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      Blood–brain barrier opening in Alzheimer’s disease using MR-guided focused ultrasound

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          Abstract

          Magnetic resonance-guided focused ultrasound in combination with intravenously injected microbubbles has been shown to transiently open the blood–brain barrier, and reduce beta-amyloid and tau pathology in animal models of Alzheimer’s disease. Here, we used focused ultrasound to open the blood–brain barrier in five patients with early to moderate Alzheimer’s disease in a phase I safety trial. In all patients, the blood–brain barrier within the target volume was safely, reversibly, and repeatedly opened. Opening the blood–brain barrier did not result in serious clinical or radiographic adverse events, as well as no clinically significant worsening on cognitive scores at three months compared to baseline. Beta-amyloid levels were measured before treatment using [ 18F]-florbetaben PET to confirm amyloid deposition at the target site. Exploratory analysis suggested no group-wise changes in amyloid post-sonication. The results of this safety and feasibility study support the continued investigation of focused ultrasound as a potential novel treatment and delivery strategy for patients with Alzheimer’s disease.

          Abstract

          Magnetic resonance-guided focused ultrasound with injected microbubbles has been used to temporarily open the blood–brain barrier (BBB) in animal models of Alzheimer's disease (AD). Here, the authors use this technology to non-invasively open the BBB in 5 patients with mild-to-moderate AD in a phase I trial, and show that the procedure is safe.

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          Clinical trial of blood-brain barrier disruption by pulsed ultrasound.

          Alexandre Carpentier, Michael Canney, Alexandre Vignot … (2016)
          The blood-brain barrier (BBB) limits the delivery of systemically administered drugs to the brain. Methods to circumvent the BBB have been developed, but none are used in standard clinical practice. The lack of adoption of existing methods is due to procedural invasiveness, serious adverse effects, and the complications associated with performing such techniques coincident with repeated drug administration, which is customary in chemotherapeutic protocols. Pulsed ultrasound, a method for disrupting the BBB, was shown to effectively increase drug concentrations and to slow tumor growth in preclinical studies. We now report the interim results of an ultrasound dose-escalating phase 1/2a clinical trial using an implantable ultrasound device system, SonoCloud, before treatment with carboplatin in patients with recurrent glioblastoma (GBM). The BBB of each patient was disrupted monthly using pulsed ultrasound in combination with systemically injected microbubbles. Contrast-enhanced magnetic resonance imaging (MRI) indicated that the BBB was disrupted at acoustic pressure levels up to 1.1 megapascals without detectable adverse effects on radiologic (MRI) or clinical examination. Our preliminary findings indicate that repeated opening of the BBB using our pulsed ultrasound system, in combination with systemic microbubble injection, is safe and well tolerated in patients with recurrent GBM and has the potential to optimize chemotherapy delivery in the brain.
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            Scanning ultrasound removes amyloid-β and restores memory in an Alzheimer's disease mouse model.

            Gerhard Leinenga, Jürgen Götz (2015)
            Amyloid-β (Aβ) peptide has been implicated in the pathogenesis of Alzheimer's disease (AD). We present a nonpharmacological approach for removing Aβ and restoring memory function in a mouse model of AD in which Aβ is deposited in the brain. We used repeated scanning ultrasound (SUS) treatments of the mouse brain to remove Aβ, without the need for any additional therapeutic agent such as anti-Aβ antibody. Spinning disk confocal microscopy and high-resolution three-dimensional reconstruction revealed extensive internalization of Aβ into the lysosomes of activated microglia in mouse brains subjected to SUS, with no concomitant increase observed in the number of microglia. Plaque burden was reduced in SUS-treated AD mice compared to sham-treated animals, and cleared plaques were observed in 75% of SUS-treated mice. Treated AD mice also displayed improved performance on three memory tasks: the Y-maze, the novel object recognition test, and the active place avoidance task. Our findings suggest that repeated SUS is useful for removing Aβ in the mouse brain without causing overt damage, and should be explored further as a noninvasive method with therapeutic potential in AD.
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              Noninvasive localized delivery of Herceptin to the mouse brain by MRI-guided focused ultrasound-induced blood-brain barrier disruption.

              Manabu Kinoshita, Nathan McDannold, Ferenc Jolesz … (2006)
              Antibody-based anticancer agents are promising chemotherapeutic agents. Among these agents, Herceptin (trastuzumab), a humanized anti-human epidermal growth factor receptor 2 (HER2/c-erbB2) monoclonal antibody, has been used successfully in patients with breast cancer. However, in patients with brain metastasis, the blood-brain barrier limits its use, and a different delivery method is needed to treat these patients. Here, we report that Herceptin can be delivered locally and noninvasively into the mouse central nervous system through the blood-brain barrier under image guidance by using an MRI-guided focused ultrasound blood-brain barrier disruption technique. The amount of Herceptin delivered to the target tissue was correlated with the extent of the MRI-monitored barrier opening, making it possible to estimate indirectly the amount of Herceptin delivered. Histological changes attributable to this procedure were minimal. This method may represent a powerful technique for the delivery of macromolecular agents such as antibodies to treat patients with diseases of the central nervous system.
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                Author and article information

                Contributors
                Nir Lipsman: nir.lipsman@sunnybrook.ca
                Journal
                Journal ID (nlm-ta): Nat Commun
                Journal ID (iso-abbrev): Nat Commun
                Title: Nature Communications
                Publisher: Nature Publishing Group UK (London )
                ISSN (Electronic): 2041-1723
                Publication date (Electronic): 25 July 2018
                Publication date PMC-release: 25 July 2018
                Publication date Collection: 2018
                Volume: 9
                Electronic Location Identifier: 2336
                Affiliations
                [1 ]ISNI 0000 0001 2157 2938, GRID grid.17063.33, Division of Neurosurgery, Sunnybrook Health Sciences Centre, , University of Toronto, ; Toronto, M4N 3M5 Canada
                [2 ]ISNI 0000 0001 2157 2938, GRID grid.17063.33, Hurvitz Brain Sciences Research Program, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, , University of Toronto, ; Toronto, M4N 3M5 Canada
                [3 ]ISNI 0000 0001 2157 2938, GRID grid.17063.33, Harquail Centre for Neuromodulation, , Sunnybrook Research Institute, ; Toronto, M4N 3M5 Canada
                [4 ]ISNI 0000 0001 2157 2938, GRID grid.17063.33, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, , University of Toronto, ; Toronto, M4N 3M5 Canada
                [5 ]ISNI 0000 0001 2157 2938, GRID grid.17063.33, Division of Neurology, Sunnybrook Health Sciences Centre, , University of Toronto, ; Toronto, M4N 3M5 Canada
                [6 ]ISNI 0000 0001 2157 2938, GRID grid.17063.33, Division of Geriatric Psychiatry, Sunnybrook Health Sciences Centre, , University of Toronto, ; Toronto, M4N 3M5 Canada
                [7 ]ISNI 0000 0001 2157 2938, GRID grid.17063.33, Department of Medical Imaging, Sunnybrook Health Sciences Centre, , University of Toronto, ; Toronto, M4N 3M5 Canada
                [8 ]ISNI 0000 0001 2157 2938, GRID grid.17063.33, Department of Laboratory Medicine and Pathobiology, , University of Toronto, ; Toronto, M5S 3H7 Canada
                [9 ]ISNI 0000 0001 2171 9311, GRID grid.21107.35, Department of Psychiatry and Behavioral Sciences and Radiology and Radiological Sciences, , Johns Hopkins University, ; Baltimore, MD 21218 USA
                [10 ]ISNI 0000 0001 2157 2938, GRID grid.17063.33, Department of Medical Biophysics, , University of Toronto, ; Toronto, M5S 3H7 Canada
                [11 ]ISNI 0000 0001 2157 2938, GRID grid.17063.33, Institute of Biomaterials and Biomedical Engineering, , University of Toronto, ; Toronto, M5S 3H7 Canada
                Article
                Publisher ID: 4529
                DOI: 10.1038/s41467-018-04529-6
                PMC ID: 6060168
                PubMed ID: 30046032
                SO-VID: 07d4e54a-dc3c-4ccc-987d-6589abd8bbf9
                Copyright © © The Author(s) 2018
                License:

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                Date received : 13 October 2017
                Date accepted : 4 May 2018
                Categories
                Subject: Article
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                issue-copyright-statement © The Author(s) 2018

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