Altered Raphe-Centered Monoamine Transporter Covariance in Early Parkinson’s Disease with Depressive Symptoms

Background/Objectives: Depression is a common non-motor manifestation of early Parkinson’s disease (PD), but its underlying neurobiological mechanisms remain incompletely understood. Although alterations in serotonergic pathways have been implicated, conventional molecular imaging studies have primarily focused on regional tracer uptake and have yielded inconsistent findings. We investigated whether raphe-centered monoamine transporter covariance and metabolic covariance are altered in early PD with depressive symptoms. Methods: Patients with early PD underwent bimodal PET imaging using extrastriatal [18F]FP-CIT PET as a putative marker of raphe-centered monoamine transporter–related organization and early-phase [18F]florbetaben PET as a surrogate of regional cerebral perfusion. Group-level covariance analyses were performed using the dorsal and median raphe nuclei as seed regions, and covariance patterns were compared between depressive and non-depressive PD groups. Regional tracer uptake was also evaluated. Results: Compared with the non-depressive group, patients with depressive PD demonstrated significantly greater dorsal raphe-associated monoamine transporter covariance involving the left precuneus, left inferior parietal lobule, and right cuneus after false discovery rate correction. In contrast, no significant between-group differences were identified for median raphe-associated monoamine transporter covariance or raphe-associated metabolic covariance after multiple-comparison correction. Regional extrastriatal [18F]FP-CIT uptake and early-phase [18F]florbetaben perfusion were also comparable between groups. Conclusions: Depressive symptoms in early PD were associated with altered dorsal raphe-centered monoamine transporter covariance in the absence of detectable regional imaging abnormalities. Group-level covariance analysis may complement conventional regional PET analyses for investigating the network-level neurobiology of depression in PD.