Theranostics 2017; 7(14):3573-3584. doi:10.7150/thno.20621

Research Paper

Investigation of the Safety of Focused Ultrasound-Induced Blood-Brain Barrier Opening in a Natural Canine Model of Aging

Meaghan Anne O'Reilly1,2✉, Ryan Matthew Jones1,2, Edward Barrett3, Anthony Schwab4, Elizabeth Head4, Kullervo Hynynen1,2,5

1. Physical Sciences Platform, Sunnybrook Research Institute, Toronto, Ontario, Canada
2. Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
3. Lovelace Respiratory Research Institute, Albuquerque, New Mexico, USA
4. Sanders-Brown Center on Aging, University of Kentucky, Lexington, Kentucky, USA
5. Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada

Abstract

Rationale: Ultrasound-mediated opening of the Blood-Brain Barrier(BBB) has shown exciting potential for the treatment of Alzheimer's disease(AD). Studies in transgenic mouse models have shown that this approach can reduce plaque pathology and improve spatial memory. Before clinical translation can occur the safety of the method needs to be tested in a larger brain that allows lower frequencies be used to treat larger tissue volumes, simulating clinical situations. Here we investigate the safety of opening the BBB in half of the brain in a large aged animal model with naturally occurring amyloid deposits.

Methods: Aged dogs naturally accumulate plaques and show associated cognitive declines. Low-frequency ultrasound was used to open the BBB unilaterally in aged beagles (9-11yrs, n=10) in accordance with institutionally approved protocols. Animals received either a single treatment or four weekly treatments. Magnetic resonance imaging(MRI) was used to guide the treatments and assess the tissue effects. The animals underwent neurological testing during treatment follow-up, and a follow-up MRI exam 1 week following the final treatment.

Results: The permeability of the BBB was successfully increased in all animals (mean enhancement: 19±11% relative to untreated hemisphere). There was a single adverse event in the chronic treatment group that resolved within 24 hrs. Follow-up MRI showed the BBB to be intact with no evidence of tissue damage in all animals. Histological analysis showed comparable levels of microhemorrhage between the treated and control hemispheres in the prefrontal cortex (single/repeat treatment: 1.0±1.4 vs 0.4±0.5/5.2±1.8 vs. 4.0±2.0). No significant differences were observed in beta-amyloid load (single/repeat: p=0.31/p=0.98) although 3/5 animals in each group showed lower Aβ loads in the treated hemisphere.

Conclusion: Whole-hemisphere opening of the BBB was well tolerated in the aged large animal brain. The treatment volumes and frequencies used are clinically relevant and indicate safety for clinical translation. Further study is warranted to determine if FUS has positive effects on naturally occurring amyloid pathology.

Keywords: Blood-Brain Barrier, Focused Ultrasound, Alzheimer's Disease

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How to cite this article:
O'Reilly MA, Jones RM, Barrett E, Schwab A, Head E, Hynynen K. Investigation of the Safety of Focused Ultrasound-Induced Blood-Brain Barrier Opening in a Natural Canine Model of Aging. Theranostics 2017; 7(14):3573-3584. doi:10.7150/thno.20621. Available from http://www.thno.org/v07p3573.htm