Imaging neuroinflammation using ¹⁸F-DPA-714 microPET after low intensity pulsed focused ultrasound treatment with microbubbles.

Objectives: MRI-guided pulsed focused ultrasound combined with the infusion of microbubbles (pFUS+MB) can cause transient blood brain barrier (BBB) disruption in targeted regions and facilitate the delivery of large molecules into the parenchyma. pFUS+MB has been advocated as an adjuvant treatment for CNS diseases, including neurodegeneration and maliganncies. However there is limited data on the long-term effects of this approach. Sterile inflammation has been described following pFUS+MB. In this study, we want to noninvasively check for neuroinflammatory changes after pFUS+MB, using PET and ¹⁸F-DPA-714, a marker of translocator protein (TSPO) upregulation /microglial activation.

Methods: Female rats were divided into three groups based on the number of weekly pFUS + MB (Optison^TM). Group 1 rats were sonicated once and imaged after 24 hours (n=6). Group 2 rats were sonicated twice (n=8) and Group 3 rats were sonicated 6 times (n=5). Both group 2 and 3 rats were imaged within an average of 10 days from last sonication. The left striatum and right hippocampus were pFUS+MB targeted in all animals. pFUS(0.3MPa)+MB infusion was performed over 9 points in the striatum and 4 points in the hippocampus at 589.636 kHz (FUS Instruments). Static ¹⁸F-DPA714 microPET/CT emission data was acquired from 30 to 60 minutes after injection of the radioligand. VOIs were drawn in the targeted areas and uptake was compared to the contralateral side. Comparison between cerebellar hemispheres in each animal served as control.

Results: ¹⁸F-DPA-714 uptake was increased at the sonication sites in all animals. The mean increased uptake in the ipsilateral compared to contralateral brain in all groups was 57.4 % in the hippocampus and 52.6% in the striatum. This corresponded to increased iba1 staining on histology. The average difference in cerebellar hemispheres (control, non sonicated) was only 2%.

Conclusion: Rats receiving pFUS + MB to open the BBB showed a clear upregulation of TSPO expression consistent with microglial activation. These results indicate the effects of pFUS+MB include a neuroinflammatory reaction. Further assessment of the long-term neuroinflammatory sequelae of pFUS+MB is necessary before this approach can be widely implemented in clinical trials. Research Support: Intramural research program: Center for Infectious Disease Imaging, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health