title: 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.
abstract: OBJECTIVE
  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.
  
  
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: From the Physical Sciences Platform (A.B., S.Y., O.H., N.E., K.H.) and Biological Sciences Platform (S.D., I.A.), Sunnybrook Research Institute, 2075 Bayview Ave, C713, Toronto, ON, Canada M4N 3M5; Department of Laboratory Medicine and Pathobiology (S.D., I.A.) and Department of Medical Biophysics (K.H.), University of Toronto, Toronto, Ontario, Canada.
authors.forename: Alison
authors.initials: A
authors.lastname: Burgess
authors.forename: Sonam
authors.initials: S
authors.lastname: Dubey
authors.forename: Sharon
authors.initials: S
authors.lastname: Yeung
authors.forename: Olivia
authors.initials: O
authors.lastname: Hough
authors.forename: Naomi
authors.initials: N
authors.lastname: Eterman
authors.forename: Isabelle
authors.initials: I
authors.lastname: Aubert
authors.forename: Kullervo
authors.initials: K
authors.lastname: Hynynen
mesh_terms: D000465:Algorithms; D000544:Alzheimer Disease / Q000473:pathology / Q000628:therapy*; D000818:Animals; D001812:Blood-Brain Barrier; D003287:Contrast Media / Q000008:administration & dosage; D004195:Disease Models, Animal; D005466:Fluorocarbons / Q000008:administration & dosage; D019786:Gadolinium DTPA / Q000008:administration & dosage; D006624:Hippocampus; D053783:Magnetic Resonance Imaging, Interventional; D051379:Mice; D008822:Mice, Transgenic; D014464:Ultrasonic Therapy
chemical_list: D003287:Contrast Media; D005466:Fluorocarbons; C064925:gadodiamide; D019786:Gadolinium DTPA; C042852:perflutren