron emission tomography (¹⁸F-FP-DTBZ PET) and resting-state functional magnetic resonance images (rs-fMRI). We also recruited additional patients with Parkinson's disease (nine depressed and 20 non-depressed) for the validation of the rs-fMRI analysis. The ¹⁸F-FP-DTBZ standardized uptake value ratio relative to the occipital lobe was used to quantify monoaminergic deficits in the striatum-mesolimbic subregion. Voxel- and volume-of-interest-based analyses were performed to investigate the functional connectivity changes in the striatum-mesolimbic circuitry of depressed patients.

Patients who were depressed exhibited greater monoaminergic deficits in the anterior dorsal and ventral putamen and the nucleus-accumbens than non-depressed patients did. Depression severity was negatively correlated with standardized uptake value ratio in the anterior ventral putamen and the nucleus-accumbens of patients with Parkinson's disease. Compared with non-depressed patients, higher functional connectivity was noted within the striatum-mesolimbic circuit in depressed patients.

In depressed Parkinson's disease patients, monoaminergic deficits are present alongside abnormally increased connectivity within the striatum-mesolimbic circuitry, highlighting this pathway as a potential target for treatment.