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

Brendel, M.; Focke, C.; Deussing, M.; Zott, B.; Blune, T.; Shi, Y.; Beyer, L.; Kleinberger, G.; Lindner, S.; Gildehaus, F.; Bartenstein, P.; Baumann, K.; Haass, C.; Herms, J.; Adelsberger, H.; Rominger, Axel Oliver (2018). Early and longitudinal microglial activation but not fibrillar amyloid accumulation predict cognitive outcome and synaptic density in PS2APP mice. European journal of nuclear medicine and molecular imaging, 45(S1), S206-S207. Springer-Verlag

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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.

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