Diffusion Tensor Imaging and Chemical Exchange Saturation Transfer MRI Evaluation on the Long-Term Effects of Pulsed Focused Ultrasound and Microbubbles Blood Brain Barrier Opening in the Rat

Tsang-Wei Tu; Zsofia I Kovacs; Maggie Sundby; Jaclyn A Witko; Georgios Z Papadakis; William C Reid; Dima A Hammoud; Joseph A Frank

doi:10.3389/fnins.2020.00908

Diffusion Tensor Imaging and Chemical Exchange Saturation Transfer MRI Evaluation on the Long-Term Effects of Pulsed Focused Ultrasound and Microbubbles Blood Brain Barrier Opening in the Rat

Front Neurosci. 2020 Aug 25:14:908. doi: 10.3389/fnins.2020.00908. eCollection 2020.

Authors

Tsang-Wei Tu^{1

2

3}, Zsofia I Kovacs^{2

4}, Maggie Sundby², Jaclyn A Witko^{2

3}, Georgios Z Papadakis⁵, William C Reid⁵, Dima A Hammoud⁵, Joseph A Frank^{2

6}

Affiliations

¹ Molecular Imaging Laboratory, Department of Radiology, Howard University College of Medicine, Washington, DC, United States.
² Frank Laboratory, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health (NIH), Bethesda, MD, United States.
³ Center for Neuroscience and Regenerative Medicine, Henry Jackson Foundation, Bethesda, MD, United States.
⁴ Institute for Biomedical Engineering, Swiss Federal Institute of Technology, Zurich, Switzerland.
⁵ Center for Infectious Disease Imaging, Clinical Center, National Institutes of Health (NIH), Bethesda, MD, United States.
⁶ National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health (NIH), Bethesda, MD, United States.

Abstract

Blood-brain barrier opening (BBBO) with pulsed Focused Ultrasound (pFUS) and microbubbles (MB) has received increasing interest as a method for neurotherapeutics of the central nervous system. In general, conventional MRI [i.e., T2w, T2^∗w, gadolinium (Gd) enhanced T1w] is used to monitor the effects of pFUS+MB on BBBO and/or assess whether sonication results in parenchymal damage. This study employed multimodal MRI techniques and ¹⁸F-Fludeoxyglucose (FDG) PET to evaluate the effects of single and multiple weekly pFUS+MB sessions on morphology and glucose utilization levels in the rat cortex and hippocampus. pFUS was performed with 0.548 MHz transducer with a slow infusion over 1 min of Optison^TM (5-8 × 10⁷ MB) in nine focal points in cortex and four in hippocampus. During pFUS+MB treatment, Gd-T1w was performed at 3 T to confirm BBBO, along with subsequent T2w, T2^∗w, DTI and glucose CEST (glucoCEST)-weighted imaging by high field 9.4 T and compared with FDG-PET and immunohistochemistry. Animals receiving a single pFUS+MB exhibited minimal hypointense voxels on T2^∗w. Brains receiving multiple pFUS+MB treatments demonstrated persistent T2w and T2^∗ abnormalities associated with changes in DTI and glucoCEST when compared to contralateral parenchyma. Decreased glucoCEST contrast was substantiated by FDG-PET in cortex following multiple sonications. Immunohistochemistry showed significantly dilated vessels and decreased neuronal glucose transporter (GLUT3) expression in sonicated cortex and hippocampus without changes in neuronal counts. These results suggest the importance to standardize MRI protocols in concert with advanced imaging techniques when evaluating long term effects of pFUS+MB BBBO in clinical trials for neurological diseases.

Keywords: CEST; DTI; FDG-PET; T2∗ abnormality; blood brain barrier; pFUS microbubble.

Abstract

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