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 [F]-FEPPA and [C]-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 [F]-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. [C]-PIB PET images were analyzed using the Logan graphical method. aMCI participants had significantly higher [C]-PIB binding in the cortical regions. No significant differences in [F]-FEPPA binding were observed between aMCI participants and healthy volunteers. In the aMCI group, [F]-FEPPA and [C]-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.

Applications of amyloid, tau, and neuroinflammation PET imaging to Alzheimer's disease and mild cognitive impairment

“…Overall, tau, amyloid, and TSPO radiotracers show good ability in the detection of AD and MCI, in addition to associated neuropathology (Table 5) Hamelin et al, 2016;Knezevic et al, 2017;Parbo et al, 2017;Parbo et al, 2018). Whilst older and using smaller samples, studies indicating negative or no association between microglial activation and Aβ accumulation (Kreisl et al, 2013;Wiley et al, 2009;Yokokura et al, 2011) highlights the need for future research to clarify the nature of this relationship using in vivo brain imaging technology.…”

“…Similar to [ 11 C]PK11195, in vivo increases in TSPO binding are associated with impairments in global cognition and memory (Hamelin et al, 2018;Kreisl et al, 2013), but also extend to domains that include visuospatial and language ability, and executive functioning, in addition to dementia severity and brain atrophy (Hamelin et al, 2018;Kreisl et al, 2013;Kreisl et al, 2016;Suridjan et al, 2015). However, some studies demonstrate no such correlations with the ADAS-Cog or MMSE (Yasuno et al, 2008;Yasuno et al, 2012) upregulated cortical tracer retention when compared to healthy controls, especially in the temporal lobe Yasuno et al, 2012), and others showing no such significant differences (Knezevic et al, 2017;Kreisl et al, 2013).…”

Early and Longitudinal Microglial Activation but Not Amyloid Accumulation Predicts Cognitive Outcome in PS2APP Mice

“…PET investigation of AD patients indicated only a low correlation between cerebral amyloid burden and cognitive performance (15), and Ab deposition precedes the onset of neuroinflammation in patients with mild cognitive impairment (16). We contend that the temporal sequences of Ab deposition and microglial activation in relation to progression of cognitive impairment is best examined through molecular imaging studies of longitudinal design.…”

Association of neuroinflammation with episodic memory: a [11C]PBR28 PET study in cognitively discordant twin pairs

“…Fewer studies have examined the association of TSPO binding particularly with EM performance. One study found that worse delayed word list recall score was associated with higher TSPO binding in the precuneus in Alzheimer’s disease ( Passamonti et al , 2018 ), while two studies did not find a correlation with delayed verbal EM test scores ( Kreisl et al , 2017 ; Knezevic et al , 2018 ).…”