Distinct Spatiotemporal Patterns of Dopaminergic and Metabolic Imaging in De Novo Parkinson's Disease.

BACKGROUND:Understanding the heterogeneity of Parkinson's disease (PD) is essential to guide patient care, prognosis, and treatment. OBJECTIVE:We used 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET), 18F-N-(3-fluoropropyl)-2β-carbomethoxy-3β-(4-iodophenyl) nortropane (18F-FP-CIT) PET, and Subtype and Stage Inference (SuStaIn) algorithm to define subtypes in drug-naive patients with PD. METHODS:A total of 147 de novo PD patients and 38 healthy individuals who underwent 18F-FDG PET, 18F-FP-CIT, and brain magnetic resonance imaging were enrolled. The SuStaIn algorithm was employed to identify FP-CIT- and FDG-based subtypes. Motor and nonmotor features were compared between them. Correlations were analyzed to assess the associations between the progression stage and motor or cognitive scores within each subtype. RESULTS:Two distinct subtypes were identified: subtype 1 (fronto-striatal hypometabolic) and subtype 2 (mixed hypermetabolic-posterior hypometabolic). In subtype 1, striatal dopamine transporter (DAT) loss was accompanied by decreases in frontal and caudate metabolism at earlier stages, whereas hypometabolism in the posterior cortical and limbic regions appeared at later stages. In subtype 2, striatal DAT deficit and hypermetabolism of the putamen, medial temporal, and anterior cingulate cortices and lateral occipital hypometabolism appeared in the early stages. This metabolic reduction subsequently involved parieto-temporal, frontal, and limbic regions. Motor deficits were comparable between the subtypes. Those with subtype 2 exhibited poorer cognitive and olfactory performance, higher anxiety scores, higher Rapid Eye Movement Behavior Disorder Screening Questionnaire scores, and lower putaminal DAT availability and asymmetry than in subtype 1. The stage correlated with cognitive decline only in subtype 2, with a marginally significant stage-by-group interaction. CONCLUSIONS:De novo PD can be classified into two distinct metabolic subtypes: fronto-striatal hypometabolic and mixed hypermetabolic-posterior hypometabolic, with nonmotor manifestations being more severe in the latter. © 2026 International Parkinson and Movement Disorder Society.