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

Al-Khishman, Nassir U.; Qi, Qi; Roseborough, Austyn D.; Levit, Alexander; Allman, Brian L.; Anazodo, Udunna; Fox, Matthew S.; Whitehead, Shawn N.; Thiessen, Jonathan D.

doi:10.1186/s13550-020-00699-x

Cited by 16 publications

(23 citation statements)

References 34 publications

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“…In agreement with these previous reports [118,119], Hu et al [120] reported no changes in [ 18 F]DPA-714 uptake in APP swe ×PS1 ΔE9 mice between 6 and 10 months of age with an increase in [ 18 F]DPA-714 SUVr becoming significant at 12 and 16 months of age. Now trying to understand the meaning of TSPO signal or lack of it, Al-Khishman et al [86] tried to determine the sensitivity of PET imaging to detect MHCII+ microglial cells as they did in a model of stroke (see above). Using the TgAPP21 transgenic rat model of AD and [ 18 F]FEPPA PET, they showed no significant increase in [ 18 F]FEPPA PET uptake in the TgAPP21 rats vs WT at 11-14 months of age, despite the same group demonstrating the presence of MHCII+ cells in previous reports [121,122].…”

Section: Alzheimer's Disease (Ad)mentioning

confidence: 99%

“…and mean SUV 3 days post-MCAO • Significant decrease in max. and mean SUV by BMSC administration at 7 days post-MCAO • BMSC administration decreases infarct volume • [ 18 F]DPA-714 in vitro ARG confirmed in vivo PET data • BMSC administration decreases the number of CD8α+ T cells and CD68 microglia in the infarct and peri-infarct areas [ 101 ] [ 18 F]VUIIS1018A Evaluation of new TSPO tracer [ 18 F]VUIIS1018A 30-min intraluminal MCAO in male SD rats (7 weeks old, 220–240 g) 7–9 days post-MCAO • Ipsilateral [ 18 F]VUIIS1018A uptake at 0.73 SUV vs contralateral uptake at 0.20 SUV at 60 min post-injection • Ipsi-/contralateral ratio: 3.5 [ 18 F]VUIIS1018A in vitro ARG and TSPO IHC confirmed in vivo PET data [ 77 ] [ 11 C]DPA-713 [ 18 F]GE-180 Head-to-head comparisons of [ 11 C]DPA-713 and [ 18 F]GE-180 Permanent distal MCAO in 3-months-old female C57BL/6J mice 2, 6 and 28 days post-MCAO Ipsi-/contralateral ratio: • At 2 days, significant increase for [ 11 C]DPA-713 (1.22) but not for [ 18 F]GE-180 (1.10) • Significant increase for [ 11 C]DPA-713 and [ 18 F]GE-180 at 6 days (2.20 and 2.06, respectively) maintained at 28 days (1.67 and 1.64, respectively) • T2 MRI for ROI delineation • Ex vivo [ 11 C]DPA-713 and [ 18 F]GE-180 ARG confirmed the PET data • CD68 and GFAP IHC confirmed the presence of activated microglia and astrogliosis in the infarct [ 80 ] [ 18 F]FEPPA Test the ability of TSPO to detect MHCII + microglia in WM post-stroke Intrastriatal injection of ET1 in male Fischer 344 strain (11–14 months) Baseline and 7 and 28 days post-MCAO TSPO infarct/cerebellum ratio: • Baseline: 0.94±0.16 • Day 7: 2.10±0.78 • Day 28: 1.77±0.35 • Similar change in peri-infarct WM but not contralateral WM • T2 MRI for ROI delineation and co-registration • IHC for TSPO confirmed the presence of microglial activation in infarct and peri-infarct WM at day 7 • No increase in TSPO in peri-infarct WM at day 28 • Contralateral NI detected by OX6 MHC IHC at day 28 was not detected by PET imaging of TSPO/iNOS IHC [ 86 ] [ 18 F]DPA-714 ...…”

Section: Models Of Acute Neuroinflammationmentioning

confidence: 99%

“…Such combination of techniques allowed the authors to determine that brain regions with early phagocytic signal (USPIO + ) at day 7 will irremediably evolve into necrotic tissue, whereas tissue exclusively positive for TSPO will remodel but remains viable thereafter (days 27 and 55 post-stroke). Looking at white matter damage after stroke, Al-Khishman et al used [ 18 F]FEPPA TSPO-PET imaging and reported a significant increase at 7 and 28 days in the striatal infarct and peri-infarct white matter (WM) [ 86 ]. In the contralateral WM, they were able to detect MHCII + cells by either [ 18 F]FEPPA TSPO-PET or TSPO IHC.…”

Section: Models Of Acute Neuroinflammationmentioning

confidence: 99%

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TSPO imaging in animal models of brain diseases

Camp

Lavisse

Roost

et al. 2021

Eur J Nucl Med Mol Imaging

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Over the last 30 years, the 18-kDa TSPO protein has been considered as the PET imaging biomarker of reference to measure increased neuroinflammation. Generally assumed to image activated microglia, TSPO has also been detected in endothelial cells and activated astrocytes. Here, we provide an exhaustive overview of the recent literature on the TSPO-PET imaging (i) in the search and development of new TSPO tracers and (ii) in the understanding of acute and chronic neuroinflammation in animal models of neurological disorders. Generally, studies testing new TSPO radiotracers against the prototypic [11C]-R-PK11195 or more recent competitors use models of acute focal neuroinflammation (e.g. stroke or lipopolysaccharide injection). These studies have led to the development of over 60 new tracers during the last 15 years. These studies highlighted that interpretation of TSPO-PET is easier in acute models of focal lesions, whereas in chronic models with lower or diffuse microglial activation, such as models of Alzheimer’s disease or Parkinson’s disease, TSPO quantification for detection of neuroinflammation is more challenging, mirroring what is observed in clinic. Moreover, technical limitations of preclinical scanners provide a drawback when studying modest neuroinflammation in small brains (e.g. in mice). Overall, this review underlines the value of TSPO imaging to study the time course or response to treatment of neuroinflammation in acute or chronic models of diseases. As such, TSPO remains the gold standard biomarker reference for neuroinflammation, waiting for new radioligands for other, more specific targets for neuroinflammatory processes and/or immune cells to emerge.

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Section: Alzheimer's Disease (Ad)mentioning

confidence: 99%

Section: Models Of Acute Neuroinflammationmentioning

confidence: 99%

Section: Models Of Acute Neuroinflammationmentioning

confidence: 99%

See 1 more Smart Citation

TSPO imaging in animal models of brain diseases

Camp

Lavisse

Roost

et al. 2021

Eur J Nucl Med Mol Imaging

View full text Add to dashboard Cite

show abstract

“…With over a 20-year history, the field of molecular imaging is now wellentrenched [1][2][3] and continuing to expand its influence over multiple imaging modalities, including optical [4], nuclear [5], magnetic resonance (MR) [6] and acoustic [7]. In all these platforms, the use of contrast agents is a central theme, to enhance tissue structure and differentiate between healthy and diseased cells.…”

Section: Introductionmentioning

confidence: 99%

Molecular Imaging with Genetically Programmed Nanoparticles

Goldhawk¹

2022

Radiopharmaceuticals - Current Research for Better Diagnosis and Therapy

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Nanoparticle research has greatly benefitted medical imaging platforms by generating new signals, enhancing detection sensitivity, and expanding both clinical and preclinical applications. For magnetic resonance imaging, the fabrication of superparamagnetic iron oxide nanoparticles has provided a means of detecting cells and has paved the way for magnetic particle imaging. As the field of molecular imaging grows and enables the tracking of cells and their molecular activities so does the possibility of tracking genetically programmed biomarkers. This chapter discusses the advantages and challenges of gene-based contrast, using the bacterial magnetosome model to highlight the requirements of in vivo iron biomineralization and reporter gene expression for magnetic resonance signal detection. New information about magnetosome protein interactions in non-magnetic mammalian cells is considered in the light of design and application(s) of a rudimentary magnetosome-like nanoparticle for molecular imaging. Central to this is the hypothesis that a magnetosome root structure is defined by essential magnetosome genes, whose expression positions the biomineral in a given membrane compartment, in any cell type. The use of synthetic biology for programming multi-component structures not only broadens the scope of reporter gene expression for molecular MRI but also facilitates the tracking of cell therapies.

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“…In a transgenic rat model of AD, using second‐generation ligand [ 18 F]FEPPA, researchers were unable to detect activated microglia that were MHC‐II‐positive. Similarly, in a rat model of stroke, TSPO PET signal was only found in the insult region, but not in remotely present MHC‐II‐positive microglia [ 67 ].…”

Section: Introductionmentioning

confidence: 99%

Towards PET imaging of the dynamic phenotypes of microglia

Beaino

Janssen

Vugts

et al. 2021

Clinical and Experimental Immunology

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There is increasing evidence showing the heterogeneity of microglia activation in neuroinflammatory and neurodegenerative diseases. It has been hypothesized that pro-inflammatory microglia are detrimental and contribute to disease progression, while anti-inflammatory microglia play a role in damage repair and remission. The development of therapeutics targeting the deleterious glial activity and modulating it into a regenerative phenotype relies heavily upon a clearer understanding of the microglia dynamics during disease progression and the ability to monitor therapeutic outcome in vivo. To that end, molecular imaging techniques are required to assess microglia dynamics and study their role in disease progression as well as to evaluate the outcome of therapeutic interventions. Positron emission tomography (PET) is such a molecular imaging technique, and provides unique capabilities for noninvasive quantification of neuroinflammation and has the potential to discriminate between microglia phenotypes and define their role in the disease process. However, several obstacles limit the possibility for selective in vivo imaging of microglia phenotypes mainly related to the poor characterization of specific targets that distinguish the two ends of the microglia activation spectrum and lack of suitable tracers. PET tracers targeting translocator protein 18 kDa (TSPO) have been extensively explored, but despite the success in evaluating neuroinflammation they failed to discriminate

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

Cited by 16 publications

References 34 publications

TSPO imaging in animal models of brain diseases

TSPO imaging in animal models of brain diseases

Molecular Imaging with Genetically Programmed Nanoparticles

Towards PET imaging of the dynamic phenotypes of microglia

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