Alison Burgess PhD, Abstract Co-Author: Nothing to Disclose

Sonam Dubey, Abstract Co-Author: Nothing to Disclose

Tam Nhan, Abstract Co-Author: Nothing to Disclose

Isabelle Aubert PhD, Abstract Co-Author: Nothing to Disclose

Kullervo H. Hynynen PhD, Presenter: Nothing to Disclose

Focused ultrasound (FUS)-mediated opening of the blood-brain barrier (BBB) can reduce amyloid pathology in a mouse model of Alzheimer's disease even in the absence of exogenous drug delivery. In this study, we determine whether the reductions in pathology by FUS-mediated BBB opening with and without antibody delivery, are correlated to changes in cognitive function. In addition, we assess how vasculature compromised by amyloid pathology responds to FUS-mediated BBB opening using real time using two-photon microscopy.

7-month-old transgenic (Tg) mice that exhibit behavioral deficits and amyloid pathology as well as aged-matched non-transgenic littermates were treated weekly with MRI-guided FUS treatments to temporarily open the BBB in the hippocampus (n=28). Treated mice received FUS+amyloid antibodies or FUS alone and were compared to untreated Tg and non-Tg controls. After 3 treatments, mice were evaluated in the Y-maze. Post-mortem histology was performed. Acute BBB opening in age-matched Tg and non-Tg mice was evaluated in real time using two photon microscopy (n=48).

In the Y-maze, Tg mice spent 61% less time exploring the novel arm than non-Tg mice due to spatial memory impairments. After FUS, Tg mice spent 99% more time in the novel arm and performed as well as the non-Tg mice suggesting that FUS improves cognition. No difference was observed between Tg mice treated with FUS+antibodies or FUS alone. Using two-photon microscopy, we observed that after FUS, the BBB was not as permeable in Tg mice (0.006 ± 0.004 min-1) compared to non-Tg mice (0.014 ± 0.008 min-1) which was attributed to less opening in plaque-coated vessels. This suggests that drug delivery may be less effective in Tg mice but that these slower leakage kinetics may improve the safety of the treatment.

This data suggests that FUS-mediated BBB opening can improve cognition without drug delivery and in the presence of compromised vasculature suggesting that FUS should be further studied as a potential treatment for Alzheimer's disease.

Pre-clinical experiments suggest that MRIgFUS has the potential to positively affect symptoms and pathology associated with Alzheimer’s disease in addition to its proven ability to improve drug delivery to the brain. Clinical ultrasound transducers are currently used in clinical trials making translation of this technology feasible.

Burgess, A, Dubey, S, Nhan, T, Aubert, I, Hynynen, K, Focused Ultrasound-mediated Blood-brain Barrier Opening for Treatment in a Mouse Model of Alzheimer's Disease.  Radiological Society of North America 2014 Scientific Assembly and Annual Meeting, - ,Chicago IL. http://archive.rsna.org/2014/14017872.html