Resolving the cellular specificity of TSPO imaging in a rat model of peripherally-induced neuroinflammation |
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| Affiliation: | 1. Department of Neuroimaging, Institute of Psychiatry, Psychology & Neuroscience, King''s College London, London, United Kingdom;2. GlaxoSmithKline, Stevenage, London, United Kingdom;3. PET Centre, St Thomas'' Hospital, London, United Kingdom;4. The Wellcome Trust Consortium for the Neuroimmunology of Mood Disorders and Alzheimer''s Disease (NIMA), United Kingdom;5. Centre for Radiopharmaceutical Chemistry, University College London, London WC1E 6BS, United Kingdom;6. School of Biomedical Engineering and Imaging Sciences, King’s College London, London SE1 7EH, United Kingdom |
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| 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. |
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| Keywords: | Astrocytes Biomarkers DPA-714 Microglia Macrophages Neurons Neuroinflammation TSPO TSPO"} {"#name":"keyword" "$":{"id":"k0045"} "$$":[{"#name":"text" "_":"18kDa translocator protein PET"} {"#name":"keyword" "$":{"id":"k0055"} "$$":[{"#name":"text" "_":"positron emission tomography LPS"} {"#name":"keyword" "$":{"id":"k0065"} "$$":[{"#name":"text" "_":"lipopolysaccharide ic LPS"} {"#name":"keyword" "$":{"id":"k0075"} "$$":[{"#name":"text" "_":"intracerebral administered LPS CNS"} {"#name":"keyword" "$":{"id":"k0085"} "$$":[{"#name":"text" "_":"central nervous system TBI"} {"#name":"keyword" "$":{"id":"k0095"} "$$":[{"#name":"text" "_":"traumatic brain injury OSEM"} {"#name":"keyword" "$":{"id":"k0105"} "$$":[{"#name":"text" "_":"ordered subset expectation maximization AUC"} {"#name":"keyword" "$":{"id":"k0115"} "$$":[{"#name":"text" "_":"area under the curve TACs"} {"#name":"keyword" "$":{"id":"k0125"} "$$":[{"#name":"text" "_":"time-activity curves SUV"} {"#name":"keyword" "$":{"id":"k0135"} "$$":[{"#name":"text" "_":"standardized uptake values ROIs"} {"#name":"keyword" "$":{"id":"k0145"} "$$":[{"#name":"text" "_":"regions of interest PFA"} {"#name":"keyword" "$":{"id":"k0155"} "$$":[{"#name":"text" "_":"paraformaldehyde DAB"} {"#name":"keyword" "$":{"id":"k0165"} "$$":[{"#name":"text" "_":"diaminobenzidine TSPO+"} {"#name":"keyword" "$":{"id":"k0175"} "$$":[{"#name":"text" "_":"TSPO positive cells Iba1+"} {"#name":"keyword" "$":{"id":"k0185"} "$$":[{"#name":"text" "_":"Iba1 positive cells TSPO+Iba1+"} {"#name":"keyword" "$":{"id":"k0195"} "$$":[{"#name":"text" "_":"double positive cells for TSPO and Iba1 TSPO+Iba1-"} {"#name":"keyword" "$":{"id":"k0205"} "$$":[{"#name":"text" "$$":[{"#name":"__text__" "_":"positive cells for TSPO and negative for Iba1 "} {"#name":"italic" "_":"Tmem119"} {"#name":"__text__" "_":" transmembrane protein 119 C–C Motif Chemokine Receptor 2 |
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