Imaging Proinflammatory Microglia in Parkinson Disease Using [11C]SMW139 PET: A Multicenter Study

Abstract

Several translocator protein (TSPO) PET studies have shown increased glial cell density in Parkinson disease (PD); however, TSPO tracers are not able to differentiate between proinflammatory and antiinflammatory processes, information that is crucial for the development and evaluation of therapies. We used [¹¹C]SMW139 PET to target the P2X7 receptor, which is expressed on proinflammatory microglia, to investigate proinflammatory signals in PD. Methods: Patients with PD (n = 15) and healthy controls (HCs) (n = 15) were included in this multicenter study. All participants underwent a 90-min [¹¹C]SMW139 PET scan with continuous online and manual blood sampling. A 2-tissue compartment model with dual-input curves (both unchanged radiopharmaceutical [i.e., parent] and radiometabolites) was used to quantify [¹¹C]SMW139. The distribution volume of the parent (V_Tp) was considered the main parameter of interest. Differences in [¹¹C]SMW139 V_Tp between patients with PD and HCs were assessed using linear mixed models with post hoc testing. Regions of interest determined a priori included the putamen, caudate nucleus, brain stem, and whole cortex. Associations between motor symptom severity, as measured by the score on Part III (Motor Evaluation) of the Unified Parkinson’s Disease Rating Scale, disease duration, and [¹¹C]SMW139 V_Tp were assessed using linear regression. Results: In the a priori regions of interest, patients with PD had a significantly higher V_Tp in the putamen (β = 0.04; P = 0.046) and whole cortex (β = 0.04; P = 0.043) compared with those of HCs. In an exploratory analysis, patients with PD also had a higher V_Tp in the orbitofrontal cortex (β = 0.04; P = 0.041) compared with that of HCs. There was no significant association between V_Tp and symptom severity (brain stem: β = −0.002; P = 0.084; caudate nucleus: β = −0.002; P = 0.164; putamen: β = −0.002; P = 0.265; whole cortex: β = −0.002; P = 0.119) or disease duration (brain stem: β = −0.01; P = 0.055; caudate nucleus: β = −0.005; P = 0.282; putamen: β = −0.01; P = 0.113; whole cortex: β = −0.007; P = 0.217) in patients with PD. Conclusion: Patients with PD showed increased P2X7 receptor binding in the putamen and brain cortex, as assessed by [¹¹C]SMW139 PET, suggesting the presence of increased levels of proinflammatory microglia.