Efficacy and safety of focused ultrasound-mediated blood-brain barrier opening in Alzheimer's disease: A systematic review and meta-analysis.

Authors: Bai M, Lyv H, Zhou X, Zhang Y, Han Z

Alzheimer's disease (AD) manifests as an insidiously progressive neurodegenerative pathology, wherein the current therapeutic armamentarium remains constrained to symptomatic management, highlighting an urgent need for innovative therapies. This meta-analysis systematically conducts an assessment of the safety and efficacy of focused ultrasound (FUS)-mediated reversible blood-brain barrier opening (BBBO) in AD, while further exploring its potential associations with cognitive function and amyloid-β (Aβ) deposition in patients. PubMed, Embase, CNKI, Cochrane Library, and Web of Science were searched in this study. The study protocol has been registered with PROSPERO (registration number, CRD42024585286). ROBINS-I tool was used to assess the risk of bias, followed by further data analysis. Fifty-seven AD patients from eight distinct clinical studies were systematically incorporated into the meta-analytical framework. The time span was from 2018 to 2023. After FUS-mediated BBBO, the analysis demonstrated significant outcomes of FUS for both safety (OR: 0.88; 95% CI: 0.75-0.98, p < 0.01) and efficacy (OR: 0.91; 95% CI: 0.61-1.00, p < 0.01). There was no deterioration of cognitive function after surgery, and the observed adverse events were minor and temporary in nature. This meta-analysis underscores the potential of FUS as a non-invasive, safe, and effective method for enhancing BBB permeability in AD patients, offering a promising avenue for targeted drug delivery and disease modification. Future multicenter studies with larger sample sizes and standardized methodologies are warranted to confirm these results and explore the integration of FUS with existing and emerging AD therapies.

Introduction

Purpose Drug delivery with BBB opening

Study Objective To systematically assess the safety and efficacy of focused ultrasound–mediated reversible blood–brain barrier opening in Alzheimer’s disease and its associations with cognitive function and amyloid-β deposition.

Animal model / Human subject Homo sapiens (Alzheimer's disease patients); strain: N/A; age: not specified; sex: not specified

Disease model Alzheimer's disease

Outcomes and Safety

Summary of Outcomes Focused ultrasound-mediated reversible BBB opening in Alzheimer's patients was safe and effective (MRI-confirmed transient BBBO, no cognitive deterioration, only minor transient adverse events) and some studies reported regional reductions in amyloid PET signal. Successful approaches were primarily MRI‑guided low‑intensity FUS with intravenous microbubbles (commonly 220 kHz transducers), neuronavigation‑guided microbubble FUS, and multi‑session protocols (biweekly or repeated sessions) targeting hippocampus/entorhinal cortex, frontal/parietal lobes, precuneus and ACC, whereas low‑intensity tFUS with insufficient power was less consistently effective.

Duration of biological effect 2–4 weeks

Safety-related matter Across eight studies (57 patients) no serious adverse events were reported; adverse events were minor and transient — including edema (4 cases), headache, microbleeds/microhemorrhage, mild cognitive confusion/NPI‑Q changes, skin erythema and superficial cerebral hemorrhage — all of which resolved on follow‑up. Cognitive function did not deteriorate after FUS-BBBO.

Brain Region

Visualization unavailable

Ultrasound Parameters

Focal Characteristics Focal depth: None; Focal length: None; Aperture size: None

Treatment frequency Multiple

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