Post-Mortem validation of in vivo 18kDa Translocator Protein (TSPO) PET as a microglial biomarker

Neuroinflammation is a feature of many neurodegenerative diseases, and can be quantified in vivo by PET imaging with radioligands for the translocator protein (TSPO, e.g. [11C]-PK11195). TSPO radioligand binding correlates with clinical severity and predicts clinical progression. However, the cellular substrate of altered TSPO binding is controversial and requires neuropathological validation. We used progressive supranuclear palsy (PSP) as a demonstrator condition, to test the hypothesis that [11C]-PK11195 PET reflects microglial changes. We included people with PSP-Richardsons syndrome who had undergone [11C]-PK11195 PET in life. In post-mortem brain tissue from the same participants we characterised cell-type specific TSPO expression with double-immunofluorescence labelling and quantified microgliosis in eight cortical and eleven subcortical regions with CD68 immunohistochemistry. Double-immunofluorescence labelling for TSPO and cell markers showed TSPO expression in microglia, astrocytes, and endothelial cells. Microglial TSPO expression was higher in donors with PSP compared to controls, which was not the case for astrocytic TSPO expression. There was a significant positive correlation between regional [11C]-PK11195 binding potential ante-mortem and the density of post-mortem CD68+ phagocytic microglia, as well as microglial TSPO expression. We conclude that [11C]-PK11195 binding in vivo is driven by microglia and can be interpreted as a biomarker of microglia-mediated neuroinflammation in tauopathies.