Imaging microglial activation and amyloid burden in amnestic mild cognitive impairment

Abstract

Amnestic mild cognitive impairment (aMCI) is defined as a transitional state between normal aging and Alzheimer's disease (AD). Given the replicated finding of increased microglial activation in AD, we sought to investigate whether microglial activation is also elevated in aMCI and whether it is related to amyloid beta (Aβ) burden in-vivo . Eleven aMCI participants and 14 healthy volunteers completed positron emission tomography (PET) scans with [¹⁸F]-FEPPA and [¹¹C]-PIB. Given the known sensitivity in affinity of second-generation TSPO radioligands, participants were genotyped for the TSPO polymorphism and only high-affinity binders were included. Dynamic [¹⁸F]-FEPPA PET images were analyzed using the 2-tissue compartment model with arterial plasma input function. Additionally, a supplementary method, the standardized uptake value ratio (SUVR), was explored. [¹¹C]-PIB PET images were analyzed using the Logan graphical method. aMCI participants had significantly higher [¹¹C]-PIB binding in the cortical regions. No significant differences in [¹⁸F]-FEPPA binding were observed between aMCI participants and healthy volunteers. In the aMCI group, [¹⁸F]-FEPPA and [¹¹C]-PIB bindings were correlated in the hippocampus. There were no correlations between our PET measures and cognition. Our findings demonstrate that while Aβ burden is evident in the aMCI stage, microglial activation may not be present.

Keywords: Alzheimer’s disease; amyloid; mild cognitive impairment; neuroinflammation; positron emission tomography.

Figure 1.

[¹¹C]-PIB distribution value ratios (DVR) in regions of interest with partial volume correction. aMCI participants (n = 11) had higher [¹¹C]-PIB binding in all regions except hippocampus. *p ≤ 0.05, **p < 0.01. The percent differences in binding are shown above each ROI.

Figure 2.

[¹⁸F]-FEPPA total volume distribution (V_T) in regions of interest with partial volume correction. No significant differences were observed between aMCI participants (n = 11) and healthy volunteers (n = 14). The percent differences in binding are shown above each ROI.

Figure 3.

Regional [¹⁸F]-FEPPA V_T for healthy volunteers and aMCI participants when stratified by PIB status. An average of 1.20 DVR in the cortical regions was used as a cut-off. No significant differences were observed between groups. PIB+=PIB-positive; PIB−=PIB−negative.

Figure 4.

Regional association between [¹⁸F]-FEPPA and [¹¹C]-PIB binding in the hippocampus. The correlation is shown in aMCI participants (n = 11) and after partial volume correction. The correlation in the hippocampus survived after Bonferroni correction for multiple comparisons.