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FUS 介导的 BBB 开放导致短暂的灌注减少和炎症,而没有急性或慢性脑损伤。

FUS-mediated BBB opening leads to transient perfusion decrease and inflammation without acute or chronic brain lesion.

机构信息

Image Guided Therapy, Pessac, France.

Univ. Grenoble Alpes, Inserm, U1216, Grenoble Institut Neurosciences, Grenoble, France.

出版信息

Theranostics. 2024 Jul 2;14(10):4147-4160. doi: 10.7150/thno.96721. eCollection 2024.


DOI:10.7150/thno.96721
PMID:38994025
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11234282/
Abstract

The permeabilization of the BBB to deliver therapeutics with MR-guided FUS redefines therapeutic strategies as it improves patient outcomes. To ensure the best translation towards clinical treatment, the evaluation of hemodynamic modifications in the CNS is necessary to refine treatment parameters. MR-guided FUS was applied at 1.5 MHz with a 50 ms burst every 1 s to open the BBB. CBF, BVf and ADC parameters were monitored with MRI. Cavitation was monitored with a PCD during the FUS sequence and classified with the IUD index into three cavitation levels. We distinctly applied the FUS in the cortex or the striatum. After the BBB permeabilization, neuroinflammation markers were quantified longitudinally. The BBB was successfully opened in all animals in this study and only one animal was classified as "hard" and excluded from the rest of the study. 30 min after FUS-induced BBB opening in the cortex, we measured a 54% drop in CBF and a 13% drop in BVf compared to the contralateral side. After permeabilization of the striatum, a 38% drop in CBF and a 15% drop in BVf were measured. CBF values rapidly returned to baseline, and 90 min after BBB opening, no significant differences were observed. We quantified the subsequent neuroinflammation, noting a significant increase in astrocytic recruitment at 2 days and microglial activation at 1 day after FUS. After 7 days, no more inflammation was visible in the brain. FUS-induced BBB opening transiently modifies hemodynamic parameters such as CBF and BVf, suggesting limited nutrients and oxygen supply to the CNS in the hour following the procedure.

摘要

MR 引导聚焦超声打开血脑屏障以递送治疗药物,重新定义了治疗策略,因为它改善了患者的预后。为了确保向临床治疗的最佳转化,有必要评估中枢神经系统的血液动力学变化,以优化治疗参数。MR 引导聚焦超声以 1.5MHz 的频率应用,每 1 秒爆发 50ms,以打开血脑屏障。通过 MRI 监测 CBF、BVf 和 ADC 参数。在 FUS 序列期间使用 PCD 监测空化,并使用 IUD 指数将其分类为三个空化水平。我们明确地将 FUS 应用于皮质或纹状体。在 BBB 通透性增加后,纵向定量测定神经炎症标志物。在这项研究中的所有动物中,BBB 均成功打开,只有一只动物被归类为“硬”,并被排除在其余研究之外。在 FUS 诱导的皮质 BBB 打开后 30 分钟,与对侧相比,我们测量到 CBF 下降 54%,BVf 下降 13%。在纹状体通透性增加后,CBF 下降 38%,BVf 下降 15%。CBF 值迅速恢复到基线,在 BBB 打开 90 分钟后,没有观察到显著差异。我们定量了随后的神经炎症,发现在 FUS 后 2 天星形胶质细胞募集显著增加,1 天微胶质细胞激活。7 天后,大脑中没有可见的炎症。FUS 诱导的 BBB 短暂性地改变了 CBF 和 BVf 等血液动力学参数,提示在该程序后的 1 小时内 CNS 的营养和氧气供应有限。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/035f/11234282/39a19e4ce184/thnov14p4147g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/035f/11234282/d9c6791bec5f/thnov14p4147g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/035f/11234282/a9edeaaace3b/thnov14p4147g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/035f/11234282/184e6d728488/thnov14p4147g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/035f/11234282/a604d95dc936/thnov14p4147g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/035f/11234282/b1260203cdf7/thnov14p4147g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/035f/11234282/b751950a7d18/thnov14p4147g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/035f/11234282/d0a64fafda78/thnov14p4147g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/035f/11234282/b727f9d20f0f/thnov14p4147g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/035f/11234282/39a19e4ce184/thnov14p4147g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/035f/11234282/d9c6791bec5f/thnov14p4147g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/035f/11234282/a9edeaaace3b/thnov14p4147g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/035f/11234282/184e6d728488/thnov14p4147g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/035f/11234282/a604d95dc936/thnov14p4147g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/035f/11234282/b1260203cdf7/thnov14p4147g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/035f/11234282/b751950a7d18/thnov14p4147g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/035f/11234282/d0a64fafda78/thnov14p4147g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/035f/11234282/b727f9d20f0f/thnov14p4147g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/035f/11234282/39a19e4ce184/thnov14p4147g009.jpg

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[1]
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[2]
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[4]
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[6]
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[8]
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引用本文的文献

[1]
Alteration of Water Exchange Rates Following Focused Ultrasound-Mediated BBB Opening in the Dorsal Striatum of Non-Human Primates: A Diffusion-Prepared pCASL Study.

bioRxiv. 2025-8-1

[2]
Data-driven feedback augments ultrasound nanotheranostics in brain tumors.

bioRxiv. 2025-5-7

本文引用的文献

[1]
Isoflurane lowers the cerebral metabolic rate of oxygen and prevents hypoxia during cortical spreading depolarization : An integrative experimental and modeling study.

J Cereb Blood Flow Metab. 2024-6

[2]
Evidence of cerebral hypoperfusion consecutive to ultrasound-mediated blood-brain barrier opening in rats.

Magn Reson Med. 2023-6

[3]
Hyperosmolar blood-brain barrier opening using intra-arterial injection of hyperosmotic mannitol in mice under real-time MRI guidance.

Nat Protoc. 2022-1

[4]
Revisiting the neurovascular unit.

Nat Neurosci. 2021-9

[5]
Cavitation-modulated inflammatory response following focused ultrasound blood-brain barrier opening.

J Control Release. 2021-9-10

[6]
Gemcitabine-loaded microbubble system for ultrasound imaging and therapy.

Acta Biomater. 2021-8

[7]
MP3: Medical Software for Processing Multi-Parametric Images Pipelines.

Front Neuroinform. 2020-11-16

[8]
A new safety index based on intrapulse monitoring of ultra-harmonic cavitation during ultrasound-induced blood-brain barrier opening procedures.

Sci Rep. 2020-6-22

[9]
Secondary effects on brain physiology caused by focused ultrasound-mediated disruption of the blood-brain barrier.

J Control Release. 2020-8-10

[10]
The SIGMA rat brain templates and atlases for multimodal MRI data analysis and visualization.

Nat Commun. 2019-12-13

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