Monoaminergic networks of cognitive and behavioral symptoms in early Parkinson's disease 

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Motor symptoms are at the core of the phenomenology and diagnostic evaluation of Parkinson’s disease (PD). However, a wide spectrum of behavioral and cognitive symptoms, including depression, anxiety, REM sleep behavior disorder (RBD), and cognitive impairment cause a significant burden for the patients. However, the neurobiological background of these debilitating non-motor symptoms remains poorly understood.  

In this study, we analyzed clinical and [123I]FP-CIT SPECT imaging data of patients with PD at baseline (n=349), 2-year follow-up (n=240)q and 4-year follow-up (n=140), and healthy controls (n=166), from the Parkinson’s Progression Markers Initiative (PPMI) cohort. Depression, anxiety, RBD, and cognition were evaluated using validated questionnaires (GDS-15, STAI, RBDSQ and MoCA). [123I]FP-CIT SPECT imaging data were warped to MNI standard space using a novel nonlinear registration workflow (Niemi et al. Mov Disord 2024). The association of [123I]FP-CIT binding with the symptoms was evaluated voxel by voxel across subcortical structures, including the striatum, thalamus, midbrain, and brainstem. The whole brain functional networks of the symptom-specific monoaminergic abnormalities were mapped using a functional connectome (n=1000), an approach we term molecular network mapping, and their receptor-level correspondences were characterized using normative transcriptional receptor maps.  

Our study revealed no significant associations at baseline. Cross-sectionally, depression was associated with lower monoamine transporter binding in the ventral striatum (VS) at 2-year follow-up and in VS and dorsal raphe nucleus (DRN) at 4-year follow-up, and trait anxiety with reduced binding in the midbrain, including the dorsal and median raphe nuclei and the locus coeruleus (LC), at 4-year follow-up. In the longitudinal analyses, lower baseline binding in these regions predicted more severe depression and trait anxiety at follow-up. RBD showed a trend of association with reduced VS binding at 2- and 4-year follow-up visits. In contrast, no association with cognition was identified.  

The functional connectivity analyses showed distinctive connectivity profiles and similarity with receptor expression for the monoaminergic abnormalities associated with depression, anxiety, and RBD. The recetor-level correspondences were characterized by serotonin receptors and histamine autoreceptors for depression; histamine, serotonin, and adrenergic receptors for anxiety; and adrenergic and serotonergic receptors for RBD. Notably, the depression and motor parkinsonism networks closely resembled networks derived from brain lesions causing these symptoms, suggesting that the identified monoaminergic networks may be causally relevant.  

The findings of our study show distinct monoaminergic abnormalities and their connectivity profiles associated with multiple non-motor symptoms in PD. The absence of an association with cognition fits a predominantly cholinergic rather than monoaminergic basis for cognitive dysfunction in PD, although the small number of cognitively impaired patients in this early-PD cohort limits power. The background of the symptoms is likely multifactorial, involving both primary and secondary changes in multiple neurotransmitter systems. Together, these results advance our understanding of the neurobiological mechanisms underlying the non-motor symptom spectrum of PD.

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