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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
Open accessAbstract
PURPOSE: To validate whether repeated magnetic resonance (MR) imaging-guided focused ultrasound treatments targeted to the hippocampus, a brain structure relevant for Alzheimer disease ( AD Alzheimer disease ), could modulate pathologic abnormalities, plasticity, and behavior in a mouse model. MATERIALS AND METHODS: All animal procedures were approved by the Animal Care Committee and are in accordance with the Canadian Council on Animal Care. Seven-month-old transgenic (TgCRND8) (Tg) mice and their nontransgenic (non-Tg) littermates were entered in the study. Mice were treated weekly with MR imaging-guided focused ultrasound in the bilateral hippocampus (1.68 MHz, 10-msec bursts, 1-Hz burst repetition frequency, 120-second total duration). After 1 month, spatial memory was tested in the Y maze with the novel arm prior to sacrifice and immunohistochemical analysis. The data were compared by using unpaired t tests and analysis of variance with Tukey post hoc analysis. RESULTS: Untreated Tg mice spent 61% less time than untreated non-Tg mice exploring the novel arm of the Y maze because of spatial memory impairments (P < .05). Following MR imaging-guided focused ultrasound, Tg mice spent 99% more time exploring the novel arm, performing as well as their non-Tg littermates. Changes in behavior were correlated with a reduction of the number and size of amyloid plaques in the MR imaging-guided focused ultrasound-treated animals (P < .01). Further, after MR imaging-guided focused ultrasound treatment, there was a 250% increase in the number of newborn neurons in the hippocampus (P < .01). The newborn neurons had longer dendrites and more arborization after MR imaging-guided focused ultrasound, as well (P < .01). CONCLUSION: Repeated MR imaging-guided focused ultrasound treatments led to spatial memory improvement in a Tg mouse model of AD Alzheimer disease . The behavior changes may be mediated by decreased amyloid pathologic abnormalities and increased neuronal plasticity.
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“A magnetic resonance guide can be a good solution to focus ultrasound in combination with intravenously injected microbubbles in order to transiently open the BBB and reduce Aβ and τau pathology in animal models of AD [258].”
From Alzheimer's Disease: Treatment Strategies and Their Limitations. (2022) · cites this paper as [258]
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“Animal studies have demonstrated safe and reversible BBB opening (4, 6, 7) as well as reduction of amyloid-beta plaque, neurogenesis, and improvement of memory.”
From Noninvasive hippocampal blood-brain barrier opening in Alzheimer's disease with focused ultrasound. (2020) · cites this paper as [6]
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“Animal studies have demonstrated safe and reversible BBB opening (4, 6, 7) as well as reduction of amyloid-beta plaque, neurogenesis, and improvement of memory.”
From Noninvasive hippocampal blood-brain barrier opening in Alzheimer's disease with focused ultrasound. (2020) · cites this paper as [6]
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Metadata
- Authors
- Burgess, A., Dubey, S., Yeung, S., Hough, O., Eterman, N., Aubert, I., & Hynynen, K.
- Affiliations
- University of Toronto (CA)
- Sunnybrook Research Institute (CA)
- Venue
- Radiology
- Published
- 2014-12
- Volume
- 273
- Issue
- 3
- Pages
- 736-745
- ISSN
- 0033-8419 (ISSN-L)
- 1527-1315
- PMC
- PMC4314115
- OpenAlex
- W2131358222
- Cited by
- 286
- References
- 31
- Citations by year
- 2026: 14 · 2025: 18 · 2024: 19 · 2023: 24 · 2022: 29 · 2021: 41 · 2020: 34 · 2019: 26 · 2018: 31 · 2017: 17 · 2016: 19 · 2015: 10 · 2014: 3
- FWCI
- 8.48
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Radiology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (FRN 119312, EB003268)
- Canadian Institutes of Health Research (R01 EB003268, FRN93063, 119312_1)
- National Institute of Biomedical Imaging and Bioengineering (R01EB003268)
- Topics
- Physical Sciences › Engineering › Biomedical Engineering › Ultrasound and Hyperthermia Applications
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Keywords
- Alzheimer's disease, hippocampus, blood-brain barrier opening, TgCRND8 mice, amyloid plaques, spatial memory, newborn neurons, neuroplasticity, dendritic branching, transgenic mouse model
- MeSH terms
- Algorithms, Alzheimer Disease, Animals, Blood-Brain Barrier, Contrast Media, Disease Models, Animal, Fluorocarbons, Hippocampus, Mice, Transgenic, Ultrasonic Therapy, Gadolinium DTPA, Mice, Magnetic Resonance Imaging, Interventional
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