Abstract
The increased expression of 18 kDa Translocator protein (TSPO) is one of the few available biomarkers of neuroinflammation that can be assessed in humans in vivo by positron emission tomography (PET). TSPO PET imaging of the central nervous system (CNS) has been widely undertaken, but to date no clear consensus has been reached about its utility in brain disorders. One reason for this could be because the interpretation of TSPO PET signal remains challenging, given the cellular heterogeneity and ubiquity of TSPO in the brain.The aim of the current study was to ascertain if TSPO PET imaging can be used to detect neuroinflammation induced by a peripheral treatment with a low dose of the endotoxin, lipopolysaccharide (LPS), in a rat model (ip LPS), and investigate the origin of TSPO signal changes in terms of their cellular sources and regional distribution. An initial pilot study utilising both [18F]DPA-714 and [11C]PK11195 TSPO radiotracers demonstrated [18F]DPA-714 to exhibit a significantly higher lesion-related signal in the intracerebral LPS rat model (ic LPS) than [11C]PK11195. Subsequently, [18F]DPA-714 was selected for use in the ip LPS study.Twenty-four hours after ip LPS, there was an increased uptake of [18F]DPA-714 across the whole brain. Further analyses of regions of interest, using immunohistochemistry and RNAscope Multiplex fluorescence V2 in situ hybridization technology, showed TSPO expression in microglia, monocyte derived-macrophages, astrocytes, neurons and endothelial cells. The expression of TSPO was significantly increased after ip LPS in a region-dependent manner: with increased microglia, monocyte-derived macrophages and astrocytes in the substantia nigra, in contrast to the hippocampus where TSPO was mostly confined to microglia and astrocytes. In summary, our data demonstrate the robust detection of peripherally-induced neuroinflammation in the CNS utilising the TSPO PET radiotracer, [18F]DPA-714, and importantly, confirm that the resultant increase in TSPO signal increase arises mostly from a combination of microglia, astrocytes and monocyte-derived macrophages.
Highlights
The increased expression of 18 kDa Translocator protein (TSPO) is one of the few available biomarkers of neuroinflammation that can be assessed in humans in vivo by positron emission tomography (PET)
A robust focal inflammatory response following intracerebral LPS rat model (ic LPS) has been detected in the present study (Supplemental Figures 1 and 2) including increased activation of microglia and astrocytes, as well as upregulation of TSPO, accompanied by induction of mRNA expression for various proinflammatory cytokines such as Tnf-α, Il-6, Il-1β, intercellular adhe sion molecules (Icam-1) and peripheral monocyte recruitment (Ly6c)
We aimed to replicate these findings with two TSPO radiotracers, [11C]PK11195 and [18F]DPA-714, in order to select the more sensitive radiotracer for the peripherally-induced neuro inflammation study, which was anticipated to present a more physiological neuroinflammatory phenotype
Summary
The increased expression of 18 kDa Translocator protein (TSPO) is one of the few available biomarkers of neuroinflammation that can be assessed in humans in vivo by positron emission tomography (PET). TSPO PET imaging of the central nervous system (CNS) has been widely undertaken, but to date no clear consensus has been reached about its utility in brain disorders. Our data demonstrate the robust detection of peripherally-induced neuroinflammation in the CNS utilising the TSPO PET radiotracer, [18F]DPA-714, and importantly, confirm that the resultant increase in TSPO signal in crease arises mostly from a combination of microglia, astrocytes and monocyte-derived macrophages. The proinflammatory role of microglia has been widely documented in the past decade due to the availability of imaging biomarkers designed to detect in vivo brain inflammation Most of these biomarkers belong to a family of positron emission tomography (PET) radiotracers that bind to an 18kD Translocator protein (TSPO) located on the outer mitochondrial membrane of various cells, with a relatively high expression in microglia (Turkheimer et al, 2015). Altered TSPO binding has been associ ated with psychiatric disorders such as depression and schizophrenia (Bauer and Teixeira, 2019; Gilhus and Deuschl, 2019), but the evidence is somewhat ambiguous (Fried et al, 2019; Miller and Goldsmith, 2019; Perry, 2018)
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