Immunotherapy for Alzheimer's disease (AD) relies on antibodies directed against toxic amyloid-beta peptide (Aβ), which circulate in the bloodstream and remove Aβ from the brain [1], [2]. In mouse models of AD, the administration of anti-Aβ antibodies directly into the brain, in comparison to the bloodstream, was shown to be more efficient at reducing Aβ plaque pathology [3], [4]. Therefore, delivering anti-Aβ antibodies to the brain of AD patients may also improve treatment efficiency. Transcranial focused ultrasound (FUS) is known to transiently-enhance the permeability of the blood-brain barrier (BBB) [5], allowing intravenously administered therapeutics to enter the brain [6]–[8]. Our goal was to establish that anti-Aβ antibodies delivered to the brain using magnetic resonance imaging-guided FUS (MRIgFUS) [9] can reduce plaque pathology. To test this, TgCRND8 mice [10] received intravenous injections of MRI and FUS contrast agents, as well as anti-Aβ antibody, BAM-10. MRIgFUS was then applied transcranially. Within minutes, the MRI contrast agent entered the brain, and BAM-10 was later found bound to Aβ plaques in targeted cortical areas. Four days post-treatment, Aβ pathology was significantly reduced in TgCRND8 mice. In conclusion, this is the first report to demonstrate that MRIgFUS delivery of anti-Aβ antibodies provides the combined advantages of using a low dose of antibody and rapidly reducing plaque pathology.

Object: The goal of this study was to explore the feasibility of using low-frequency magnetic resonance (MR) image–guided focused ultrasound as a noninvasive method for the temporary disruption of the blood–brain barrier (BBB) at targeted locations. Methods: Rabbits were placed inside a clinical 1.5-tesla MR imaging unit, and sites in their brains were targeted for 20-second burst sonications (frequency 260 kHz). The peak pressure amplitude during the burst varied between 0.1 and 0.9 MPa. Each sonication was performed after an intravenous injection of an ultrasound contrast agent (Optison). The disruption of the BBB was evaluated with the aid of an injection of an MR imaging contrast agent (MAG-NEVIST). Additional tests involving the use of MION-47, a 20-nm magnetic nanoparticle contrast agent, were also performed. The animals were killed at different time points between 3 minutes and 5 weeks postsonication, after which light or electron microscopic evaluation was performed. The threshold for BBB disruption was approximately 0.2 MPa. More than 80% of the brain sites sonicated showed BBB disruption when the pressure amplitude was 0.3 MPa; at 0.4 MPa, this percentage was greater than 90%. Tissue necrosis, ischemia, and apoptosis were not found in tissue in which the pressure amplitude was less than 0.4 MPa; however, in a few areas of brain tissue erythrocytes were identified outside blood vessels following exposures of 0.4 MPa or higher. Survival experiments did not show any long-term adverse events. Conclusions: These results demonstrate that low-frequency ultrasound bursts can induce local, reversible disruption of the BBB without undesired long-term effects. This technique offers a potential noninvasive method for targeted drug delivery in the brain aided by a relatively simple low-frequency device.

MRgFUS is a safe, noninvasive method to deliver spatially targeted monoclonal antibody across the BBB in patients with brain tumors.