Localized Blood–Brain Barrier Opening in Ovine Model Using Image-Guided Transcranial Focused Ultrasound

Yoon, Kyungho; Lee, Wonhye; Chen, Emily; Lee, Ji Eun; Croce, Phillip; Cammalleri, Amanda; Foley, Lori; Tsao, Allison L.; Yoo, Seung‐Schik

doi:10.1016/j.ultrasmedbio.2019.05.023

Cited by 24 publications

(19 citation statements)

References 96 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Therapeutic ultrasound is an alternative strategy for clearing amyloid by transiently opening the blood-brain barrier (BBB) and allowing for the uptake of blood-borne factors and therapeutic agents [ 8 ]. Given that ultrasound parameters are highly tunable, this technique can be safely applied to a range of species, including mice [ 9 , 10 ], dogs [ 11 ], sheep [ 12 , 13 ], and macaques [ 14 , 15 ] as well as humans [ 16 ]. Even without using a therapeutic agent (such as an antibody), repeated opening of the BBB with the scanning ultrasound (SUS) approach in 12 and 22 month-old APP23 mice has been shown to activate microglia, thereby reducing amyloid and improving memory performance [ 17 , 18 ].…”

Section: Introductionmentioning

confidence: 99%

A comparative study of the effects of Aducanumab and scanning ultrasound on amyloid plaques and behavior in the APP23 mouse model of Alzheimer disease

2021

View full text Add to dashboard Cite

Background Aducanumab is an anti-amyloid-β (Aβ) antibody that achieved reduced amyloid pathology in Alzheimer’s disease (AD) trials; however, it is controversial whether it also improved cognition, which has been suggested would require a sufficiently high cumulative dose of the antibody in the brain. Therapeutic ultrasound, in contrast, has only begun to be investigated in human AD clinical trials. We have previously shown that scanning ultrasound in combination with intravenously injected microbubbles (SUS), which temporarily and safely opens the blood-brain barrier (BBB), removes amyloid and restores cognition in APP23 mice. However, there has been no direct testing of how the effects of SUS compare to immunotherapy or whether a combination therapy is more effective. Methods In a study comprising four treatment arms, we tested the efficacy of an Aducanumab analog, Adu, both in comparison to SUS, and as a combination therapy, in APP23 mice (aged 13–22 months), using sham as a control. The active place avoidance (APA) test was used to test spatial memory, and histology and ELISA were used to measure amyloid. Brain antibody levels were also determined. Results We found that both Adu and SUS reduced the total plaque area in the hippocampus with no additive effect observed with the combination treatment (SUS + Adu). Whereas in the cortex where there was a trend towards reducing the total plaque area from either Adu or SUS, only the combination treatment yielded a statistically significant decrease in total plaque area compared to sham. Only the SUS and SUS + Adu groups included animals that had their plaque load reduced to below 1% from above 10%. There was a robust improvement in spatial memory for the SUS + Adu group only, and in this group the level of Adu, when measured 3 days post-treatment, was 5-fold higher compared to those mice that received Adu on its own. Together, these findings suggest that SUS should be considered as a treatment option for AD. Alternatively, a combination trial using Aducanumab together with ultrasound to increase brain levels of the antibody may be warranted.

show abstract

Section: Introductionmentioning

confidence: 99%

A comparative study of the effects of Aducanumab and scanning ultrasound on amyloid plaques and behavior in the APP23 mouse model of Alzheimer disease

2021

View full text Add to dashboard Cite

show abstract

Section: Introductionmentioning

confidence: 99%

“…Therapeutic ultrasound is an alternative strategy for clearing amyloid by transiently opening the blood-brain barrier (BBB) and allowing for the uptake of blood-borne factors and therapeutic agents [8]. Given that ultrasound parameters are highly tunable, this technique can be safely applied to a range of species, including mice [9, 10], dogs [11], sheep [12, 13], macaques [14, 15] and also humans [16]. Even without using a therapeutic agent (such as an antibody), repeated opening of the BBB with the scanning ultrasound (SUS) approach in 12 and 22 month-old APP23 mice has been shown to activate microglia and thereby reduce amyloid and improve memory performance [17, 18], that was dependent on BBB opening rather than simply applying ultrasound as a pressure wave to induce neuromodulatory effects [19].…”

Section: Introductionmentioning

confidence: 99%

A comparative study of the effects of Aducanumab and scanning ultrasound on amyloid plaques and behavior in the APP23 mouse model of Alzheimer disease

Leinenga

Götz

2021

Preprint

View full text Add to dashboard Cite

BackgroundAducanumab is an anti-amyloid-β (Aβ) antibody that achieved reduced amyloid pathology in Alzheimer’s disease (AD) trials, but it is controversial whether it also improved cognition. It has been claimed that this would require a sufficiently high cumulative dose of the antibody in the brain. Therapeutic ultrasound, in contrast, has only begun to be investigated in human AD clinical trials. We have previously shown that scanning ultrasound in combination with intravenously injected microbubbles (SUS), that temporarily and safely opens the blood-brain barrier (BBB), removes amyloid and restores cognition in APP23 mice. It has not been directly tested how the effects of SUS compare to immunotherapy or whether a combination therapy is more effective.MethodsIn a study comprising four treatment arms, we tested the efficacy of an Aducanumab analogue, Adu, in comparison to SUS, as well as a combination therapy in APP23 mice, using sham as a control (aged 13-22 months). The active place avoidance (APA) test was used to test spatial memory, and histology and ELISA were used to measure amyloid. Brain antibody levels were also determined.ResultsWe found that both Adu and SUS reduced the total plaque area in the hippocampus to a similar degree, with no additive effect in the combination treatment (SUS+Adu). Whereas there was only a trend towards a reduction for both Adu and SUS in the cortex, the combination trial yielded a statistically significant reduction compared to sham. Only the SUS and SUS+Adu groups included animals that had their plaque load reduced to below 1% from above 10%. There was a robust improvement in spatial memory for SUS+Adu only. In this group, when measured three days post-treatment, Adu levels were still 5-fold increased in the combination therapy compared to delivery of Adu on its own.Together, these findings suggest that SUS should be seriously considered as a treatment option for AD. Alternatively, a combination trial using Aducanumab together with ultrasound to increase brain levels of Aducanumab may be warranted, as the two approaches may engage different (albeit shared) clearance mechanisms.

show abstract

“…In this study, BBB permeabilization was performed in rats by using 0. 4 In a recent paper published by Yoon et al [69], DCE-MRI was used to validate BBB opening in ovine models by detecting MR-CA extravasation. Through pharmacokinetic and independent component analysis, the authors showed local disruption of the BBB without hemorrhage for an AP of 0.48 MPa.…”

Section: Mri Acquisitions For Bbb-opening Evaluationmentioning

confidence: 99%

Magnetic Resonance Methods for Focused Ultrasound-Induced Blood-Brain Barrier Opening

et al. 2020

View full text Add to dashboard Cite

Since its discovery in 2001, the interest in the low-intensity focused ultrasound (FUS)-mediated blood-brain barrier (BBB) disruption to deliver genes and drugs to brain tissue has increased steadily. Increasingly sophisticated sonication protocols and dedicated hardware are being developed to efficiently and safely permeabilize the BBB, and novel magnetic resonance (MR)-based technologies have been designed to guide FUS-induced BBB opening protocols. MR imaging (MRI) allows not only to more precisely target brain regions and evaluate the outcome of sonication in terms of enhanced BBB permeability but also to control the effects of ultrasound on brain structure and function. This review summarizes the state of the art in current MRI hardware and methods used in BBB opening protocols both in pre-clinical and clinical settings.

show abstract

Localized Blood–Brain Barrier Opening in Ovine Model Using Image-Guided Transcranial Focused Ultrasound

Cited by 24 publications

References 96 publications

A comparative study of the effects of Aducanumab and scanning ultrasound on amyloid plaques and behavior in the APP23 mouse model of Alzheimer disease

A comparative study of the effects of Aducanumab and scanning ultrasound on amyloid plaques and behavior in the APP23 mouse model of Alzheimer disease

A comparative study of the effects of Aducanumab and scanning ultrasound on amyloid plaques and behavior in the APP23 mouse model of Alzheimer disease

Magnetic Resonance Methods for Focused Ultrasound-Induced Blood-Brain Barrier Opening

Contact Info

Product

Resources

About