Striatal DAT binding fully mediates caffeine’s effect on motor progression in Parkinson disease

Background Parkinson’s disease (PD) is characterized by decreased striatal dopamine transporter (DAT) binding and progressive motor impairment. The role of caffeine in patients with established PD remains controversial, and the pathway linking caffeine intake, DAT levels and motor symptoms has not been fully elucidated. Purpose This study aimed to examine the influence of caffeine consumption on striatal DAT binding and core motor symptoms in PD. We also explored whether altered DAT binding mediated the relationship between caffeine and motor dysfunction, and evaluated the long-term effect of caffeine on the progression of motor symptoms. Methods Data of 83 healthy controls and 261 idiopathic PD patients were retrieved from the PPMI database and grouped by caffeine intake status. Striatal specific binding ratio (SBR) was measured using [¹²³I] FP-CIT SPECT. Correlation and mediation analyses were performed based on the full cohort of 261 PD patients. Longitudinal progression was assessed via generalized estimating equations (GEE) in 207 PD patients with valid 1–4 years follow-up data. Results Caffeine intake significantly reduced striatal DAT binding across all participants. In the PD cohort, lower DAT binding correlated with severe rigidity and bradykinesia, and fully mediated the adverse effects of caffeine on these two symptoms. Longitudinal analysis in PD patients confirmed that caffeine intake accelerated the progression of rigidity and bradykinesia, with no significant effect on resting tremors. Conclusion Caffeine consumption downregulates striatal DAT binding in PD, which further exacerbates rigidity and bradykinesia progression. Unlike its potential preventive effect on PD onset, sustained caffeine intake acts as an unfavorable lifestyle factor for established PD. This finding provides novel mechanistic evidence for individualized lifestyle intervention in PD management.