Focused ultrasound safely opens BBB in Alzheimer’s patients

Magnetic resonance-guided focused ultrasound (MRgFUS) can be used to safely open the blood-brain barrier (BBB) in patients with Alzheimer’s disease, researchers from Sunnybrook Health Sciences Centre of the University of Toronto in Ontario announced at the Alzheimer’s Association International Conference (AAIC) held in Chicago in July. Findings of this landmark phase 1 pilot trial to demonstrate the technical feasibility and preliminary clinical safety of focally, reversibly, and repetitively opening BBB were presented at AAIC and published online July 25th in Nature Communications.

The BBB surrounds the small blood vessels of the brain to protect it from toxins and infectious agents, but also blocks the effective delivery of therapeutic compounds to the brain. Preclinical research has demonstrated that MRgFUS has the ability to open the BBB with a high degree of spatial and temporal specificity when coupled with injected microbubbles.

The research team enrolled five patients with mild-to-moderate stage Alzheimer’s disease and demonstrated amyloid deposition in the area of the brain being targeted. The primary objective of the open-label, prospective, proof-of-concept trial was to evaluate the clinical safety and technical feasibility of using non-invasive MRgFUS and also to measure the influence on clinical and beta-amyloid imaging markers of Alzheimer’s disease.

A MRI scan was performed for surgical planning, with a region of white matter in the right frontal lobe selected for BBB opening. Once a target region was identified, patients received a weight-based intravenous injection of microbubble contrast followed by an application of low-frequency focused ultrasound to the target. Tissue temperature at the sonicated region was monitored in real time with MR thermography and a power ramp test was performed with the first microbubble injection at each new target to determine the optimal power required for safe opening of the BBB. All five patients successfully completed the first procedure.

Co-principal investigator Nir Lipsman, MD, PhD, Director of the Harquail Centre for Neuromodulation, reported that the average maximum sonication power was 4.6W with an average of 3.6 sonications administered for stage 1 for five patients and 4.5W for 7.5 sonications for stage 2 for four patients. The BBB opening was achieved at approximately 50% power. The combination of injected microbubbles and focused ultrasound opened the BBB within seconds with a high degree of specificity and accuracy. T1-weighted images taken immediately after the sonication showed a discreet rectangular-shaped gadolinium contrast extravasation within the 10 x 10 x 7 mm³ sonicated volume in the right frontal lobe. This demonstrated increased BBB permeability. Resolution of enhancement indicating closure of the BBB was visible 24 hours following the procedure.

One patient did not undergo the second stage of the study performed one month later due to an unrelated respiratory illness. The patients tolerated the procedures well and none experienced serious adverse events. “Acoustic feedback monitoring, contrast enhanced MR images, and physical examinations between sonication were key in determining a safe power for BBB opening and detecting any adverse events such as bleeding,” wrote the authors.

The factors which the authors cited to achieved uniform BBB opening included:

• Use of a ramp test to determine the optimal power;
• Volume and type of tissue targeted;
• Microbubble size and dose;
• Microbubble handling; and,
• Coordination between sonication and microbubble injection.

“While it is still early in development, in the future focused ultrasound may provide a non-invasive, effective way of delivering large molecules such as antibodies or even stem cells directly to the brain to help patients with Alzheimer’s,” said co-principal investigator Sandra Black, MD, professor of medicine (neurology) and director of the brain sciences program at Sunnybrook Research Institute. “We are pioneering exciting potential innovative treatment options for patients.”

A phase 2a clinical trial to continue the investigation of safety and efficacy using focused ultrasound to breach the BBB in a larger group of Alzheimer’s patients will begin in the fall.

REFERENCE

1. Lipsman N, Meng Y, Bethune AJ, et al. Blood-brain barrier opening in Alzheimer’s disease using MR-guided focused ultrasound. Nat Commun. 2018 9(1):23362018.