Dataset Information

Molecular Imaging of Immune Cell Dynamics During De- and Remyelination in the Cuprizone Model of Multiple Sclerosis by [18F]DPA-714 PET and MRI.

ABSTRACT: Background: Activation and dysregulation of innate, adaptive and resident immune cells in response to damage determine the pathophysiology of demyelinating disorders. Among the plethora of involved cells, microglia/macrophages and astrocytes play an important role in the pathogenesis of demyelinating disorders. The in-depth investigation of the spatio-temporal profile of these cell types in vivo may inform about the exact disease state and localization as well as may allow to monitor therapeutic modulation of the components of the neuroinflammatory response during the course of multiple sclerosis (MS). In this study, we aimed to non-invasively decipher the degree and temporal profile of neuroinflammation (TSPO - [18F]DPA-714 PET) in relation to selected magnetic resonance imaging (MRI) parameters (T2 maps) in the cuprizone (CPZ)-induced model of demyelination. Methods: C57Bl6 (n=30) mice were fed with a standard chow mixed with 0.2% (w/w) CPZ for 4 (n=10; demyelination) and 6 weeks (n=10; spontaneous remyelination). The degree of neuroinflammation at de- and remyelination was assessed by [18F]DPA-714 PET, multi-echo T2 MRI, autoradiography and immunohistochemistry. Results: CPZ-induced brain alterations were confirmed by increase of T2 relaxation times in both white and grey matter after 3 and 5 weeks of CPZ. Peak [18F]DPA-714 was found in the corpus callosum (CC, white matter), the hippocampus (HC, grey matter) and thalamus (grey matter) after 4 weeks of CPZ treatment and declined after 6 weeks of CPZ. Ex vivo autoradiography and dedicated immunofluorescence showed demyelination/remyelination with corresponding increased/decreased TSPO levels in the CC and hippocampus, confirming the spatial distribution of [18F]DPA-714 in vivo. The expression of TSPO microglia and astrocytes is time-dependent in this model. Microglia predominantly express TSPO at demyelination, while the majority of astrocytes express TSPO during remyelination. The combination of PET- and MRI-based imaging biomarkers demonstrated the regional and temporal development of the CPZ model-associated neuroinflammatory response in grey and white matter regions. Conclusions: The combination of [18F]DPA-714 PET and T2 mapping may allow to further elucidate the regional and temporal profile of inflammatory signals depending on the myelination status, although the underlying inflammatory microenvironment changes. A combination of the described imaging biomarkers may facilitate the development of patient-tailored strategies for immunomodulatory and neuro-restorative therapies in MS.

SUBMITTER: Zinnhardt B

PROVIDER: S-EPMC6485187 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Publications

Molecular Imaging of Immune Cell Dynamics During De- and Remyelination in the Cuprizone Model of Multiple Sclerosis by [18F]DPA-714 PET and MRI.

Zinnhardt Bastian B Belloy Michaël M Fricke Inga B IB Orije Jasmien J Guglielmetti Caroline C Hermann Sven S Wagner Stefan S Schäfers Michael M Van der Linden Annemie A Jacobs Andreas H AH

Theranostics 20190220 6

Background: Activation and dysregulation of innate, adaptive and resident immune cells in response to damage determine the pathophysiology of demyelinating disorders. Among the plethora of involved cells, microglia/macrophages and astrocytes play an important role in the pathogenesis of demyelinating disorders. The in-depth investigation of the spatio-temporal profile of these cell types in vivo may inform about the exact disease state and localization as well as may allow to monit ...[more]

PMID: 31037121

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Project description:BACKGROUND:Cerebral stroke is a severe and frequent condition that requires rapid and reliable diagnosis. If administered shortly after the first symptoms manifest themselves, IV thrombolysis has been shown to increase the functional prognosis by restoring brain reperfusion. However, a better understanding of the pathophysiology of stroke should help to identify potential new therapeutic targets. Stroke is known to induce an inflammatory brain reaction that involves overexpression of the 18-kDa translocator protein (TSPO) in glial cells and infiltrated leukocytes, which can be visualised by positron emission tomography (PET). We aimed to evaluate post-stroke neuroinflammation using the PET TSPO radioligand (18)?F-DPA-714. METHODS:Nine patients underwent (18)?F-DPA-714 PET and magnetic resonance imaging (MRI) between 8 and 18 days after the ictus. Co-registration of MRI and PET images was used to define three volumes of interest (VOIs): core infarction, contralateral region, and cerebellum ipsilateral to the stroke lesion. Time activity curves were obtained from each VOI, and ratios of mean and maximum activities between the VOIs were calculated. RESULTS:We observed an increased uptake of (18)?F-DPA-714 co-localised with the infarct tissue and extension beyond the region corresponding to the damage in the blood brain barrier. No correlation was identified between (18)?F-DPA-714 uptake and infarct volume. (18)?F-DPA-714 uptake in ischemic lesion (mainly associated with TSPO expression in the infarct area and in the surrounding neighbourhood) slowly decreased from 10 min pi to the end of the PET acquisition, remaining higher than that in both contralateral region and ipsilateral cerebellum. CONCLUSION:Our results show that (18)?F-DPA-714 uptake after acute ischemia is mainly associated with TSPO expression in the infarct area and in the surrounding neighbourhood. We also demonstrated that the kinetics of (18)?F-DPA-714 differs in injured tissue compared to normal tissue. Therefore, (18)?F-DPA-714 may be useful in assessing the extent of neuroinflammation associated with acute stroke and could also help to predict clinical outcomes and functional recovery, as well as to assess therapeutic strategies, such as the use of neuroprotective/anti-inflammatory drugs.

Project description:BACKGROUND:Various studies by MRI exhibit that the corpus callosum (CC) is the most vulnerable to cuprizone administration, detecting the demyelination and remyelination process using different MRI parameters are, however, lacking. PURPOSE:To investigate the sensitivity of multiparametric MRI both in vivo and ex vivo for demyelination and remyelination. STUDY TYPE:Prospective. ANIMAL MODEL:A cuprizone mice model with an age-matched control group (n = 5), 4-week cuprizone exposure group followed by 9-week on a normal diet (n = 6), and a 13-week cuprizone exposure group (n = 6). FIELD STRENGTH/SEQUENCE:3D gradient recalled echo, T2 -weighted, and diffusion tensor imaging (DTI) at 7.0T and 9.4T. ASSESSMENT:Quantification of DTI metrics, quantitative susceptibility mapping (QSM), and T2 -weighted imaging intensity in major white matter bundles. STATISTICAL TESTS:Nonparametric permutation tests were used with a cluster-forming threshold as 3.09 (equivalent to P = 0.001), and the significant level as P = 0.05 with family-wise correction. RESULTS:In vivo susceptibility values increased from -11.7 to -0.7 ppb (P < 0.001) in CC and from -13.7 to -5.1 ppb (P < 0.001) in the anterior commissure (AC) after the 13-week cuprizone exposure. Ex vivo susceptibility values increased from -25.4 to 7.4 ppb (P < 0.001) in CC and from -41.6 to -15.8 ppb (P < 0.001) in AC. Susceptibility values showed high variations to demyelination for in vivo studies (94.0% in CC, 62.8% in AC). Susceptibility values exhibited higher variations than radial diffusivity for ex vivo studies (129.1% vs. 28.3% in CC, 62.0% vs. 25.0% in AC). In addition to the differential susceptibility variations in different white matter tracts, intraregional demyelination variation was also present not only in CC but also in the AC area by voxel-based analysis. DATA CONCLUSION:QSM is sensitive to the demyelination process of cuprizone exposure, which can be a complementary technique to conventional T2 -weighted images and DTI metrics. LEVEL OF EVIDENCE:2 Technical Efficacy Stage: 2 J. Magn. Reson. Imaging 2019;50:1852-1865.

Dataset Information

Molecular Imaging of Immune Cell Dynamics During De- and Remyelination in the Cuprizone Model of Multiple Sclerosis by [18F]DPA-714 PET and MRI.

Publications

Molecular Imaging of Immune Cell Dynamics During De- and Remyelination in the Cuprizone Model of Multiple Sclerosis by [<sup>18</sup>F]DPA-714 PET and MRI.

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