Extensive Frontal Focused Ultrasound-Mediated Blood-Brain Barrier Opening for the Treatment of Alzheimer’s Disease: An Open-Label Prospective Study

Abstract

Abstract Background: 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 plaques and behavioral improvement. We aimed to evaluate the safety, feasibility, and potential benefits of repeated extensive BBB opening. Methods: In this open-label prospective study, six patients with AD were enrolled at the Severance Hospital in Korea from July 2022 to July 2023. FUS-mediated BBB opening was performed three times at 2-month intervals targeting the bilateral frontal lobe regions (Average 43.1 cm3). We performed 18F-florbetaben (FBB) positron emission tomography within 4 weeks before the first procedure and within 2 weeks after the third procedure. We calculated the FBB standardized uptake value ratios (SUVRs). Results: All patients completed the study without any acute treatment-related adverse events. Global FBB-SUVR decreased in four patients (amyloid-decrease group) and increased in two patients (amyloid-increase group) after BBB opening, compared with baseline. Compared with the amyloid-decrease group, the amyloid-increase group demonstrated a higher clinical dementia rating sum of boxes but a lower global FBB-SUVR at baseline. The amyloid-increase group demonstrated higher pretrial variability in the mini-mental status examination than the amyloid-decrease group. Conclusions: Repeated and extensive BBB opening in the frontal lobe is safe and feasible for patients with AD. However, meticulous exclusion is required for patients with cognitive fluctuations and less prominent amyloid accumulation, which could be attributed to concomitant Lewy body pathology.