Spatiotemporal Progression Patterns of Striatal Dopamine Depletion and Cerebral Hypoperfusion in Parkinson's Disease

Abstract

Background: The identification of Parkinson's disease (PD) subtypes is crucial for predicting the disease course and designing personalized therapeutic strategies. Objectives: The aim of the study was to characterize the heterogeneity of the spatiotemporal evolutionary patterns of striatal dopamine depletion and cerebral hypoperfusion in PD. Methods: We retrospectively enrolled 708 patients with newly diagnosed PD and 50 healthy controls who underwent dual-phase 18F-FP-CIT PET scans. We applied subtype and stage inference (SuStaIn) to delineate three PD subtypes after quantifying the dual-phase F-18-FP-CIT PET data. We compared the baseline clinical features as well as the longitudinal motor and cognitive outcomes between subtypes. Results: Subtype 1 (n = 406) initially presented with asymmetric dopamine loss in the posterior putamen, followed by dopaminergic deficits in other striatal subregions and, later, cerebral hypoperfusion. Subtype 2 (n = 205) exhibited diffuse and symmetric striatal dopamine loss in the early stages, followed by cerebral hypoperfusion in the mid-stages. Subtype 3 (n = 89) initially showed the parieto-occipital hypoperfusion, followed by cerebral hypoperfusion in other cortical areas and striatal dopamine depletion. Subtype 2 had an older age of onset, and subtype 3 had a younger age of onset and a lower prevalence of rapid eye movement sleep behavior disorder. Time-dependent Cox regression models showed that the risk of dementia conversion within a follow-up period of 4 years was higher in subtypes 2 and 3 (hazard ratios 1.772 and 2.802, respectively) than subtype 1, after the confounding effects were adjusted. The risk of developing levodopa-induced dyskinesia and freezing of gait was comparable between subtypes. Conclusions: The spatiotemporal trajectories of striatal dopamine depletion and cerebral hypoperfusion on dual-phase F-18-FP-CIT PET images could serve as a potential progression marker for cognitive decline in early-stage PD.