Time Courses of Cortical Glucose Metabolism and Microglial Activity Across the Life Span of Wild-Type Mice: A PET Study

Abstract

Contrary to findings in the human brain, F-FDG PET shows cerebral hypermetabolism of aged wild-type (WT) mice relative to younger animals, supposedly due to microglial activation. Therefore, we used dual-tracer small-animal PET to examine directly the link between neuroinflammation and hypermetabolism in aged mice. WT mice (5-20 mo) were investigated in a cross-sectional design using F-FDG ( = 43) and translocator protein (TSPO) (F-GE180; = 58) small-animal PET, with volume-of-interest and voxelwise analyses. Biochemical analysis of plasma cytokine levels and immunohistochemical confirmation of microglial activity were also performed. Age-dependent cortical hypermetabolism in WT mice relative to young animals aged 5 mo peaked at 14.5 mo (+16%, < 0.001) and declined to baseline at 20 mo. Similarly, cortical TSPO binding increased to a maximum at 14.5 mo (+15%, < 0.001) and remained high to 20 mo, resulting in an overall correlation between F-FDG uptake and TSPO binding (R = 0.69, < 0.005). Biochemical and immunohistochemical analyses confirmed the TSPO small-animal PET findings. Age-dependent neuroinflammation is associated with the controversial observation of cerebral hypermetabolism in aging WT mice.

[18F]GE180 positron emission tomographic imaging indicates a potential double‐hit insult in the intrahippocampal kainate mouse model of temporal lobe epilepsy

“…However, several recent studies confirmed [ 18 F]GE180 PET in vivo findings by immunohistochemical and/or autoradiographic analyses. [28][29][30][31] Furthermore, our imaging data are generally in line with existing immunohistological characterization of the animal model used. 18,19 Following SE induced by intrahippocampal kainate injection, almost all mice develop epileptiform EEG activity after a latent period varying between 3 and 14 days in duration, 14,25,32 whereas tracer uptake was found to reapproach baseline levels in both the ipsilateral and the contralateral hippocampus only between 7 and 14 weeks after SE.…”

Obesity impacts brain metabolism and structure independently of amyloid and tau pathology in healthy elderly

“…In this sense, although brain glucose metabolism is considered a marker of neuronal activity, FDG-PET signal has recently been demonstrated to be also located in astrocytes [44]. In addition, animal studies combining FDG-PET and PET with tracers for activated microglia confirmed a highly colocalized signal of increase of glucose metabolism and neuroinflammation in both wild-type aging mice and in AD transgenic mice [45,46]. Interestingly, in wild-type mice uncoupling glucose metabolism and neuroinflammation was observed at older ages, i.e neuroinflammation persisted but glucose metabolism returned to baseline values.…”

Longitudinal Microglial Activation in Tau Transgenic P301S Mice Predicts Increased Tau Accumulation and Deteriorated Spatial Learning

“…Because understanding the role of neuroinflammation in AD and non-AD tauopathies is of crucial importance, we undertook longitudinal monitoring of microglial activation in P301S mice by means of tracer 18 F-GE-180 binds to the 18 kDa translocator protein (TSPO) expressed in activated microglial cells in living mouse brain, showing excellent correlation with ex vivo validation in several different amyloid-β mouse models [16][17][18][19]. We now aimed to test the predictive value of early microglial activation in this tau mouse model by undertaking serial 18 F-GE-180 µPET until 6.4 months of age, augmented by analyses of spatial learning with the Morris water maze test (MWM) and glucose metabolism with 18 F-fluorodesoxyglucose ( 18 F-FDG) µPET.…”

“…µPET Image Analysis All analyses were performed using PMOD (V3.5, PMOD technologies, Basel, Switzerland). After coregistration to an MRI mouse atlas [17], we conducted intensity normalization of images to standardized-uptake-value (SUV) relative to uptake in the myocardium for 18 F-GE-180 µPET [22] and by conventional SUV calculation for 18 F-FDG µPET. Predefined bilateral cortical (CTX, 24 mm ³ ), bilateral hippocampal (HIP, 11 mm ³ ), cerebellum (CBL, 12 mm ³ ), and brainstem (BRST, 12 mm ³ ) target volumes of interest (VOIs) were applied for both tracers (Fig.…”

“…A standard free-floating immunofluorescence (IF) protocol was performed in cortex and brainstem areas matching the µPET brain regions. As previously described [9,17], fixed 20-µm thick brain sections were first rinsed either overnight or for 48 h in PBS with 0.2% Triton X-100 containing one following primary antibodies: rabbit monoclonal IBA1 (1:500. Wako: , mouse monoclonal phospho-Tau (Ser202, Thr2015 (AT8), 1:500.…”