AbstractAutonomic dysfunction is a common non-motor symptom in Parkinson’s disease (PD). Dopamine and serotonin are known to play a role in autonomic regulation, and, therefore, PD-related degeneration of serotonergic and dopaminergic neurons in these regions may be associated with autonomic dysfunction. We sought to clarify the association between extrastriatal serotonergic and striatal dopaminergic degeneration and the severity of autonomic symptoms, including gastrointestinal, pupillomotor, thermoregulatory, cardiovascular, and urinary dysfunction. We performed hierarchical multiple regression analyses to determine the relationships between (extra)striatal serotonergic and dopaminergic degeneration and autonomic dysfunction in 310 patients with PD. We used [¹²³I]FP-CIT SPECT binding to presynaptic serotonin (SERT) and dopamine (DAT) transporters as a measure of the integrity of these neurotransmitter systems, and the SCOPA-AUT (Scales for Outcomes in Parkinson’s Disease—Autonomic) questionnaire to evaluate the perceived severity of autonomic dysfunction. Motor symptom severity, medication status, and sex were added to the model as covariates. Additional analyses were also performed using five subdomains of the SCOPA-AUT: cardiovascular, gastrointestinal, urinary, thermoregulatory, and pupillomotor symptoms. We found that autonomic symptoms were most significantly related to lower [¹²³I]FP-CIT binding ratios in the right caudate nucleus and were mainly driven by gastrointestinal and cardiovascular dysfunction. These results provide a first look into the modest role of dopaminergic projections towards the caudate nucleus in the pathophysiology of autonomic dysfunction in PD, but the underlying mechanism warrants further investigation.