scholarly journals Expression of Translocator Protein and [18F]-GE180 Ligand Uptake in Multiple Sclerosis Animal Models

Cells ◽  
2019 ◽  
Vol 8 (2) ◽  
pp. 94 ◽  
Author(s):  
Anne Nack ◽  
Matthias Brendel ◽  
Julia Nedelcu ◽  
Markus Daerr ◽  
Stella Nyamoya ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Corpus Callosum ◽  
Pet Imaging ◽  
Cellular Localization ◽  
Grey Matter ◽  
Axonal Injury ◽  
Cell Types ◽  
Translocator Protein ◽  
Double Labelling ◽  
Tspo Expression

Positron emission tomography (PET) ligands targeting the translocator protein (TSPO) represent promising tools to visualize neuroinflammation in multiple sclerosis (MS). Although it is known that TSPO is expressed in the outer mitochondria membrane, its cellular localization in the central nervous system under physiological and pathological conditions is not entirely clear. The purpose of this study was to assess the feasibility of utilizing PET imaging with the TSPO tracer, [18F]-GE180, to detect histopathological changes during experimental demyelination, and to determine which cell types express TSPO. C57BL/6 mice were fed with cuprizone for up to 5 weeks to induce demyelination. Groups of mice were investigated by [18F]-GE180 PET imaging at week 5. Recruitment of peripheral immune cells was triggered by combining cuprizone intoxication with MOG35–55 immunization (i.e., Cup/EAE). Immunofluorescence double-labelling and transgene mice were used to determine which cell types express TSPO. [18F]-GE180-PET reliably detected the cuprizone-induced pathology in various white and grey matter regions, including the corpus callosum, cortex, hippocampus, thalamus and caudoputamen. Cuprizone-induced demyelination was paralleled by an increase in TSPO expression, glia activation and axonal injury. Most of the microglia and around one-third of the astrocytes expressed TSPO. TSPO expression induction was more severe in the white matter corpus callosum compared to the grey matter cortex. Although mitochondria accumulate at sites of focal axonal injury, these mitochondria do not express TSPO. In Cup/EAE mice, both microglia and recruited monocytes contribute to the TSPO expressing cell populations. These findings support the notion that TSPO is a valuable marker for the in vivo visualization and quantification of neuropathological changes in the MS brain. The pathological substrate of an increase in TSPO-ligand binding might be diverse including microglia activation, peripheral monocyte recruitment, or astrocytosis, but not axonal injury.

scholarly journals Translocator Protein PET Imaging for Glial Activation in Multiple Sclerosis

2010 ◽  
Vol 6 (3) ◽  
pp. 354-361 ◽  
Author(s):  
Unsong Oh ◽  
Masahiro Fujita ◽  
Vasiliki N. Ikonomidou ◽  
Iordanis E. Evangelou ◽  
Eiji Matsuura ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Pet Imaging ◽  
Glial Activation ◽  
Translocator Protein

scholarly journals TSPO PET detects acute neuroinflammation but not diffuse chronically activated MHCII microglia in the rat

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Nassir U. Al-Khishman ◽  
Qi Qi ◽  
Austyn D. Roseborough ◽  
Alexander Levit ◽  
Brian L. Allman ◽  
...  
Keyword(s):  
Corpus Callosum ◽  
Tracer Uptake ◽  
Translocator Protein ◽  
Imaging Biomarkers ◽  
Wild Type ◽  
Activated Microglia ◽  
Fischer 344 ◽  
Histocompatibility Complex ◽  
Prodromal Alzheimer’S Disease ◽  
Tspo Expression

Abstract Background Accurate and sensitive imaging biomarkers are required to study the progression of white matter (WM) inflammation in neurodegenerative diseases. Radioligands targeting the translocator protein (TSPO) are considered sensitive indicators of neuroinflammation, but it is not clear how well the expression of TSPO coincides with major histocompatibility complex class II (MHCII) molecules in WM. This study aimed to test the ability of TSPO to detect activated WM microglia that are immunohistochemically positive for MHCII in rat models of prodromal Alzheimer’s disease and acute subcortical stroke. Methods Fischer 344 wild-type (n = 12) and TgAPP21 (n = 11) rats were imaged with [18F]FEPPA PET and MRI to investigate TSPO tracer uptake in the corpus callosum, a WM region known to have high levels of MHCII activated microglia in TgAPP21 rats. Wild-type rats subsequently received an endothelin-1 (ET1) subcortical stroke and were imaged at days 7 and 28 post-stroke before immunohistochemistry of TSPO, GFAP, iNOS, and the MHCII rat antigen, OX6. Results [18F]FEPPA PET was not significantly affected by genotype in WM and only detected increases near the ET1 infarct (P = 0.033, infarct/cerebellum uptake ratio: baseline = 0.94 ± 0.16; day 7 = 2.10 ± 0.78; day 28 = 1.77 ± 0.35). Immunohistochemistry confirmed that only the infarct (TSPO cells/mm2: day 7 = 555 ± 181; day 28 = 307 ± 153) and WM that is proximal to the infarct had TSPO expression (TSPO cells/mm2: day 7 = 113 ± 93; day 28 = 5 ± 7). TSPO and iNOS were not able to detect the chronic WM microglial activation that was detected with MHCII in the contralateral corpus callosum (day 28 OX6% area: saline = 0.62 ± 0.38; stroke = 4.30 ± 2.83; P = .029). Conclusion TSPO was only expressed in the stroke-induced insult and proximal tissue and therefore was unable to detect remote and non-insult-related chronically activated microglia overexpressing MHCII in WM. This suggests that research in neuroinflammation, particularly in the WM, would benefit from MHCII-sensitive radiotracers.

scholarly journals Neuron-specific activation of necroptosis signaling in multiple sclerosis cortical grey matter

2021 ◽  
Vol 141 (4) ◽  
pp. 585-604 ◽  
Author(s):  
Carmen Picon ◽  
Anusha Jayaraman ◽  
Rachel James ◽  
Catriona Beck ◽  
Patricia Gallego ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Signaling Pathway ◽  
Cortical Neurons ◽  
Grey Matter ◽  
Molecular Mechanisms ◽  
Fold Increase ◽  
Cell Types ◽  
Meningeal Inflammation ◽  
Cortical Grey Matter

AbstractSustained exposure to pro-inflammatory cytokines in the leptomeninges is thought to play a major role in the pathogenetic mechanisms leading to cortical pathology in multiple sclerosis (MS). Although the molecular mechanisms underlying neurodegeneration in the grey matter remain unclear, several lines of evidence suggest a prominent role for tumour necrosis factor (TNF). Using cortical grey matter tissue blocks from post-mortem brains from 28 secondary progressive MS subjects and ten non-neurological controls, we describe an increase in expression of multiple steps in the TNF/TNF receptor 1 signaling pathway leading to necroptosis, including the key proteins TNFR1, FADD, RIPK1, RIPK3 and MLKL. Activation of this pathway was indicated by the phosphorylation of RIPK3 and MLKL and the formation of protein oligomers characteristic of necrosomes. In contrast, caspase-8 dependent apoptotic signaling was decreased. Upregulation of necroptotic signaling occurred predominantly in macroneurons in cortical layers II–III, with little expression in other cell types. The presence of activated necroptotic proteins in neurons was increased in MS cases with prominent meningeal inflammation, with a 30-fold increase in phosphoMLKL+ neurons in layers I–III. The density of phosphoMLKL+ neurons correlated inversely with age at death, age at progression and disease duration. In vivo induction of chronically elevated TNF and INFγ levels in the CSF in a rat model via lentiviral transduction in the meninges, triggered inflammation and neurodegeneration in the underlying cortical grey matter that was associated with increased neuronal expression of TNFR1 and activated necroptotic signaling proteins. Exposure of cultured primary rat cortical neurons to TNF induced necroptosis when apoptosis was inhibited. Our data suggest that neurons in the MS cortex are dying via TNF/TNFR1 stimulated necroptosis rather than apoptosis, possibly initiated in part by chronic meningeal inflammation. Neuronal necroptosis represents a pathogenetic mechanism that is amenable to therapeutic intervention at several points in the signaling pathway.

scholarly journals A higher proportion of ermin-immunopositive oligodendrocytes in areas of remyelination

PLoS ONE ◽  
2021 ◽  
Vol 16 (8) ◽  
pp. e0256155
Author(s):  
Intakhar Ahmad ◽  
Stig Wergeland ◽  
Eystein Oveland ◽  
Lars Bø
Keyword(s):  
Multiple Sclerosis ◽  
White Matter ◽  
Corpus Callosum ◽  
Mouse Model ◽  
Grey Matter ◽  
Early Stage ◽  
Relative Proportion ◽  
Normal Appearing White Matter ◽  
The Brain

Incomplete remyelination is frequent in multiple sclerosis (MS)-lesions, but there is no established marker for recent remyelination. We investigated the role of the oligodendrocyte/myelin protein ermin in de- and remyelination in the cuprizone (CPZ) mouse model, and in MS. The density of ermin+ oligodendrocytes in the brain was significantly decreased after one week of CPZ exposure (p < 0.02). The relative proportion of ermin+ cells compared to cells positive for the late-stage oligodendrocyte marker Nogo-A increased at the onset of remyelination in the corpus callosum (p < 0.02). The density of ermin-positive cells increased in the corpus callosum during the CPZ-phase of extensive remyelination (p < 0.0001). In MS, the density of ermin+ cells was higher in remyelinated lesion areas compared to non-remyelinated areas both in white- (p < 0.0001) and grey matter (p < 0.0001) and compared to normal-appearing white matter (p < 0.001). Ermin immunopositive cells in MS-lesions were not immunopositive for the early-stage oligodendrocyte markers O4 and O1, but a subpopulation was immunopositive for Nogo-A. The data suggest a relatively higher proportion of ermin immunopositivity in oligodendrocytes compared to Nogo-A indicates recent or ongoing remyelination.

scholarly journals Evaluation of the PBR/TSPO Radioligand [18F]DPA-714 in a Rat Model of Focal Cerebral Ischemia

2009 ◽  
Vol 30 (1) ◽  
pp. 230-241 ◽  
Author(s):  
Abraham Martín ◽  
Raphaël Boisgard ◽  
Benoit Thézé ◽  
Nadja Van Camp ◽  
Bertrand Kuhnast ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Pet Imaging ◽  
Time Course ◽  
Focal Cerebral Ischemia ◽  
Quantitative Information ◽  
Translocator Protein ◽  
Experimental Stroke ◽  
Tspo Expression

Focal cerebral ischemia leads to an inflammatory reaction involving an overexpression of the peripheral benzodiazepine receptor (PBR)/18-kDa translocator protein (TSPO) in the cerebral monocytic lineage (microglia and monocyte) and in astrocytes. Imaging of PBR/TSPO by positron emission tomography (PET) using radiolabeled ligands can document inflammatory processes induced by cerebral ischemia. We performed in vivo PET imaging with [18F]DPA-714 to determine the time course of PBR/TSPO expression over several days after induction of cerebral ischemia in rats. In vivo PET imaging showed significant increase in DPA ( N,N-diethyl-2-(2-(4-(2-fluoroethoxy)phenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)acetamide) uptake on the injured side compared with that in the contralateral area on days 7, 11, 15, and 21 after ischemia; the maximal binding value was reached 11 days after ischemia. In vitro autoradiography confirmed these in vivo results. In vivo and in vitro [18F]DPA-714 binding was displaced from the lesion by PK11195 and DPA-714. Immunohistochemistry showed increased PBR/TSPO expression, peaking at day 11 in cells expressing microglia/macrophage antigens in the ischemic area. At later times, a centripetal migration of astrocytes toward the lesion was observed, promoting the formation of an astrocytic scar. These results show that [18F]DPA-714 provides accurate quantitative information of the time course of PBR/TSPO expression in experimental stroke.

scholarly journals [11C]PIB PET imaging can detect white and grey matter demyelination in a non-human primate model of progressive multiple sclerosis

2019 ◽  
Vol 35 ◽  
pp. 108-115 ◽  
Author(s):  
Robert H.F. Carvalho ◽  
Caroline C. Real ◽  
Simone Cinini ◽  
Alexandre T. Garcez ◽  
Fabio L.S. Duran ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Pet Imaging ◽  
Grey Matter ◽  
Progressive Multiple Sclerosis ◽  
Primate Model ◽  
Human Primate

PET imaging of glucose metabolism, neuroinflammation and demyelination in the lysolecithin rat model for multiple sclerosis

2014 ◽  
Vol 20 (11) ◽  
pp. 1443-1452 ◽  
Author(s):  
Daniele de Paula Faria ◽  
Erik FJ de Vries ◽  
Jurgen WA Sijbesma ◽  
Carlos A Buchpiguel ◽  
Rudi AJO Dierckx ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Glucose Metabolism ◽  
Corpus Callosum ◽  
Disease Progression ◽  
Pet Imaging ◽  
Microglia Activation ◽  
Sprague Dawley ◽  
Positron Emission ◽  
The Right

Background: Injection of lysolecithin in the central nervous system results in demyelination accompanied by local activation of microglia and recruitment of monocytes. Positron-emission tomography (PET) imaging, using specific tracers, may be an adequate technique to monitor these events in vivo and therefore may become a tool for monitoring disease progression in multiple sclerosis (MS) patients. Objectives: The objective of this paper is to evaluate the potential of PET imaging in monitoring local lesions, using [11C]MeDAS, [11C]PK11195 and [18F]FDG as PET tracers for myelin density, microglia activation and glucose metabolism, respectively. Methods: Sprague-Dawley rats were stereotactically injected with either 1% lysolecithin or saline in the corpus callosum and striatum of the right brain hemisphere. PET imaging was performed three days, one week and four weeks after injection. Animals were terminated after PET imaging and the brains were explanted for (immuno)histochemical analysis. Results: PET imaging was able to detect local demyelination induced by lysolecithin in the corpus callosum and striatum with [11C]MeDAS and concomitant microglia activation and monocyte recruitment with [11C]PK11195. [18F]FDG imaging demonstrated that glucose metabolism was maintained in the demyelinated lesions. Conclusion: PET imaging with multiple tracers allows simultaneous in vivo monitoring of myelin density, neuroinflammation and brain metabolism in small MS-like lesions, indicating its potential to monitor disease progression in MS patients.

scholarly journals Translocator Protein 18 kDa (TSPO) Expression in Multiple Sclerosis Patients

2012 ◽  
Vol 8 (1) ◽  
pp. 51-57 ◽  
Author(s):  
Erin Harberts ◽  
Dibyadeep Datta ◽  
Selby Chen ◽  
Jillian E. Wohler ◽  
Unsong Oh ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Translocator Protein ◽  
Translocator Protein 18 Kda ◽  
Multiple Sclerosis Patients ◽  
Tspo Expression

TSPO-PET Imaging to Assess Cerebral Microglial Activation in Multiple Sclerosis

2017 ◽  
Vol 37 (05) ◽  
pp. 546-557 ◽  
Author(s):  
Howard Weiner ◽  
Rohit Bakshi ◽  
Tarun Singhal
Keyword(s):  
Multiple Sclerosis ◽  
Gray Matter ◽  
Pet Imaging ◽  
Microglial Activation ◽  
Adaptive Immune System ◽  
Translocator Protein ◽  
Current Status ◽  
Future Research ◽  
Adaptive Immune ◽  
Positron Emission

AbstractThe adaptive immune system, particularly T cells and more recently B cells, is considered to play a major role in the pathogenesis of multiple sclerosis (MS). In addition to adaptive immune mechanisms, innate central nervous system (CNS) immunity, particularly mediated by microglia, may play a key role in MS pathogenesis. Microglial activation has been demonstrated throughout the MS disease course and at various locations in the CNS, including white and gray matter lesions as well as normal appearing white and gray matter. Activated microglia overexpress an 18 kilodalton mitochondrial translocator protein (TSPO), which is otherwise expressed at low levels during the resting state. Several positron emission tomography (PET) ligands targeting TSPO have been developed to enable the assessment of microglial activation. In this article, we review the biological basis, methodological aspects, and current status of TSPO-PET imaging in MS and discuss future research directions.

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