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

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.

Sonodynamic therapy induces oxidative stress, DNA damage and apoptosis in glioma cells

“…3 Opening the BBB by using ultrasound has recently attracted many researchers' attention, because this process is reversible and nondestructive, minimizing damage to surrounding normal brain tissues. [4][5][6] Leinenga et al have reported that scanning ultrasound can transiently open the BBB in order to remove amyloid-b peptide and restore the memory of a mouse model of Alzheimer's disease. 7 Landhuis proposed the technique of transcranial ultrasound modulation, which has brought new hope to the treatment of many brain diseases.…”

MRI and histological evaluation of pulsed focused ultrasound and microbubbles treatment effects in the brain

“…pFUS+MB BBBD studies continue to require optimization of the FUS parameter feature space (i.e., FUS transducer frequency, PNP, US burst duration, pulse repetition frequency, numbers of focal targets, MB size, dose and infusion rate) in order to adequately deliver agents or cover the canvas of brain pathology to stimulate an endogenous response that may improve functional outcomes 45 , 47 , 49 , 52 - 54 . Moreover, consistency in the MRI acquisitions (i.e., Gd dose, slice thickness, T1w, T2w and T2*w imaging parameters) across studies is needed to ensure that pathological changes in the targeted brain are not overlooked.…”

Time course of focused ultrasound effects on β-amyloid plaque pathology in the TgCRND8 mouse model of Alzheimer’s disease

“…An acoustic controller increases pressures until microbubble emissions that are characteristic of stable cavitation are detected, thereby increasing BBB permeability and remaining below the threshold for tissue damage 48 , 49 . Using this method, successful BBB opening has been achieved in various animal models 17 , 48 , 50 without causing edema, vacuolations, or neuronal loss, and with minimal to no erythrocyte extravasation 48 .…”