TSPO PET binding in vivo reflects increased phagocytic microglia at post mortem in people with frontotemporal dementia

Brain inflammation is a key feature of frontotemporal dementia (FTD). TSPO PET is widely used as an in vivo proxy for neuroinflammation, but whether the elevated signal reflects microglial, astrocytic, or vascular pathology is controversial. We paired ante mortem [11C]PK11195 TSPO PET with post mortem neuropathology in 10 individuals with FTD (5 FTLD-tau, 5 FTLD-TDP) and 5 controls, combining CD68 immunohistochemistry across 17 regions, multiplex immunofluorescence pairing TSPO with microglial/macrophagic (IBA1, CD68), astrocytic (GFAP) and endothelial (CD31) markers, and three-dimensional single-cell reconstruction. CD68 burden was elevated in FTD, concentrated in white matter, and correlated with regional TSPO PET binding across pathologies ({beta} = 8.40, P < 0.001). Only the CD68-TSPO co-localised fraction tracked the PET signal, with no TSPO upregulation per-cell. The elevated TSPO PET signal in FTD likely reflects an increased burden of lysosome-enriched CD68+ microglia, supporting TSPO PET as a microglial-burden biomarker in both FTLD-tau and FTLD-TDP.