Post-mortem validation of in vivo TSPO PET as a microglial biomarker

Abstract

Neuroinflammation is a feature of many neurodegenerative diseases and is 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-Richardson's syndrome who had undergone 11C-PK11195 PET in life (n = 8). In post-mortem brain tissue from the same participants, we characterized cell-type specific TSPO expression and quantified microgliosis in eight cortical and 11 subcortical regions. Double-immunofluorescence labelling for TSPO and cell markers showed TSPO expression in microglia, astrocytes and endothelial cells. Microglial (and not astrocytic) TSPO levels were higher in donors with PSP compared to control subjects (n = 3), and correlated with changes in microglial burden. There was a significant positive correlation between regional 11C-PK11195 binding potential ante-mortem and the burden of post-mortem CD68+ phagocytic microglia, as well as microglial TSPO levels. We conclude that in vivo disease-related changes in 11C-PK11195 binding is largely driven by microglia and can be interpreted as a biomarker of microglia-mediated neuroinflammation in tauopathies.