Increased microglial activation in patients with Parkinson disease using [18F]-DPA714 TSPO PET imaging

Abstract

Increasing evidence suggests that neuroinflammation is active in Parkinson disease (PD) and contributes to neurodegeneration. This process can be studied in vivo with PET and radioligands targeting TSPO, upregulated in activated microglia. Initial PET studies investigating microglial activation in PD with the [ 11 C]-PK11195 have provided inconclusive results. Here we assess the presence and distribution of neuroinflammatory response in PD patients using [ 18 F]-DPA714 and to correlate imaging biomarkers to dopamine transporter imaging and clinical status. Methods: PD patients (n = 24, Hoehn and Yahr I-III) and 28 healthy controls were scanned with [ 18 F]-DPA714 and [ 11 C]-PE2I and analyzed. They were all genotyped for TSPO polymorphism. Regional binding parameters were estimated (reference Logan graphical approach with supervised cluster analysis). Impact of TSPO genotype was analyzed using Wilcoxon signed-rank test. Differences between groups were investigated using a two-way ANOVA and Tukey post hoc tests. Results: PD patients showed significantly higher [ 18 F]-DPA714 binding compared to healthy controls bilaterally in the midbrain (p < 0.001), the frontal cortex (p = 0.001), and the putamen contralateral to the more clinically affected hemibody (p = 0.038). Microglial activation in these regions did not correlate with the severity of motor symptoms, disease duration nor putaminal [ 11 C]-PE2I uptake. However, there was a trend toward a correlation between cortical TSPO binding and disease duration (p = 0.015 uncorrected, p = 0.07 after Bonferroni correction). Conclusion: [ 18 F]-DPA714 binding confirmed that there is a specific topographic pattern of microglial activation in the nigro-striatal pathway and the frontal cortex of PD patients.

Microglia in Neurodegenerative Events—An Initiator or a Significant Other?

“…These findings were obtained with a first-generation probe [ [11]C]-PK11195 for which subsequent studies using a second generation probe did not readily substantiate [194]. More recent work, using [ 18 F]-DPA714 and adjusting for TSPO polymorphism, reported higher levels of binding in the midbrain, frontal cortex, and putamen of PD patients [195].…”

Evidence of Inflammation in Parkinson’s Disease and Its Contribution to Synucleinopathy

“…36 Significantly higher microglial activation was also shown with 18 F-DPA714 in the midbrain, frontal cortex, and putamen of PD patients relative to controls. 38 In summary, microglial activation has been evidenced in vivo by PET studies in the premotor or clinical stages of PD. It should be noted that different activation patterns occur in various brain regions as an effect of the ligand used, which is a limitation of such studies.…”

“…In addition to 11 C-PK11195 PET, microglial activation has been identified by other PET imaging ligands with improved binding qualities, such as 11 C-DPA713, 18 F-FEPPA, and 18 F-DPA714. [36][37][38] In a study using 11 C-DPA713, a significant increase in uptake was shown in the occipital, temporal, and parietal cortex of the brains of PD patients. 36 Significantly higher microglial activation was also shown with 18 F-DPA714 in the midbrain, frontal cortex, and putamen of PD patients relative to controls.…”

Is Chelation Therapy a Potential Treatment for Parkinson’s Disease?

“…These new tracers, including [ 18 F]-FEPPA, [ 11 C]-PBR28, [ 11 C]-DPA713, or [ 18 F]-DPA714, which are more sensitive to the polymorphism rs6971, are located in the TSPO gene that is responsible for the different affinity patterns [ 61 ]. Increased microglial activations have been found in nigrostriatal pathways including midbrain and putamen as well as frontal cortex; however, no significant associations with clinical measures were demonstrated with second-generation TSPO tracers [ 62 ].…”