Ye Byoung Seok, Chang Kyung Won, Kang Sungwoo, Jeon Seun, Chang Jin Woo
1Department of Neurology, Yonsei University College of Medicine, Seoul.
3Yonsei Metabolism-Dementia Research Institute, Seoul; and.
J Neurosurg. 2025 Jan 10;142(5):1263-1270. doi: 10.3171/2024.8.JNS24989. Print 2025 May 1.
Focused ultrasound (FUS)-mediated blood-brain barrier (BBB) opening is safe and potentially beneficial in patients with Alzheimer's disease (AD) for the removal of amyloid-beta (Aβ) plaques. However, the optimal BBB opening intervals and number of treatment sessions for clinical improvement remain undefined. Therefore, the aim of this study was to evaluate the safety and benefits of repeated and more extensive BBB opening alone.
In this open-label prospective study, 6 patients with AD were enrolled from June 2022 to July 2023. FUS-mediated BBB opening was performed three times at 2-month intervals targeting the bilateral frontal lobes. 18F-florbetaben positron emission tomography (FBB-PET) was performed before the first procedure and after the third procedure. Patients were administered neuropsychological and neuropsychiatric evaluations.
All 6 participants completed the study without any acute treatment-related adverse events. An extensive area of BBB opening (mean 43.1 cm3), more than twice as large as the opening volume (mean 20 cm3) in the authors' previous study, was confirmed by contrast-enhanced MRI. FBB-PET scans demonstrated a 14.9-Centiloid average decrease in Aβ plaques in 4 of the 6 participants (67%), but the Aβ plaques increased in 2 participants after BBB opening, compared with baseline. No significant changes were observed in the Korean version of the Mini-Mental State Examination in either group. Caregiver-Administered Neuropsychiatric Inventory scores improved in 5 of 6 participants (83%), indicating an improvement in neuropsychiatric symptoms.
This study confirmed the safety and efficacy of more frequent and extensive bilateral frontal BBB opening over multiple sessions in patients with AD. Furthermore, this is the first clinical trial to demonstrate improvement in neuropsychiatric symptoms through BBB opening alone, without concurrent administration of antibody medications.
聚焦超声（FUS）介导的血脑屏障（BBB）开放对阿尔茨海默病（AD）患者清除β淀粉样蛋白（Aβ）斑块而言安全且可能有益。然而，临床改善所需的最佳BBB开放间隔时间和治疗次数仍不明确。因此，本研究旨在评估单纯重复且更广泛的BBB开放的安全性和益处。
在这项开放标签前瞻性研究中，2022年6月至2023年7月招募了6例AD患者。以2个月为间隔，针对双侧额叶进行3次FUS介导的BBB开放。在首次手术前和第三次手术后进行18F-氟贝他班正电子发射断层扫描（FBB-PET）。对患者进行神经心理学和神经精神学评估。
所有6名参与者均完成了研究，未出现任何与急性治疗相关的不良事件。对比增强MRI证实BBB开放区域广泛（平均43.1 cm³），比作者之前研究中的开放体积（平均20 cm³）大两倍多。FBB-PET扫描显示，6名参与者中有4名（67%）的Aβ斑块平均减少了14.9个Centiloid，但与基线相比，2名参与者在BBB开放后Aβ斑块增加。两组的韩国版简易精神状态检查表均未观察到显著变化。6名参与者中有5名（83%）的照料者管理的神经精神学量表评分有所改善，表明神经精神症状有所改善。
本研究证实了在AD患者中多次更频繁、更广泛地双侧额叶BBB开放的安全性和有效性。此外，这是第一项仅通过BBB开放而不同时给予抗体药物来证明神经精神症状得到改善的临床试验。
