Beyond nigrostriatal dopamine transporter loss: whole-brain DAT depletion patterns discriminate PD phenotypes

PURPOSE: To map whole-brain dopamine transporter (DAT) depletion patterns in Parkinson’s disease (PD) using 11C-CFT PET and evaluate their utility in distinguishing tremor-dominant (TD) and postural instability/gait difficulty (PIGD) subtypes in early PD. METHODS: This retrospective study included 197 PD patients (80 TD, 117 PIGD) and 21 healthy controls. 11C-CFT PET quantified DAT availability across nigrostriatal and extrastriatal regions. Differential DAT availability was assessed using FDR-corrected t-tests and Cohen’s d. LASSO-optimized features from nigrostriatal (NS), extranigral (ONS), and whole-brain (WB) regions informed three classification models (Support vector machine, Logistic Regression, Random Forest), evaluated via Receiver Operating Characteristic analysis. RESULTS: 197 patients (mean age 50 ± 10 years; 112 men) were evaluated. Beyond classical nigrostriatal reductions, PD patients exhibited significant DAT loss in mesolimbic (nucleus accumbens, amygdala), mesocortical (insula), and brainstem-cerebellar regions. PIGD patients demonstrated greater contralateral striatal (putamen: d = 0.58, caudate: d = 0.50; p < 0.05) and limbic (nucleus accumbens: d = 0.51; p = 0.01) DAT depletion compared to TD. The WB model incorporating striatal and extranigral features (posterior putamen, olfactory cortex, parietal regions) achieved superior subtype discrimination (AUC = 0.90) versus NS (AUC = 0.80) and ONS (AUC = 0.82) models. DAT availability in nucleus accumbens correlated with gait freezing (ρ=-0.28; p < 0.001) and autonomic scores (ρ=-0.34; p < 0.001). CONCLUSION: 11C-CFT PET reveals distinct whole-brain DAT depletion patterns in PD subtypes, extending beyond nigrostriatal degeneration. The WB model’s superior diagnostic accuracy underscores the critical role of extranigral dopaminergic circuits as biomarkers for early phenotypic stratification. These findings redefine PD as a multisystem dopaminergic disorder and provide a neuroimaging basis for precision phenotyping and therapeutic targeting.