Hammoud Laboratory, Center for Infectious Disease Imaging, Clinical Center, National Institutes of Health, 10 Center Drive, Building 10, Room 1C-368, Bethesda, MD, 20892, USA.
University of Texas, MD Anderson Cancer Center, Houston, USA.
J Neuroinflammation. 2019 Jul 25;16(1):155. doi: 10.1186/s12974-019-1543-z.
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.
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.
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.
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.
磁共振成像（MRI）引导的脉冲聚焦超声联合微泡（pFUS+MB）可在靶向区域诱导短暂的血脑屏障开放（BBBO）。pFUS+MB 通过促进神经治疗药物的输送，已被提倡作为神经退行性疾病和恶性肿瘤的辅助治疗方法。最近有研究报道，pFUS+MB 诱导的 BBBO 后会出现无菌性神经炎症。在这项研究中，我们使用 18F-DPA714（TSPO 标志物）的 PET 成像来评估单次和多次 pFUS+MB 治疗后的神经炎症变化。
三组 Sprague-Dawley 雌性大鼠接受 MRI 引导的 pFUS+MB（Optison™；每只大鼠 5-8×10 MB）治疗，靶向左额叶皮质和右侧海马体。A 组大鼠单次超声处理，B 组大鼠两次超声处理，C 组大鼠每周超声处理六次。被动空化检测反馈（PCD）控制超声过程中的峰值负压。我们在超声后立即进行 T1 加权扫描以评估 BBBO 的效率，并进行 T2*-加权扫描以评估低信号像素。在 A 组中，在超声后 24 小时进行 [18F]DPA-714 PET/CT 扫描，在 B 组和 C 组中，在最后一次超声后的平均 10 天内进行 [18F]DPA-714 PET/CT 扫描。计算靶向区域与对侧大脑相比的 T1 增强、T2*值和 [18F]DPA-714 注射剂量/cc（%ID/cc）比值。对小胶质细胞激活/星形胶质细胞增生进行组织学评估。
在所有组中，与非超声处理的大脑相比，超声处理后的 [18F]DPA-714 结合增加（%ID/cc 比值>1）。免疫组织病理学显示，与对侧大脑相比，超声处理的额皮质中微胶质和星形胶质细胞标志物的染色增加，而在超声处理的海马体中则较少。使用 MRI，我们记录了超声后的即刻 BBB 破坏，并在 24 小时后观察到 BBBO 的缓解。我们发现随着超声次数的增加，T2*低信号像素增多。在接受两次和六次超声后的动物的纵向组中，PET 上没有发现神经炎症的累积增加。
我们使用 [18F]DPA-714 PET 记录了与 pFUS+MB 相关的体内神经炎症变化。我们的方案（利用 PCD 反馈来最小化损伤）导致了单次超声后 24 小时内可见的神经炎症。我们的发现得到了免疫组织化学的支持，显示了小胶质细胞的激活和星形胶质细胞的增生。在临床试验实施之前，应评估旨在破坏 BBB 的实验性超声参数的神经炎症后遗症。
