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

Overview

Journal J Neuroinflammation

Publisher Biomed Central

Date 2019 Jul 27

PMID 31345243

Citations 30

Authors

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

Affiliations

Soon will be listed here.

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 × 10 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.

Citing Articles

Single Exposure to Low-Intensity Focused Ultrasound Causes Biphasic Opening of the Blood-Brain Barrier Through Secondary Mechanisms.

Arsiwala T, Blethen K, Wolford C, Pecar G, Panchal D, Kielkowski B Pharmaceutics. 2025; 17(1).

PMID: 39861723 PMC: 11768402. DOI: 10.3390/pharmaceutics17010075.

Characterization of focused ultrasound blood-brain barrier disruption effect on inflammation as a function of treatment parameters.

Angolano C, Hansen E, Ajjawi H, Nowlin P, Zhang Y, Thunemann N Biomed Pharmacother. 2024; 182:117762.

PMID: 39719739 PMC: 11803570. DOI: 10.1016/j.biopha.2024.117762.

Comprehensive assessment of blood-brain barrier opening and sterile inflammatory response: unraveling the therapeutic window.

Martinez P, Song J, Garay F, Song K, Mufford T, Steiner J Sci Rep. 2024; 14(1):17036.

PMID: 39043894 PMC: 11266505. DOI: 10.1038/s41598-024-67916-8.

Focused Ultrasound-Mediated Disruption of the Blood-Brain Barrier for AAV9 Delivery in a Mouse Model of Huntington's Disease.

Owusu-Yaw B, Zhang Y, Garrett L, Yao A, Shing K, Batista A Pharmaceutics. 2024; 16(6).

PMID: 38931834 PMC: 11206648. DOI: 10.3390/pharmaceutics16060710.

Using focused ultrasound to modulate microglial structure and function.

Grewal S, de Andrade E, Kofoed R, Matthews P, Aubert I, Tremblay M Front Cell Neurosci. 2024; 17:1290628.

PMID: 38164436 PMC: 10757935. DOI: 10.3389/fncel.2023.1290628.

References

Hynynen K, McDannold N, Vykhodtseva N, Jolesz F . Noninvasive MR imaging-guided focal opening of the blood-brain barrier in rabbits. Radiology. 2001; 220(3):640-6. DOI: 10.1148/radiol.2202001804. View

Pardridge W . Drug and gene delivery to the brain: the vascular route. Neuron. 2002; 36(4):555-8. DOI: 10.1016/s0896-6273(02)01054-1. View

Borden M, Kruse D, Caskey C, Zhao S, Dayton P, Ferrara K . Influence of lipid shell physicochemical properties on ultrasound-induced microbubble destruction. IEEE Trans Ultrason Ferroelectr Freq Control. 2006; 52(11):1992-2002. PMC: 1388091. DOI: 10.1109/tuffc.2005.1561668. View

Venneti S, Lopresti B, Wiley C . The peripheral benzodiazepine receptor (Translocator protein 18kDa) in microglia: from pathology to imaging. Prog Neurobiol. 2006; 80(6):308-22. PMC: 1849976. DOI: 10.1016/j.pneurobio.2006.10.002. View

Neuwelt E, Abbott N, Abrey L, Banks W, Blakley B, Davis T . Strategies to advance translational research into brain barriers. Lancet Neurol. 2007; 7(1):84-96. DOI: 10.1016/S1474-4422(07)70326-5. View

McDannold N, Vykhodtseva N, Hynynen K . Effects of acoustic parameters and ultrasound contrast agent dose on focused-ultrasound induced blood-brain barrier disruption. Ultrasound Med Biol. 2008; 34(6):930-7. PMC: 2459318. DOI: 10.1016/j.ultrasmedbio.2007.11.009. View

Sheikov N, McDannold N, Sharma S, Hynynen K . Effect of focused ultrasound applied with an ultrasound contrast agent on the tight junctional integrity of the brain microvascular endothelium. Ultrasound Med Biol. 2008; 34(7):1093-104. PMC: 2518085. DOI: 10.1016/j.ultrasmedbio.2007.12.015. View

Raymond S, Treat L, Dewey J, McDannold N, Hynynen K, Bacskai B . Ultrasound enhanced delivery of molecular imaging and therapeutic agents in Alzheimer's disease mouse models. PLoS One. 2008; 3(5):e2175. PMC: 2364662. DOI: 10.1371/journal.pone.0002175. View

Vykhodtseva N, McDannold N, Hynynen K . Progress and problems in the application of focused ultrasound for blood-brain barrier disruption. Ultrasonics. 2008; 48(4):279-96. PMC: 2569868. DOI: 10.1016/j.ultras.2008.04.004. View

10.

Alonso A, Reinz E, Jenne J, Fatar M, Schmidt-Glenewinkel H, Hennerici M . Reorganization of gap junctions after focused ultrasound blood-brain barrier opening in the rat brain. J Cereb Blood Flow Metab. 2010; 30(7):1394-402. PMC: 2949216. DOI: 10.1038/jcbfm.2010.41. View

11.

Martin A, Boisgard R, Kassiou M, Dolle F, Tavitian B . Reduced PBR/TSPO expression after minocycline treatment in a rat model of focal cerebral ischemia: a PET study using [(18)F]DPA-714. Mol Imaging Biol. 2010; 13(1):10-5. DOI: 10.1007/s11307-010-0324-y. View

12.

Choi J, Selert K, Gao Z, Samiotaki G, Baseri B, Konofagou E . Noninvasive and localized blood-brain barrier disruption using focused ultrasound can be achieved at short pulse lengths and low pulse repetition frequencies. J Cereb Blood Flow Metab. 2010; 31(2):725-37. PMC: 3049526. DOI: 10.1038/jcbfm.2010.155. View

13.

Tung Y, Vlachos F, Choi J, Deffieux T, Selert K, Konofagou E . In vivo transcranial cavitation threshold detection during ultrasound-induced blood-brain barrier opening in mice. Phys Med Biol. 2010; 55(20):6141-55. PMC: 4005785. DOI: 10.1088/0031-9155/55/20/007. View

14.

Chen G, Nunez G . Sterile inflammation: sensing and reacting to damage. Nat Rev Immunol. 2010; 10(12):826-37. PMC: 3114424. DOI: 10.1038/nri2873. View

15.

Mullin L, Gessner R, Kwan J, Kaya M, Borden M, Dayton P . Effect of anesthesia carrier gas on in vivo circulation times of ultrasound microbubble contrast agents in rats. Contrast Media Mol Imaging. 2011; 6(3):126-31. PMC: 3341737. DOI: 10.1002/cmmi.414. View

16.

Itani M, Mattrey R . The effect of inhaled gases on ultrasound contrast agent longevity in vivo. Mol Imaging Biol. 2011; 14(1):40-6. PMC: 3258392. DOI: 10.1007/s11307-011-0475-5. View

17.

Tempany C, McDannold N, Hynynen K, Jolesz F . Focused ultrasound surgery in oncology: overview and principles. Radiology. 2011; 259(1):39-56. PMC: 3064817. DOI: 10.1148/radiol.11100155. View

18.

Kuhnast B, Damont A, Hinnen F, Catarina T, Demphel S, Le Helleix S . [18F]DPA-714, [18F]PBR111 and [18F]FEDAA1106-selective radioligands for imaging TSPO 18 kDa with PET: automated radiosynthesis on a TRACERLAb FX-FN synthesizer and quality controls. Appl Radiat Isot. 2011; 70(3):489-97. DOI: 10.1016/j.apradiso.2011.10.015. View

19.

Gomez D, Martinez J, Hanson L, Frey 2nd W, Toth C . Intranasal treatment of neurodegenerative diseases and stroke. Front Biosci (Schol Ed). 2011; 4(1):74-89. DOI: 10.2741/252. View

20.

OReilly M, Hynynen K . Blood-brain barrier: real-time feedback-controlled focused ultrasound disruption by using an acoustic emissions-based controller. Radiology. 2012; 263(1):96-106. PMC: 3309801. DOI: 10.1148/radiol.11111417. View