Multimodal PET study in 33 PD patients and 25 controls found expected striatal dopaminergic deficits and regional serotonergic reductions but no group differences or longitudinal change in synaptic density (11C‑UCB‑J), with limited clinical correlations.

Supports use of DAT and SERT imaging for phenotyping and trial stratification while the absence of detectable synaptic loss at mild–moderate stages informs biomarker selection and timing for neuroprotective therapeutic strategies.

Parkinson's disease (PD) is a neurodegenerative disease characterised by molecular and structural brain changes detectable through advanced imaging. Understanding alterations in neurotransmitter systems and synaptic density, and their clinical relevance, is critical for identifying disease-specific biomarkers and therapeutic targets. This study included 33 PD patients (27 idiopathic PD (iPD) and 6 LRRK2 mutation carriers) (5.2 ± 3.6 years from diagnosis, 2.1 ± 0.7 Hoehn & Yahr OFF state) and 25 healthy controls (HC). Longitudinal data were collected for 20 iPD and 22 HC (10-33 months post-baseline; 20.2 ± 7.3 months). Participants underwent clinical assessments, structural magnetic resonance imaging, 11C-UCB-J positron emission tomography (PET) to assess synaptic density, 11C-DASB PET to assess serotonin transporter density, and 123I-FP-CIT single-photon emission computed tomography to assess dopamine transporter density. Analyses included baseline group comparisons, clinical correlations, and longitudinal assessments. At baseline, lower 123I-FP-CIT uptake in caudate and putamen (p < 0.001) and reduced 11C-DASB binding in the insular cortex (p = 0.003), parietal lobe (p = 0.009), caudate (p < 0.001), and putamen (p = 0.002) were observed in PD compared to HC. Some baseline correlations emerged between imaging metrics and symptom scales in PD, though these were limited. Despite progression in motor impairment, autonomic dysfunction, and overall disability in PD, no significant longitudinal changes or group × time interactions were detected for molecular imaging measures. This study confirmed dopaminergic and serotonergic dysfunction in PD. Synaptic density did not differ between groups or change over time, suggesting synaptic loss may be minimal at mild-to-moderate disease stages. These findings highlight how different molecular imaging markers reflect distinct aspects and timescales of PD pathophysiology.