A comprehensive review of advanced focused ultrasound (FUS) microbubbles-mediated treatment of Alzheimer's disease.

Alzheimer's disease (AD) is characterized by progressive neurodegeneration, memory loss, and cognitive impairment leading to dementia and death. The blood-brain barrier (BBB) prevents the delivery of drugs into the brain, which can limit their therapeutic potential in the treatment of AD. Therefore, there is a need to develop new approaches to bypass the BBB for appropriate treatment of AD. Recently, focused ultrasound (FUS) has been shown to disrupt the BBB, allowing therapeutic agents to penetrate the brain. In addition, microbubbles (MBs) as lipophilic carriers can penetrate across the BBB and deliver the active drug into the brain tissue. Therefore, combined with FUS, the drug-encapsulated MBs can pass through the ultrasound-disrupted zone of the BBB and diffuse into the brain tissue. This review provides clear and concise statements on the recent advances of the various FUS-mediated MBs-based carriers developed for delivering AD-related drugs. In addition, the sonogenetics-based FUS/MBs approaches for the treatment of AD are highlighted. The future perspectives and challenges of ultrasound-based MBs drug delivery in AD are then discussed.

Introduction

Purpose Drug delivery with BBB opening

Study Objective To review recent advances in focused ultrasound-mediated microbubble-based drug delivery (including sonogenetics approaches) for treating Alzheimer's disease and to discuss future perspectives and challenges.

Disease model Alzheimer's disease

Outcomes and Safety

Summary of Outcomes Focused ultrasound combined with microbubbles reversibly opens the blood–brain barrier to permit delivery of antibodies, nanoparticles and drugs and, in animal models, increased hippocampal neurogenesis, newborn neurons, improved spatial memory and recovery of AChE activity with no serious reported side effects; angiogenic transcriptional changes were also observed. Effective FUS parameters discussed included lower-frequency FUS (greater brain penetrability), MB-assisted low-intensity FUS protocols, and MR-guided FUS (MRgFUS) has been piloted in humans.

Duration of biological effect 18 days

Safety-related matter Numerous preclinical studies reported no serious side effects and no chemical or genetic changes from FUS-induced microbubble (MB) drug delivery for AD, but the review also highlights safety concerns such as heating, cavitation, and mechanical forces, notes incompletely understood cellular/molecular mechanisms, and calls for more clinical data and improved safety, precise targeting, and pharmacokinetic evaluation.

Brain Region

Visualization unavailable

Ultrasound Parameters

Focal Characteristics focal depth: None; focal length: None; aperture size: None

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