scholarly journals A quantitative neuropathological assessment of translocator protein expression in multiple sclerosis

Brain ◽  
2019 ◽  
Vol 142 (11) ◽  
pp. 3440-3455 ◽  
Author(s):  
Erik Nutma ◽  
Jodie A Stephenson ◽  
Rianne P Gorter ◽  
Joy de Bruin ◽  
Deirdre M Boucherie ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Protein Expression ◽  
Translocator Protein ◽  
Inflammatory Phenotype ◽  
The Brain ◽  
Tspo Expression

Radioligands targeting the 18 kDa translocator protein (TSPO) are increasingly used to visualise inflammation in the brain. Nutma et al. report that TSPO expression in multiple sclerosis lesions originates mainly from astrocytes and microglia, but is not restricted to cells with a specific pro-inflammatory phenotype.

scholarly journals From positron emission tomography to cell analysis of the 18-kDa Translocator Protein in mild traumatic brain injury

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Clément Delage ◽  
Nicolas Vignal ◽  
Coralie Guerin ◽  
Toufik Taib ◽  
Clément Barboteau ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Positron Emission Tomography ◽  
Flow Cytometry ◽  
Microglial Activation ◽  
Translocator Protein ◽  
Emission Tomography ◽  
Flow Cytometry Analysis ◽  
Positron Emission ◽  
The Brain ◽  
Tspo Expression

AbstractTraumatic brain injury (TBI) leads to a deleterious neuroinflammation, originating from microglial activation. Monitoring microglial activation is an indispensable step to develop therapeutic strategies for TBI. In this study, we evaluated the use of the 18-kDa translocator protein (TSPO) in positron emission tomography (PET) and cellular analysis to monitor microglial activation in a mild TBI mouse model. TBI was induced on male Swiss mice. PET imaging analysis with [18F]FEPPA, a TSPO radiotracer, was performed at 1, 3 and 7 days post-TBI and flow cytometry analysis on brain at 1 and 3 days post-TBI. PET analysis showed no difference in TSPO expression between non-operated, sham-operated and TBI mice. Flow cytometry analysis demonstrated an increase in TSPO expression in ipsilateral brain 3 days post-TBI, especially in microglia, macrophages, lymphocytes and neutrophils. Moreover, microglia represent only 58.3% of TSPO+ cells in the brain. Our results raise the question of the use of TSPO radiotracer to monitor microglial activation after TBI. More broadly, flow cytometry results point the lack of specificity of TSPO for microglia and imply that microglia contribute to the overall increase in TSPO in the brain after TBI, but is not its only contributor.

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

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 Activated microglia do not increase 18 kDa translocator protein ( TSPO ) expression in the multiple sclerosis brain

Glia ◽  
2021 ◽  
Author(s):  
Erik Nutma ◽  
Emeline Gebro ◽  
Manuel C. Marzin ◽  
Paul Valk ◽  
Paul M. Matthews ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Translocator Protein ◽  
Activated Microglia ◽  
Tspo Expression

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 De novo Neurosteroidogenesis in Human Microglia: Involvement of the 18 kDa Translocator Protein

2021 ◽  
Vol 22 (6) ◽  
pp. 3115
Author(s):  
Lorenzo Germelli ◽  
Eleonora Da Pozzo ◽  
Chiara Giacomelli ◽  
Chiara Tremolanti ◽  
Laura Marchetti ◽  
...  
Keyword(s):  
Neurotrophic Factor ◽  
De Novo ◽  
Neuroactive Steroids ◽  
Translocator Protein ◽  
Compensatory Mechanism ◽  
Human Microglia ◽  
De Novo Biosynthesis ◽  
Murine Microglia ◽  
Synthetic Ligand ◽  
Tspo Expression

Neuroactive steroids are potent modulators of microglial functions and are capable of counteracting their excessive reactivity. This action has mainly been ascribed to neuroactive steroids released from other sources, as microglia have been defined unable to produce neurosteroids de novo. Unexpectedly, immortalized murine microglia recently exhibited this de novo biosynthesis; herein, de novo neurosteroidogenesis was characterized in immortalized human microglia. The results demonstrated that C20 and HMC3 microglial cells constitutively express members of the neurosteroidogenesis multiprotein machinery—in particular, the transduceosome members StAR and TSPO, and the enzyme CYP11A1. Moreover, both cell lines produce pregnenolone and transcriptionally express the enzymes involved in neurosteroidogenesis. The high TSPO expression levels observed in microglia prompted us to assess its role in de novo neurosteroidogenesis. TSPO siRNA and TSPO synthetic ligand treatments were used to reduce and prompt TSPO function, respectively. The TSPO expression downregulation compromised the de novo neurosteroidogenesis and led to an increase in StAR expression, probably as a compensatory mechanism. The pharmacological TSPO stimulation the de novo neurosteroidogenesis improved in turn the neurosteroid-mediated release of Brain-Derived Neurotrophic Factor. In conclusion, these results demonstrated that de novo neurosteroidogenesis occurs in human microglia, unravelling a new mechanism potentially useful for future therapeutic purposes.

scholarly journals GMP-compliant fully automated radiosynthesis of [18F]FEPPA for PET/MRI imaging of regional brain TSPO expression

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Chi-Wei Chang ◽  
Chuang-Hsin Chiu ◽  
Ming-Hsien Lin ◽  
Hung-Ming Wu ◽  
Tsung-Hsun Yu ◽  
...  
Keyword(s):  
Mr Imaging ◽  
Western Blotting ◽  
Second Generation ◽  
Mrna Levels ◽  
Automated Radiosynthesis ◽  
Lps Challenge ◽  
Tnf Α ◽  
The Brain ◽  
Tspo Expression

Abstract Background Expression of translocator protein (TSPO) on the outer mitochondrial membrane of activated microglia is strongly associated with neuroinflammation. The second-generation PET ligand [18F]FEPPA specifically binds TSPO to enable in vivo visualization and quantification of neuroinflammation. We optimized a fully automated radiosynthesis method and evaluated the utility of [18F]FEPPA, the second-generation PET ligand specifically binds TSPO, in a mouse model of systemic LPS challenge to detect TSPO-associated signals of central and peripheral inflammation. In vivo dynamic PET/MR imaging was performed in LPS-induced and control mice after [18F]FEPPA administration. The relationship between the [18F]FEPPA signal and the dose of LPS was assessed. The cytokine levels (i.e., TNF-α, Il-1β, Il-6) in LPS-induced mice were measured by RT-PCR. Standard uptake value (SUV), total volume of distribution (VT) and area under the curve (AUC) were determined based on the metabolite-uncorrected plasma input function. Western blotting and immunostaining were used to measure TSPO expression in the brain. Results The fully automated [18F]FEPPA radiosynthesis produced an uncorrected radiochemical yield of 30 ± 2% within 80 min, with a radiochemical purity greater than 99% and specific activity of 148.9‒216.8 GBq/µmol. Significant differences were observed in the brain after [18F]FEPPA administration: SUV, VT and AUC were 1.61 ± 0.1, 1.25 ± 0.12 and 1.58 ± 0.09-fold higher in LPS-injected mice than controls. TNF-α, Il-1β and Il-6 mRNA levels were also elevated in the brains of LPS-injected mice. Western blotting revealed TSPO (p < 0.05) and Iba-1 (p < 0.01) were upregulated in the brain after LPS administration. In LPS-injected mice, TSPO immunoactivity colocalized with Iba-1 in the cerebrum and TSPO was significantly overexpressed in the hippocampus and cerebellum. The peripheral organs (heart, lung) of LPS-injected mice had higher [18F]FEPPA signal-to-noise ratios than control mice. Conclusions Based on the current data on ligand specificity and selectivity in central tissues using 7 T PET/MR imaging, we demonstrate that [18F]FEPPA accumulations significant increased in the specific brain regions of systemic LPS-induced neuroinflammation (5 mg/kg). Future investigations are needed to determine the sensitivity of [18F]FEPPA as a biomarker of neuroinflammation as well as the correlation between the PET signal intensity and the expression levels of TSPO.

scholarly journals Signal quality as Achilles’ heel of graph theory in functional magnetic resonance imaging in multiple sclerosis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Johan Baijot ◽  
Stijn Denissen ◽  
Lars Costers ◽  
Jeroen Gielen ◽  
Melissa Cambron ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Signal To Noise Ratio ◽  
Pearson Correlation ◽  
Signal Quality ◽  
Network Parameters ◽  
Fmri Signal ◽  
Noise Ratio ◽  
Global And Local ◽  
The Brain ◽  
Local Brain

AbstractGraph-theoretical analysis is a novel tool to understand the organisation of the brain.We assessed whether altered graph theoretical parameters, as observed in multiple sclerosis (MS), reflect pathology-induced restructuring of the brain's functioning or result from a reduced signal quality in functional MRI (fMRI). In a cohort of 49 people with MS and a matched group of 25 healthy subjects (HS), we performed a cognitive evaluation and acquired fMRI. From the fMRI measurement, Pearson correlation-based networks were calculated and graph theoretical parameters reflecting global and local brain organisation were obtained. Additionally, we assessed metrics of scanning quality (signal to noise ratio (SNR)) and fMRI signal quality (temporal SNR and contrast to noise ratio (CNR)). In accordance with the literature, we found that the network parameters were altered in MS compared to HS. However, no significant link was found with cognition. Scanning quality (SNR) did not differ between both cohorts. In contrast, measures of fMRI signal quality were significantly different and explained the observed differences in GTA parameters. Our results suggest that differences in network parameters between MS and HS in fMRI do not reflect a functional reorganisation of the brain, but rather occur due to reduced fMRI signal quality.

Sign in / Sign up

Export Citation Format

Share Document