title: Analysis of focused ultrasound-induced blood-brain barrier permeability in a mouse model of Alzheimer's disease using two-photon microscopy.
abstract: Transcranial focused ultrasound (FUS) can cause temporary, localized increases in blood-brain barrier (BBB) permeability for effective drug delivery to the brain. In pre-clinical models of Alzheimer's disease, FUS has successfully been used to deliver therapeutic agents and endogenous therapeutic molecules to the brain leading to plaque reduction and improved behavior. However, prior to moving to clinic, questions regarding how the compromised vasculature in Alzheimer's disease responds to FUS need to be addressed. Here, we used two-photon microscopy to study changes in FUS-mediated BBB permeability in transgenic (TgCRND8) mice and their non-transgenic littermates. A custom-built ultrasound transducer was attached to the skull, covering a cranial window. Methoxy-X04 was used to visualize amyloid deposits in vivo. Fluorescent intravascular dyes were used to identify leakage from the vasculature after the application of FUS. Dye leakage occurred in both transgenic and non-transgenic mice at similar acoustic pressures but exhibited different leakage kinetics. Calculation of the permeability constant demonstrated that the vasculature in the transgenic mice was much less permeable after FUS than the non-transgenic littermates. Further analysis demonstrated that the change in vessel diameter following FUS was lessened in amyloid coated vessels. These data suggest that changes in vessel diameter may be directly related to permeability and the presence of amyloid plaque may reduce the permeability of a vessel after FUS. This study indicates that the FUS parameters used for the delivery of therapeutic agents to the brain may need to be adjusted for application in Alzheimer's disease.
authors.affiliation: Physical Sciences Platform, Sunnybrook Research Institute, Toronto, ON, Canada. Electronic address: aburgess@sri.utoronto.ca.
authors.forename: Alison
authors.initials: A
authors.lastname: Burgess
authors.affiliation: Physical Sciences Platform, Sunnybrook Research Institute, Toronto, ON, Canada; Medical Biophysics, University of Toronto, Toronto, ON, Canada.
authors.forename: Tam
authors.initials: T
authors.lastname: Nhan
authors.affiliation: Physical Sciences Platform, Sunnybrook Research Institute, Toronto, ON, Canada.
authors.forename: Clare
authors.initials: C
authors.lastname: Moffatt
authors.affiliation: Biomedical Engineering, University of Virginia, Charlottesville, VA, USA.
authors.forename: A L
authors.initials: AL
authors.lastname: Klibanov
authors.affiliation: Physical Sciences Platform, Sunnybrook Research Institute, Toronto, ON, Canada; Medical Biophysics, University of Toronto, Toronto, ON, Canada.
authors.forename: Kullervo
authors.initials: K
authors.lastname: Hynynen
mesh_terms: D000475:Alkenes; D000544:Alzheimer Disease / Q000188:drug therapy / Q000473:pathology*; D000818:Animals; D001555:Benzene Derivatives; D001812:Blood-Brain Barrier / Q000378:metabolism* / Q000473:pathology; D001921:Brain / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D016657:Cerebral Amyloid Angiopathy / Q000378:metabolism / Q000473:pathology; D016503:Drug Delivery Systems / Q000295:instrumentation*; D005260:Female; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D036641:Microscopy, Fluorescence, Multiphoton; D010539:Permeability; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology; D013267:Stilbenes; D014465:Ultrasonics / Q000295:instrumentation*
chemical_list: C465418:1,4-bis(4'-hydroxystyryl)-2-methoxybenzene; D000475:Alkenes; D001555:Benzene Derivatives; D013267:Stilbenes
keywords: Alzheimer's disease; Blood–brain barrier; Cerebral amyloid angiopathy; Focused ultrasound; Permeability; Two-photon microscopy