In vivo imaging of sterile microglial activation in rat brain after disrupting the blood-brain barrier with pulsed focused ultrasound: [18F]DPA-714 PET study
Abstract Background Magnetic resonance imaging (MRI)-guided pulsed focused ultrasound combined with the infusion of microbubbles (pFUS+MB) induces transient blood-brain barrier opening (BBBO) in targeted regions. pFUS+MB, through the facilitation of neurotherapeutics’ delivery, has been advocated as...
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BMC
2019-07-01
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Series: | Journal of Neuroinflammation |
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Online Access: | http://link.springer.com/article/10.1186/s12974-019-1543-z |
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doaj-6788de3fcd904623a90e43649e8e4191 |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Sanhita Sinharay Tsang-Wei Tu Zsofia I. Kovacs William Schreiber-Stainthorp Maggie Sundby Xiang Zhang Georgios Z. Papadakis William C. Reid Joseph A. Frank Dima A. Hammoud |
spellingShingle |
Sanhita Sinharay Tsang-Wei Tu Zsofia I. Kovacs William Schreiber-Stainthorp Maggie Sundby Xiang Zhang Georgios Z. Papadakis William C. Reid Joseph A. Frank Dima A. Hammoud In vivo imaging of sterile microglial activation in rat brain after disrupting the blood-brain barrier with pulsed focused ultrasound: [18F]DPA-714 PET study Journal of Neuroinflammation Neuroinflammation [18F]DPA-714 PET Pulsed focused ultrasound Magnetic resonance imaging Translocator protein |
author_facet |
Sanhita Sinharay Tsang-Wei Tu Zsofia I. Kovacs William Schreiber-Stainthorp Maggie Sundby Xiang Zhang Georgios Z. Papadakis William C. Reid Joseph A. Frank Dima A. Hammoud |
author_sort |
Sanhita Sinharay |
title |
In vivo imaging of sterile microglial activation in rat brain after disrupting the blood-brain barrier with pulsed focused ultrasound: [18F]DPA-714 PET study |
title_short |
In vivo imaging of sterile microglial activation in rat brain after disrupting the blood-brain barrier with pulsed focused ultrasound: [18F]DPA-714 PET study |
title_full |
In vivo imaging of sterile microglial activation in rat brain after disrupting the blood-brain barrier with pulsed focused ultrasound: [18F]DPA-714 PET study |
title_fullStr |
In vivo imaging of sterile microglial activation in rat brain after disrupting the blood-brain barrier with pulsed focused ultrasound: [18F]DPA-714 PET study |
title_full_unstemmed |
In vivo imaging of sterile microglial activation in rat brain after disrupting the blood-brain barrier with pulsed focused ultrasound: [18F]DPA-714 PET study |
title_sort |
in vivo imaging of sterile microglial activation in rat brain after disrupting the blood-brain barrier with pulsed focused ultrasound: [18f]dpa-714 pet study |
publisher |
BMC |
series |
Journal of Neuroinflammation |
issn |
1742-2094 |
publishDate |
2019-07-01 |
description |
Abstract Background Magnetic resonance imaging (MRI)-guided pulsed focused ultrasound combined with the infusion of microbubbles (pFUS+MB) induces transient blood-brain barrier opening (BBBO) in targeted regions. pFUS+MB, through the facilitation of neurotherapeutics’ delivery, has been advocated as an adjuvant treatment for neurodegenerative diseases and malignancies. Sterile neuroinflammation has been recently described following pFUS+MB BBBO. In this study, we used PET imaging with [18F]-DPA714, a biomarker of translocator protein (TSPO), to assess for neuroinflammatory changes following single and multiple pFUS+MB sessions. Methods Three groups of Sprague-Dawley female rats received MRI-guided pFUS+MB (Optison™; 5–8 × 107 MB/rat) treatments to the left frontal cortex and right hippocampus. Group A rats were sonicated once. Group B rats were sonicated twice and group C rats were sonicated six times on weekly basis. Passive cavitation detection feedback (PCD) controlled the peak negative pressure during sonication. We performed T1-weighted scans immediately after sonication to assess efficiency of BBBO and T2*-weighted scans to evaluate for hypointense voxels. [18F]DPA-714 PET/CT scans were acquired after the BBB had closed, 24 h after sonication in group A and within an average of 10 days from the last sonication in groups B and C. Ratios of T1 enhancement, T2* values, and [18F]DPA-714 percent injected dose/cc (%ID/cc) values in the targeted areas to the contralateral brain were calculated. Histological assessment for microglial activation/astrocytosis was performed. Results In all groups, [18F]DPA-714 binding was increased at the sonicated compared to non-sonicated brain (%ID/cc ratios > 1). Immunohistopathology showed increased staining for microglial and astrocytic markers in the sonicated frontal cortex compared to contralateral brain and to a lesser extent in the sonicated hippocampus. Using MRI, we documented BBB disruption immediately after sonication with resolution of BBBO 24 h later. We found more T2* hypointense voxels with increasing number of sonications. In a longitudinal group of animals imaged after two and after six sonications, there was no cumulative increase of neuroinflammation on PET. Conclusion Using [18F]DPA-714 PET, we documented in vivo neuroinflammatory changes in association with pFUS+MB. Our protocol (utilizing PCD feedback to minimize damage) resulted in neuroinflammation visualized 24 h post one sonication. Our findings were supported by immunohistochemistry showing microglial activation and astrocytosis. Experimental sonication parameters intended for BBB disruption should be evaluated for neuroinflammatory sequelae prior to implementation in clinical trials. |
topic |
Neuroinflammation [18F]DPA-714 PET Pulsed focused ultrasound Magnetic resonance imaging Translocator protein |
url |
http://link.springer.com/article/10.1186/s12974-019-1543-z |
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doaj-6788de3fcd904623a90e43649e8e41912020-11-25T02:36:55ZengBMCJournal of Neuroinflammation1742-20942019-07-0116111110.1186/s12974-019-1543-zIn vivo imaging of sterile microglial activation in rat brain after disrupting the blood-brain barrier with pulsed focused ultrasound: [18F]DPA-714 PET studySanhita Sinharay0Tsang-Wei Tu1Zsofia I. Kovacs2William Schreiber-Stainthorp3Maggie Sundby4Xiang Zhang5Georgios Z. Papadakis6William C. Reid7Joseph A. Frank8Dima A. Hammoud9Hammoud Laboratory, Center for Infectious Disease Imaging, Clinical Center, National Institutes of HealthFrank Laboratory, Radiology and Imaging Sciences, Clinical Center, National Institutes of HealthFrank Laboratory, Radiology and Imaging Sciences, Clinical Center, National Institutes of HealthHammoud Laboratory, Center for Infectious Disease Imaging, Clinical Center, National Institutes of HealthFrank Laboratory, Radiology and Imaging Sciences, Clinical Center, National Institutes of HealthImaging Probe Development Center, National Heart, Lung, and Blood Institute, National Institutes of HealthHammoud Laboratory, Center for Infectious Disease Imaging, Clinical Center, National Institutes of HealthHammoud Laboratory, Center for Infectious Disease Imaging, Clinical Center, National Institutes of HealthFrank Laboratory, Radiology and Imaging Sciences, Clinical Center, National Institutes of HealthHammoud Laboratory, Center for Infectious Disease Imaging, Clinical Center, National Institutes of HealthAbstract Background Magnetic resonance imaging (MRI)-guided pulsed focused ultrasound combined with the infusion of microbubbles (pFUS+MB) induces transient blood-brain barrier opening (BBBO) in targeted regions. pFUS+MB, through the facilitation of neurotherapeutics’ delivery, has been advocated as an adjuvant treatment for neurodegenerative diseases and malignancies. Sterile neuroinflammation has been recently described following pFUS+MB BBBO. In this study, we used PET imaging with [18F]-DPA714, a biomarker of translocator protein (TSPO), to assess for neuroinflammatory changes following single and multiple pFUS+MB sessions. Methods Three groups of Sprague-Dawley female rats received MRI-guided pFUS+MB (Optison™; 5–8 × 107 MB/rat) treatments to the left frontal cortex and right hippocampus. Group A rats were sonicated once. Group B rats were sonicated twice and group C rats were sonicated six times on weekly basis. Passive cavitation detection feedback (PCD) controlled the peak negative pressure during sonication. We performed T1-weighted scans immediately after sonication to assess efficiency of BBBO and T2*-weighted scans to evaluate for hypointense voxels. [18F]DPA-714 PET/CT scans were acquired after the BBB had closed, 24 h after sonication in group A and within an average of 10 days from the last sonication in groups B and C. Ratios of T1 enhancement, T2* values, and [18F]DPA-714 percent injected dose/cc (%ID/cc) values in the targeted areas to the contralateral brain were calculated. Histological assessment for microglial activation/astrocytosis was performed. Results In all groups, [18F]DPA-714 binding was increased at the sonicated compared to non-sonicated brain (%ID/cc ratios > 1). Immunohistopathology showed increased staining for microglial and astrocytic markers in the sonicated frontal cortex compared to contralateral brain and to a lesser extent in the sonicated hippocampus. Using MRI, we documented BBB disruption immediately after sonication with resolution of BBBO 24 h later. We found more T2* hypointense voxels with increasing number of sonications. In a longitudinal group of animals imaged after two and after six sonications, there was no cumulative increase of neuroinflammation on PET. Conclusion Using [18F]DPA-714 PET, we documented in vivo neuroinflammatory changes in association with pFUS+MB. Our protocol (utilizing PCD feedback to minimize damage) resulted in neuroinflammation visualized 24 h post one sonication. Our findings were supported by immunohistochemistry showing microglial activation and astrocytosis. Experimental sonication parameters intended for BBB disruption should be evaluated for neuroinflammatory sequelae prior to implementation in clinical trials.http://link.springer.com/article/10.1186/s12974-019-1543-zNeuroinflammation[18F]DPA-714 PETPulsed focused ultrasoundMagnetic resonance imagingTranslocator protein |