2026/01/28 by Michael Tran Duong, Sandhitsu R. Das, Pulkit Khandelwal +10 · 1 voice
Medicine · #Parkinson's Disease Mechanisms and Treatments #Neurological disorders and treatments #Parkinson's Disease and Spinal Disorders
paper · pdf · doi:10.1002/mds.70186
openalex publication_date 2026/01/28 · openalex created_date 2026/01/29 · openalex updated_date 2026/07/27
Abstract 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, 123 I‐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 pTau 181 /amyloid‐β 42 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. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.