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

Abstract Brain inflammation is a key feature of frontotemporal dementia (FTD). Positron emission tomography (PET) of the 18 kDa translocator protein (TSPO) is widely used as an in vivo proxy for neuroinflammation, but whether the elevated signal reflects microglial, astrocytic or vascular pathology remains controversial, and this has not previously been resolved in FTD using matched ante mortem imaging and post-mortem tissue. We paired ante mortem [ 11 C]PK11195 TSPO–PET with quantitative post-mortem neuropathology in 10 individuals with FTD (5 FTLD-tau, 5 FTLD–TDP) and 5 age- and sex-matched controls, combining CD68 immunohistochemistry across 17 brain regions, multiplex immunofluorescence pairing TSPO with microglial/macrophagic (IBA1, CD68), astrocytic (GFAP) and endothelial (CD31) markers in three frontotemporal cortical regions, and three-dimensional single-cell reconstruction of individual microglia. CD68 area fraction was elevated in FTD relative to controls, predominantly in white matter, and was positively associated with regional TSPO–PET-binding potential across the cohort ( β = 8.66, P < 0.001), with comparable slopes in FTLD-tau and FTLD–TDP. Total tissue TSPO-area fraction was likewise increased in FTD and tracked regional PET binding in two independently processed slide sets. Of the four cell-type markers, only the CD68–TSPO co-localised fraction was positively associated with the PET signal ( β = +0.0041, P = 0.015, P FDR = 0.062), with null or negative associations for IBA1, GFAP and CD31. At single-cell resolution, IBA1+ microglia that were also CD68+ carried more absolute TSPO and were larger than CD68− microglia, without an increase in the TSPO fraction of cell volume. The elevated TSPO–PET signal in FTD, therefore, likely reflects an increased burden of CD68+ phagocytic microglia rather than TSPO expression in other cell types, supporting TSPO–PET as a microglial-burden biomarker across both FTLD-tau and FTLD–TDP.