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. 2022 Mar 7;39(3):427–439. doi: 10.1007/s11095-022-03185-2

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© The Author(s) 2022

Open AccessThis 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 3 — Schematic representation of blood-brain barrier opening in Alzheimer’s disease patient in vivo and patient-derived model in vitro. (a) Schematic of a magnetic resonance (MR)-guided ExAblate device used in the first successful blood-brain barrier (BBB) opening in Alzheimer’s disease (AD) patients. System consists of a hemispherical helmet lined with >1000 independent transducer elements delivering low frequency ultrasound treatment to the prescribed target. The helmet is positioned in the specialised MRI bed with stereotaxic frame and the space between patient’s head and the helmet filled with degassed water for acoustic coupling. Microbubble (MB) administration is carried out using repeated bolus injection or a continuous infusion. Reversible BBB opening occurs in the defined ultrasound focal zone. (b) Schematic of AD patient-derived human BBB opening in vitro. Somatic cells (e.g. fibroblasts or blood cells) are obtained from familial AD patients and reprogrammed to human induced pluripotent stem cells (hiPSC) by introduction of cocktail of reprogramming factors. hiPSC are used to generate brain endothelial-like cells (iBEC) and develop patient-derived in vitro AD BBB model. In vitro BBB is exposed to focused ultrasound and MB in the degassed water, leading to BBB opening and improved permeability of 5 kDa dextran. [44, 84]. AD-Alzheimer’s disease; BBB-blood-brain barrier; FUS-focused ultrasound; hiPSC-human induced pluripotent stem cell; iBEC- brain endothelial-like cells; kDa-kilodalton; MB-microbubble; Figure created with BioRender.com.