Early and longitudinal microglial activation but not fibrillar amyloid accumulation predict cognitive outcome and synaptic density in PS2APP mice

Introduction: Microglial activation is one hallmark in the pathophysiology of neurodegenerative diseases. However, results are still inconclusive whether neuroinflammation has beneficial or detrimental effects on cognitive outcome. 18kDa translocator protein (TSPO) PET imaging now facilitates to monitor regional alterations of microglial activity in vivo. Therefore, we objected to correlate serial measures of TSPO and amyloid PET with the terminal cognitive assessment in the PS2APP amyloid mouse model. Methods: N=10 PS2APP (TG) mice and N=7 C57Bl/6 (WT) mice were imaged from 8 to 13 months of age by TSPO PET (F-18-GE180) and amyloid PET (F-18-Florbetaben). Morris water maze (MWM) was performed at 13.5 months of age. Z-score differences were obtained voxel-wise for TG mice versus WT mice at each time-point. Z-score images of serial PET were summed to an area under the curve (AUC) map for each individual TG mouse. Baseline and AUC maps of TSPO activation and amyloidosis were correlated voxel-wise with findings of cognitive testing deriving from MWM. The entire forebrain and brain regions associated with spatial learning were likewise evaluated to investigate general effects. Immunohistochemical and biochemical experiments were performed at study termination. Synaptic density served as a validation marker for MWM. Results: TG mice indicated a distinct poorer performance in MWM when compared to WT at 13 months of age (distance: +436%, p<0.01 / escape latency: +244%, p<0.001). A better cognitive outcome was associated with higher TSPO activation at baseline in the forebrain (R = 0.71, p<0.05) and even stronger in brain areas involved in spatial learning (R = 0.82, p<0.01). Peak clusters of the amygdala and entorhinal cortices showed a very strong association between the baseline TSPO signal and terminal MWM performance (R = 0.95, p<0.001). Higher longitudinal TSPO activation by AUC maps tended to correlate with a better clinical outcome in the forebrain (R = 0.45, p=n.s.), and in brain areas involved in spatial learning (R = 0.60, p=n.s.). Peak clusters of longitudinal TSPO activation in hippocampal areas were significantly associated with terminal MWM performance (R = 0.68, p<0.05). Synaptic density showed similar correlations and validated MWM results. Fibrillar amyloidosis did not correlate with the cognitive outcome neither at baseline nor considering the whole imaging period (all R < 0.3). Conclusions: Early and longitudinal microglial response seems beneficial for preserving the cognitive performance in PS2APP mice. Fibrillar amyloidosis was in contrast not associated with cognitive performance.