背景:聚焦超声(FUS)介导的血脑屏障(BBB)开放正在研究中,作为神经变性的治疗方式,然而它对人类的影响还不完全清楚。这里,我们评估了阿尔茨海默病(AD)患者多灶性脑部位对FUS给药的生理反应.
方法:在一所三级神经科学研究所,参加2期临床试验的8例AD患者(平均年龄65岁,38%F),每2周使用220kHzFUS传感器结合全身给药微泡,接受3例连续靶向BBB开放手术.总之,评估了77个治疗部位,并涵盖了海马,额叶,和顶叶大脑区域。FUS后成像变化,包括敏感性效应和时空基于钆的造影剂增强模式,使用系列3.0特斯拉MRI进行分析。
结果:FUS后MRI显示预期的脑实质内造影剂外渗是由于所有目标脑部位的BBB开放。BBB打开后,在脑内静脉周围始终观察到静脉给药的对比示踪剂浓度过高.BBB关闭后,在FUS干预的24-48小时内,观察到实质内静脉的通透性,并持续长达一周。值得注意的是,在FUS治疗后11天,还引发了脑实质膜外静脉通透和相关的CSF积液,在所有参与者完成自发解决之前。检测到轻度易感性效应,然而,任何参与者均未发生明显的颅内出血或其他严重不良反应.
结论:FUS介导的BBB开放在AD患者的多灶性脑区是安全且可重复的。FUS后示踪剂增强现象表明人类存在全脑静脉周围液体流出途径,并显示出涉及延迟,BBB破坏后的亚急性期。延迟反应性静脉和静脉周围变化与动态一致,对上游毛细血管操纵的区域渗出性反应。需要对这些FUS相关的成像现象和脑内静脉腔室变化进行进一步的临床前和临床研究,以阐明该途径的生理学以及在有或没有辅助神经治疗剂的情况下施用的FUS的生物学效应。
背景:ClinicalTrials.gov标识符:NCT03671889,注册于2018年9月14日。
BACKGROUND: Focused ultrasound (FUS)-mediated blood-brain barrier (BBB) opening is under investigation as a therapeutic modality for neurodegeneration, yet its effects in humans are incompletely understood. Here, we assessed physiologic responses to FUS administered in multifocal brain sites of persons with Alzheimer\'s disease (AD).
METHODS: At a tertiary neuroscience institute, eight participants with AD (mean age 65, 38% F) enrolled in a phase 2 clinical trial underwent three successive targeted BBB opening procedures at 2 week intervals using a 220 kHz FUS transducer in combination with systemically administered microbubbles. In all, 77 treatment sites were evaluated and encompassed hippocampal, frontal, and parietal brain regions. Post-FUS imaging changes, including susceptibility effects and spatiotemporal gadolinium-based contrast agent enhancement patterns, were analyzed using serial 3.0-Tesla MRI.
RESULTS: Post-FUS MRI revealed expected intraparenchymal contrast extravasation due to BBB opening at all targeted brain sites. Immediately upon BBB opening, hyperconcentration of intravenously-administered contrast tracer was consistently observed around intracerebral veins. Following BBB closure, within 24-48 h of FUS intervention, permeabilization of intraparenchymal veins was observed and persisted for up to one week. Notably, extraparenchymal meningeal venous permeabilization and associated CSF effusions were also elicited and persisted up to 11 days post FUS treatment, prior to complete spontaneous resolution in all participants. Mild susceptibility effects were detected, however no overt intracranial hemorrhage or other serious adverse effects occurred in any participant.
CONCLUSIONS: FUS-mediated BBB opening is safely and reproducibly achieved in multifocal brain regions of persons with AD. Post-FUS tracer enhancement phenomena suggest the existence of a brain-wide perivenous fluid efflux pathway in humans and demonstrate reactive physiological changes involving these conduit spaces in the delayed, subacute phase following BBB disruption. The delayed reactive venous and perivenous changes are consistent with a dynamic, zonal exudative response to upstream capillary manipulation. Further preclinical and clinical investigations of these FUS-related imaging phenomena and of intracerebral perivenous compartment changes are needed to elucidate physiology of this pathway as well as biological effects of FUS administered with and without adjuvant neurotherapeutics.
BACKGROUND: ClinicalTrials.gov identifier: NCT03671889, registered 9/14/2018.