PT - JOURNAL ARTICLE AU - Gloria Biechele AU - Tanja Blume AU - Maximilian Deussing AU - Benedikt Zott AU - Yuan Shi AU - Xianyuan Xiang AU - Nicolai Franzmeier AU - Gernot Kleinberger AU - Finn Peters AU - Katharina Ochs AU - Carola Focke AU - Christian Sacher AU - Karin Wind AU - Claudio Schmidt AU - Simon Lindner AU - Franz-Josef Gildehaus AU - Florian Eckenweber AU - Leonie Beyer AU - Barbara von Ungern-Sternberg AU - Peter Bartenstein AU - Karlheinz Baumann AU - Mario M. Dorostkar AU - Axel Rominger AU - Paul Cumming AU - Michael Willem AU - Helmuth Adelsberger AU - Jochen Herms AU - Matthias Brendel TI - Pre-therapeutic Microglia Activation and Sex Determine Therapy Effects of Chronic Immunomodulation AID - 10.1101/2021.05.30.445761 DP - 2021 Jan 01 TA - bioRxiv PG - 2021.05.30.445761 4099 - http://biorxiv.org/content/early/2021/05/31/2021.05.30.445761.short 4100 - http://biorxiv.org/content/early/2021/05/31/2021.05.30.445761.full AB - Modulation of the innate immune system is emerging as a promising therapeutic strategy against Alzheimer’s disease (AD). However, determinants of a beneficial therapeutic effect are ill-understood. Thus, we investigated the potential of 18 kDa translocator protein positron-emission-tomography (TSPO-PET) for assessment of microglial activation in mouse brain before and during chronic immunomodulation. Serial TSPO-PET was performed during five months of chronic microglia modulation by stimulation of peroxisome proliferator-activated receptor (PPAR)-γ with pioglitazone in two different mouse models of AD (PS2APP, AppNL-G-F). Using mixed statistical models on longitudinal TSPO-PET data, we tested for effects of therapy and sex on treatment response. We tested correlations of baseline with longitudinal measures of TSPO-PET, and correlations between PET results with spatial learning performance and β-amyloid accumulation of individual mice. Immunohistochemistry was used to determine the molecular source of the TSPO-PET signal. Pioglitazone-treated female PS2APP and AppNL-G-F mice showed attenuation of the longitudinal increases in TSPO-PET signal when compared to vehicle controls, whereas treated male AppNL-G-F mice showed the opposite effect. Baseline TSPO-PET strongly predicted changes in microglial activation in treated mice (R=−0.874, p<0.0001) but not in vehicle controls (R=−0.356, p=0.081). Reduced TSPO-PET signal upon treatment was associated with better spatial learning and higher fibrillar β-amyloid accumulation. Immunohistochemistry confirmed activated microglia to be the source of the TSPO-PET signal (R=0.952, p<0.0001). TSPO-PET represents a sensitive biomarker for monitoring of immunomodulation and closely reflects activated microglia. Pre-therapeutic assessment of baseline microglial activation and sex are strong predictors of individual immunomodulation effects and could serve for responder stratification.Competing Interest StatementK.B. is an employee of Roche. M.B. received speaker honoraria from GE healthcare, Roche and LMI and is an advisor of LMI.