| Raymond et al., 200888 Raymond SB, Treat LH, Dewey JD, McDannold NJ, Hynynen K, Bacskai BJ. Ultrasound enhanced delivery of molecular imaging and therapeutic agents in Alzheimer's disease mouse models. PloS one. 2008;3(5):e2175.
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Mouse |
Sonication, with temporary interruption of the BBB, allowed the entry of therapeutic agents and molecular imaging agents. |
| Choi et al., 200899 Choi JJ, Wang S, Brown TR, Small SA, Duff KE, Konofagou EE. Noninvasive and transient blood-brain barrier opening in the hippocampus of Alzheimer's double transgenic mice using focused ultrasound. Ultrason imaging. 2008;30(3):189-200
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Mouse |
FUS allowed the opening of BBB and the entry of molecules by microbubbles. The extent of the opening and closing time of the BBB depend on the region of the brain. |
| Jordão et al., 20101010 Jordão JF, Ayala-Grosso CA, Markham K, Huang Y, Chopra R, McLaurin J, Aubert I. Antibodies targeted to the brain with image-guided focused ultrasound reduces amyloid-b plaque load in the TgCRND8 mouse model of Alzheimer's disease. PloS one. 2010;5(5):e10549.
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Mouse |
FUS associated with administration of anti-b-amyloid antibody (BAM 10) in transgenic mice (TgCRND8) promoted a significant reduction of b-amyloid peptide plaques. |
| Konofagou et al., 20121111 Konofagou EE, Tung Y, Choi J, Deffieux T, Baseri B, Vlachos F. Ultrasound-Induced Blood-Brain Barrier Opening. Curr Pharm Biotechnol. 2012;13(7):1332-45.
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Mouse |
FUS with microbubbles targeting the hippocampus demonstrated increased BBB permeability by at least two orders of magnitude. Therapeutic molecules that improve cognition and brain aging successfully crossed the BBB. BBB permeability depended on the pressure used and the size of the microbubbles. |
| Jordão et al., 20131212 Jordão JF, Thévenot E, Markham-Coultes K, Scarcelli T, Weng YQ, Xhima K, et al. Amyloid-b plaque reduction, endogenous antibody delivery and glial activation by brain-targeted, transcranial focused ultrasound. Exp Neurol. 2013;248:16-29.
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Mouse |
After a single FUS session, b-amyloid plaque size was reduced by 20%, while the total plaque surface was reduced by 13%. Histological studies showed the entry of endogenous antibodies into the b-amyloid plaque and the activation of microglia and astrocytes. |
| Burgess et al., 20141313 Burgess A, Nhan T, MoffattC, Klibanov AL, Hynynen K. Analysis of focused ultrasound-induced blood-brain barrier permeability in a mouse model of Alzheimer's disease using two-photon microscopy. J Control Release. 2014; 192:243-8.
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Mouse |
After the use of FUS, the permeability of the vessels of the transgenic mice (TgCRND8) and non-transgenic were compared. Transgenic vessels with amyloid plaques proved much more impermeable and had a smaller diameter after FUS. |
| Burgess et al., 20141414 Burgess A, Dubey S, Yeung S, Hough O, Eterman N, Aubert I, Hynynen K. Alzheimer disease in a mouse model: MR imaging-guided focused ultrasound targeted to the hippocampus opens the blood-brain barrier and improves pathologic abnormalities and behavior. Radiology. 2014;273(3):736-45.
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Mouse |
After sonication, there was a 99% improvement in the spatial memory activity of transgenic mice (TgCRND8), as well as a 250% increase in the number of new neurons in the hippocampus with longer and arborized dendrites. |
| Nisbet et al., 20171515 Nisbet R M, Van der Jeugd A, Leinenga G, Evans H T, Janowicz P W, Götz J. Combined effects of scanning ultrasound and a tau-specific single chain antibody in a tau transgenic mouse model. Brain. 2017;140(5):1220-30.
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Mouse |
Administration of 2N tau isoform-specific single chain antibody fragment (RN2N), combined with the use of FUS in scanner mode, significantly improved brain distribution and efficacy. |
| Alecou, Giannakou & Damianou 20171616 Alecou T, Giannakou M, Damianou C. Amyloid b Plaque Reduction With Antibodies Crossing the Blood-Brain Barrier, Which Was Opened in 3 Sessions of Focused Ultrasound in a Rabbit Model. J Ultrasound Med. 2017;36(11):2257-70.
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Rabbit |
Administration of antibodies to b-amyloid protein reduced the number of plaques from 200 to 170/cm2, while the concomitant use of FUS and antibodies decreased levels from 200 to 78/cm2. Repeated application of FUS increased the reduction of b-amyloid plaques. |
| O'Reilly et al., 20171717 O'Reilly MA, Hough O, Hynynen K. Blood-Brain Barrier Closure Time After Controlled Ultrasound-Induced Opening Is Independent of Opening Volume. J Ultrasound Med. 2017;36(3):475-83.
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Rat |
A study was performed to analyze the relationship between the opening volume of BBB and its closing time. Closing time of the BBB was independent of opening volume. It was suggested that larger volume opening can be done safely. |
| O'Reilly et al., 20171818 O'Reilly M A, Jones R M, Barrett E, Schwab A, Head E, Hynynen K. Investigation of the Safety of Focused Ultrasound-Induced Blood-Brain Barrier Opening in a Natural Canine Model of Aging. Theranostics. 2017;7(14):3573.
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Dog |
The opening of the BBB from a complete hemisphere of the brain by sonication was well tolerated by beagles (9-11 years old), indicating the clinical safety of the method. There was no significant reduction in b-amyloid load. Further studies are needed to determine whether there are benefits in natural pathologies associated with b-amyloid plaques. |
| Liu et al., 20181919 Liu M, Jevtic S, Markham-Coultes K, Ellens NP, O'Reilly MA, Hynynen K, et al. Investigating the efficacy of a combination Ab-targeted treatment in a mouse model of Alzheimer's disease. Brain Res. 2018;1678:138-45.
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Mouse |
This study aimed to analyze the association between FUS with anti-b-amyloid antibody (BAM-10) and scyllo-inositol. There was no summation of the benefits of FUS with BAM-10 associated with scyllo-inositol. Both were efficient alone or combined, reducing b-amyloid plaque and increasing astrocyte activation, but were not more effective when used together. |
| Hsu et al, 20182020 Hsu PH, Lin YT, Chung YH, Lin KJ, Yang LY, Yen TC, Liu HL. Focused Ultrasound-Induced Blood-Brain Barrier Opening Enhances GSK-3 Inhibitor Delivery for Amyloid-Beta Plaque Reduction. Sci Rep. 2018;8(1) 12882.
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Mouse |
This study aimed to evaluate whether the use of FUS-induced BBB opening could enhance the delivery of GSK-3 inhibitor, which would promote an additive effect on b-amyloid clearance, as well as reduce its synthesis in transgenic AD mice models. The procedure was performed unilaterally, using the contralateral hemisphere as a reference. Immunohistochemistry showed that GSK-3 inhibitors reduced GSK-3 activity by up to 61.3% with the addition of FUS, and autoradiography showed significant b-amyloid reduction. |
| Eguchi et al, 20182121 Eguchi K, Shindo T, Ito K, Ogata T, Kurosawa R, Kagaya Y, et al. Whole-brain low-intensity pulsed ultrasound therapy markedly improves cognitive dysfunctions in mouse models of dementia-Crucial roles of endothelial nitric oxide synthase. Brain Stimul. 2018;11(5):959-73.
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Mouse |
Therapeutic FUS in the hippocampus exerts a neuroprotective action on dementia. The study evaluated the efficacy and safety of LIPUS throughout the brain in mice with 2 types of dementia: vascular dementia and Alzheimer's dementia. In both models, LIPUS therapy substantially improved cognitive deficits (labyrinth Y test and/or passive evasion test), improved cerebral blood flow and regulated endothelial related genes. |
| Xu et al, 20182222 Xu M, Zhou H, Liu Y, Sun J, Xie W, Zhao P, Liu J. Ultrasoundexcited Protoporphyrin IX Modified Multifunctional Nanoparticles as a Strong Inhibitors of Tau Phosphorylation and b-Amyloid Aggregation. ACS Appl Mater Interfaces. 2018;10(39):32965-80
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Mouse |
The failure of many clinical trials suggests inefficacy in the treatment of AD using only one target. This study used multiple targets through a nano-drug protoporphyrin IX (PX) modified oxidized mesoporous carbon (OMCN) nanospheres (PX @ OMCN @ PEG (OP) @RVGs), which appears to be an efficient inhibitor of phosphorylated tau. Also, PX, together with FUS, significantly reduced b-amyloid plaque aggregation. |
