Imaging Microglial/Macrophage Activation in Spinal Cords of Experimental Autoimmune Encephalomyelitis Rats by Positron Emission Tomography Using the Mitochondrial 18 kDa Translocator Protein Radioligand [<sup>18</sup>F]DPA-714

Abourbeh, Galith; Thézé, Benoît; Maroy, Renaud; Dubois, Albertine; Brulon, Vincent; Fontyn, Yoann; Dollé, Frédéric; Tavitian, Bertrand; Boisgard, Raphaël

doi:10.1523/jneurosci.2900-11.2012

Cited by 100 publications

(91 citation statements)

References 45 publications

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“…Ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles have recently been demonstrated to detect CNS infiltrating monocyte/ macrophages in research settings (Vellinga et al, 2008). PET ligands targeting the 18 kDa translocator protein, which is upregulated with inflammation, detect neuroinflammation in human diseases including multiple sclerosis and in animal models, but the effectiveness of these PET markers remains to be seen (Banati et al, 2000;Papadopoulos et al, 2006;Chauveau et al, 2009Chauveau et al, , 2011Abourbeh et al, 2012;Xie et al, 2012). Promising advances in imaging myelination have been reported including myelin water imaging (MacKay et al, 1994;Du et al, 2007;Laule et al, 2008;Hwang et al, 2010;Prasloski et al, 2012), magnetization transfer (Inglese et al, 2003;Schmierer et al, 2004Schmierer et al, , 2007aDortch et al, 2011;Stikov et al, 2011;Underhill et al, 2011), optical imaging (Wang et al, 2011a) and myelin-specific PET markers (Wang et al, 2009;Wu et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Differentiation and quantification of inflammation, demyelination and axon injury or loss in multiple sclerosis

Wang

Sun

Wang

et al. 2015

Brain

146

189

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Axon injury/loss, demyelination and inflammation are the primary pathologies in multiple sclerosis lesions. Despite the prevailing notion that axon/neuron loss is the substrate of clinical progression of multiple sclerosis, the roles that these individual pathological processes play in multiple sclerosis progression remain to be defined. An imaging modality capable to effectively detect, differentiate and individually quantify axon injury/loss, demyelination and inflammation, would not only facilitate the understanding of the pathophysiology underlying multiple sclerosis progression, but also the assessment of treatments at the clinical trial and individual patient levels. In this report, the newly developed diffusion basis spectrum imaging was used to discriminate and quantify the underlying pathological components in multiple sclerosis white matter. Through the multiple-tensor modelling of diffusion weighted magnetic resonance imaging signals, diffusion basis spectrum imaging resolves inflammation-associated cellularity and vasogenic oedema in addition to accounting for partial volume effects resulting from cerebrospinal fluid contamination, and crossing fibres. Quantitative histological analysis of autopsied multiple sclerosis spinal cord specimens supported that diffusion basis spectrum imaging-determined cellularity, axon and myelin injury metrics closely correlated with those pathologies identified and quantified by conventional histological staining. We demonstrated in healthy control subjects that diffusion basis spectrum imaging rectified inaccurate assessments of diffusion properties of white matter tracts by diffusion tensor imaging in the presence of cerebrospinal fluid contamination and/or crossing fibres. In multiple sclerosis patients, we report that diffusion basis spectrum imaging quantitatively characterized the distinct pathologies underlying gadolinium-enhanced lesions, persistent black holes, non-enhanced lesions and non-black hole lesions, a task yet to be demonstrated by other neuroimaging approaches. Diffusion basis spectrum imaging-derived radial diffusivity (myelin integrity marker) and non-restricted isotropic diffusion fraction (oedema marker) correlated with magnetization transfer ratio, supporting previous reports that magnetization transfer ratio is sensitive not only to myelin integrity, but also to inflammation-associated oedema. Our results suggested that diffusion basis spectrum imaging-derived quantitative biomarkers are highly consistent with histology findings and hold promise to accurately characterize the heterogeneous white matter pathology in multiple sclerosis patients. Thus, diffusion basis spectrum imaging can potentially serve as a non-invasive outcome measure to assess treatment effects on the specific components of underlying pathology targeted by new multiple sclerosis therapies. Keywords: diffusion basis spectrum imaging; diffusion tensor imaging; white matter injury; inflammation; multiple sclerosis Abbreviations: DTI = diffusion tensor imaging; DBSI = diffusion...

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Section: Discussionmentioning

confidence: 99%

Differentiation and quantification of inflammation, demyelination and axon injury or loss in multiple sclerosis

Wang

Sun

Wang

et al. 2015

Brain

146

189

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“…TSPO, an 18KDa protein upregulated with microglia activation, may be useful for monitoring neuroinflammation in the human brain. TSPO is upregulated, not only during pathological insults of the brain, including AD (Yasuno et al, 2012;Kreisl et al, 2013), experimental autoimmune encephalomyelitis (Abourbeh et al, 2012;Mattner et al, 2013) F-GE180 PET whole-brain time-activity curves of WT and APP/PS1dE9 Tg mice were generated after pre-injection with either saline or cold tracer. The time frames used for image reconstruction were as follows: 1 min ϫ 8 ϩ 2 min ϫ 6 ϩ 10 min ϫ 10. n ϭ 1 per group.…”

Section: Discussionmentioning

confidence: 99%

In VivoDetection of Age- and Disease-Related Increases in Neuroinflammation by¹⁸F-GE180 TSPO MicroPET Imaging in Wild-Type and Alzheimer's Transgenic Mice

Le²,

et al. 2015

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Alzheimer's disease (AD) is the most common cause of dementia. Neuroinflammation appears to play an important role in AD pathogenesis. Ligands of the 18 kDa translocator protein (TSPO), a marker for activated microglia, have been used as positron emission tomography (PET) tracers to reflect neuroinflammation in humans and mouse models. Here, we used the novel TSPO-targeted PET tracer 18 F-GE180 (flutriciclamide) to investigate differences in neuroinflammation between young and old WT and APP/PS1dE9 transgenic (Tg) mice. In vivo PET scans revealed an overt age-dependent elevation in whole-brain uptake of 18 F-GE180 in both WT and Tg mice, and a significant increase in whole-brain uptake of 18 F-GE180 (peak-uptake and retention) in old Tg mice compared with young Tg mice and all WT mice. Similarly, the 18 F-GE180 binding potential in hippocampus was highest to lowest in old Tg Ͼ old WT Ͼ young Tg Ͼ young WT mice using MRI coregistration. Ex vivo PET and autoradiography analysis further confirmed our in vivo PET results: enhanced uptake and specific binding (SUV 75% ) of 18 F-GE180 in hippocampus and cortex was highest in old Tg mice followed by old WT, young Tg, and finally young WT mice.18 F-GE180 specificity was confirmed by an in vivo cold tracer competition study. We also examined 18 F-GE180 metabolites in 4-month-old WT mice and found that, although total radioactivity declined over 2 h, of the remaining radioactivity, ϳ90% was due to parent 18 F-GE180. In conclusion, 18 F-GE180 PET scans may be useful for longitudinal monitoring of neuroinflammation during AD progression and treatment.

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“…A noninvasive imaging technique such as PET could differentiate and quantify MS hallmarks and thus could be an important tool to monitor therapeutic response and help to better understand drug mechanisms. The potential of PET for imaging several hallmarks of MS was shown in animal models (4)(5)(6)(7)(8)(9)(10)(11)(12)(13) and in patients (14)(15)(16)(17)(18)(19)(20)(21)(22), but different hallmarks were not longitudinally measured at the same time in these studies. Despite the fact that MS comprises multiple aspects that are important for therapy monitoring and drug development, PET is not yet regularly applied in a clinical setting.…”

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confidence: 91%

PET Imaging of Disease Progression and Treatment Effects in the Experimental Autoimmune Encephalomyelitis Rat Model

et al. 2014

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Imaging Microglial/Macrophage Activation in Spinal Cords of Experimental Autoimmune Encephalomyelitis Rats by Positron Emission Tomography Using the Mitochondrial 18 kDa Translocator Protein Radioligand [¹⁸F]DPA-714

Cited by 100 publications

References 45 publications

Differentiation and quantification of inflammation, demyelination and axon injury or loss in multiple sclerosis

Differentiation and quantification of inflammation, demyelination and axon injury or loss in multiple sclerosis

In VivoDetection of Age- and Disease-Related Increases in Neuroinflammation by¹⁸F-GE180 TSPO MicroPET Imaging in Wild-Type and Alzheimer's Transgenic Mice

PET Imaging of Disease Progression and Treatment Effects in the Experimental Autoimmune Encephalomyelitis Rat Model

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Imaging Microglial/Macrophage Activation in Spinal Cords of Experimental Autoimmune Encephalomyelitis Rats by Positron Emission Tomography Using the Mitochondrial 18 kDa Translocator Protein Radioligand [18F]DPA-714

Cited by 100 publications

References 45 publications

Differentiation and quantification of inflammation, demyelination and axon injury or loss in multiple sclerosis

Differentiation and quantification of inflammation, demyelination and axon injury or loss in multiple sclerosis

In VivoDetection of Age- and Disease-Related Increases in Neuroinflammation by18F-GE180 TSPO MicroPET Imaging in Wild-Type and Alzheimer's Transgenic Mice

PET Imaging of Disease Progression and Treatment Effects in the Experimental Autoimmune Encephalomyelitis Rat Model

Contact Info

Product

Resources

About

Imaging Microglial/Macrophage Activation in Spinal Cords of Experimental Autoimmune Encephalomyelitis Rats by Positron Emission Tomography Using the Mitochondrial 18 kDa Translocator Protein Radioligand [¹⁸F]DPA-714

In VivoDetection of Age- and Disease-Related Increases in Neuroinflammation by¹⁸F-GE180 TSPO MicroPET Imaging in Wild-Type and Alzheimer's Transgenic Mice