Discordance of Dopaminergic Dysfunction and Subcortical Atrophy by α-Synuclein Status in Sporadic and Genetic Parkinson's Disease

Background: Parkinson's disease (PD) is characterized by predominantly neuronal α-synuclein pathology and dopaminergic dysfunction. Cerebrospinal fluid (CSF) seeding amplification assays (SAA) detect α-synuclein aggregates in vivo, but not all patients with PD have a positive SAA. This pathological heterogeneity among patients may not be entirely captured by binary results from α-synuclein SAA positivity (S+) versus negativity (S–). To further dissect this biological variability, we explored spatial neuroimaging differences in S+ versus S– patients. Objective: The study aim was to investigate how SAA status influences imaging measures of dopamine denervation and atrophy. Methods: We compare SAA status with CSF proteinopathy markers, ¹²³I-Ioflupane dopamine transporter (DAT), and magnetic resonance imaging (MRI) in participants with sporadic (n = 490), LRRK2-associated (n = 158), and GBA-associated (n = 80) PD from the Parkinson's Progression Markers Initiative (PPMI). Results: Between 64% and 95% of participants in these groups have S+ status. For all groups, S+ participants have decreased putamen DAT neurotransmission compared to S– participants, whereas S– participants have reduced MRI volume in basal ganglia structures relative to S+ participants. With striatal DAT/MRI ratios, S+ participants have disproportionately lower putamen DAT uptake relative to atrophy. In exploratory analyses, participants with cognitive impairment or hyposmia are associated with worse DAT/MRI discordance. By CSF markers, S– participants with sporadic PD have higher CSF pTau₁₈₁/amyloid-β₄₂ ratio, suggesting Alzheimer's copathology. Conclusions: S+ patients exhibit more dopaminergic deficit, whereas S– patients have more subcortical atrophy across sporadic and genetic PD. Together, our findings reveal structure/function and DAT/MRI discordance, providing insight into biomarkers and pathophysiology of synucleinopathy and PD.