Abstracts from the International Society for Therapeutic Ultrasound Conference 2017
Journal of Therapeutic Ultrasound
Correspondence: Zsofia I. Kovacs Journal of Therapeutic Ultrasound 2018, 6(Suppl 1):O1 OBJECTIVES Blood brain barrier (BBB) disruption with MR-guided pulsed focused ultrasound (pFUS) and microbubbles (MB) has been advocated as a noninvasive adjuvant treatment for malignancies and neurodegenerative diseases. A sterile inflammatory reaction has been recently described in the brain as a result of pFUS+MB (Kovacs et al. 2016). However, one potential issue of weekly pFUS+MB treatments is the lack of
... data on the longterm effects on inflammation. The purpose of this study was to evaluate the effects of multiple weekly courses of pFUS+MB exposures in the rat brain using micro-Positron Emmision Tomography (PET) and 18F-DPA-714, a marker of translocator protein (TSPO) upregulation/microglial activation and an indication of neuroinflammation. METHODS Female rats were assigned to three different groups based on the number of weekly pFUS+MB: Group 1: pFUS+MB x1, PET scans performed 24 hours later (n=6) ; Group 2: pFUS +MB x2 with PET scans performed within 10 days after 2nd sonication (n=5) ; and Group 3: pFUS+MB x6 with PET scans performed 7-9 days later (n=5). The left striatum (str) and right hippocampus (hc) were targeted in all animals. 100 μl of MB (OptisonTM, GE Healthcare, Little Chalfont, UK) was administered intravenously over 1 minute starting 30 secs before pFUS. Acoustic energy was delivered to the brain using "BBB configuration function" based on algorithm reported (O'Reilly et al. 2012) to determine optimal acoustic pressure for BBB opening via 1.5f 0 and 2.5f 0 ultra harmonic acoustic emission detection for every single pulse (9 focal points, 120 sec/9 focal pointsstriatum, 120 sec/4 focal pointshippocampus) using an 825 kHz hydrophone with a single-element spherical FUS transducer (center frequency: 589.636 kHz; focal number: 0.8; aperture: 7.5 cm; RK-100, FUS Instruments, Toronto, Ontario, Canada). T2* map were created from multiecho gradient echo sequence at 3T (Achieva, Philips Healthcare, Andover, MA) through the rat brain with TE=7 msec, echo train length 5 and echo spacing 7 and Tr=1500 msec. T2* maps were created by fitting signal intensity at each voxel to a single exponential fit with in-house software and histogram analysis was performed on volume of interests (VOI). Static microPET/CT scans emission data was acquired 30-60 min after injection of 18F-DPA-714. VOIs were drawn in the targeted areas and uptake was compared to the contralateral unaffected side. Uptake values were normalized to cerebellum. RESULTS 18F-DPA-714 uptake was increased at the sonication sites in all locations (Fig. 1) . The ratio of the percent increase in SUV between pFUS+MB treated striatum and hippocampus to contralateral side is depicted in graph (mean+/-SEM) clearly showing large increase in uptake for both regions compared to normal brain. The neuroinflammatory changes persisted for at least 14 days after 2 weekly sonications. The coefficient of variation for PET scans was <10%. This corresponded to Iba1 activation visible on histology. Figure 2 contains normalized histograms from VOI for Group 2 and Group 3 rats derived from pFUS+MB treated (ipsilateral) and contralateral brain that shows a shift to lower T2* values for sonicated regions. CONCLUSIONS Rats receiving pFUS+MB to open the BBB showed a clear upregulation of TSPO expression consistent with microglial activation/neuroinflammation, even after one sonication session. Histograms derived from T2* maps MRI clearly shows that sonication with BBB algorithm results in left shift in T2* values that would be consistent with hypointense voxels on T2*w MRI and abnormatilies on histolology. These preliminary results contradict current assumptions that the effects of pFUS+MB are confined primarily to the endothelium and vessel wall. Further assessment of the long-term effects of pFUS+MB is necessary before this approach can be widely implemented in clinical trials.