In the first peer-reviewed published report of its kind, Sunnybrook researchers have achieved a critical first step in demonstrating that focused ultrasound can be used to safely open the blood-brain barrier (BBB) in patients with Alzheimer’s disease.
The study, “Blood-Brain Barrier Opening in Alzheimer’s Disease Using MR-guided Focused Ultrasound,” has been published in Nature Communications.
The clinical team made history by being the first in the world to demonstrate that they can open the BBB safely and non-invasively in patients with Alzheimer’s disease, in their phase 1 trial which began in May 2017.
The research didn’t just prove what they set out to do – their investigation also led to a unique finding.
Dr. Nir Lipsman is the study’s lead author and Director of the Harquail Centre for Neuromodulation at Sunnybrook Health Sciences Centre.
Dr. Sandra Black, the study co-principal investigator is an internationally renowned Professor of Medicine (Neurology) at Sunnybrook and the University of Toronto.
What is the blood-brain barrier?
Dr. Lipsman: The blood-brain barrier is a physical barrier comprised of cells that physically prevents compounds circulating in the bloodstream from entering the brain. In many ways, this is good, because we want to prevent a lot of dangerous things from getting into the brain unnecessarily. But the barrier also blocks potentially useful things from accessing the brain as well, including medications, antibodies, chemotherapy agents or potentially effective treatments for brain disorders like Alzheimer’s disease. As a result, there may be effective treatments for brain conditions but we can’t get them into the brain in sufficient concentrations to have an effect.
How is focused ultrasound used to open the blood-brain barrier?
Dr. Black: MRI-guided low frequency ultrasound (sound waves) can target small blood vessels precisely in a specific area of the brain. Microscopic bubbles along with the ultrasound are timed exactly when they’re reaching the specific area of the brain, to open up the blood-brain barrier. The ultrasound causes the microbubbles to gently loosen cells that make up the BBB and create a small opening. We are pioneering exciting potential innovative treatment options for patients.
What has your study investigation determined?
Dr. Lipsman: This is an exciting world first. We recruited, enrolled and treated six patients in a phase one trial where we opened the blood brain barrier in a very discreet part of the brain in patients with mild to moderate Alzheimer’s disease. The goal was to demonstrate that the blood brain barrier could be opened safely, and that it could be done reversibly and repeatedly over time..”
Dr. Black: We even saw something very unique. For the first time live in an human being we could see some of the contrast (called gadolinium) injected into the blood going into the brain and then exiting through the spaces along the walls of the small vessels, which are called perivascular spaces.
Past research has determined that the perivascular spaces seem to serve as a pathway that gets toxins, like amyloid – the rogue protein in Alzheimer’s disease – out of the brain. It’s the brain’s lymphatic system, only discovered a few years ago. Seeing this during our study was gratifying as it actually proves the spaces are there. We know this disposal is happening, but to actually see the perivascular spaces doing their job was very cool.
View video about this world first and meet the first patient:
How will this impact patients?
Dr. Lipsman: Opening the blood-brain barrier is still highly investigational. Publishing our Phase 1 results in Nature Communications is a critical first step.
We have now developed a phase 2 trial in Alzheimer’s that we hope will be ready to recruit patients in the Fall. The plan is to expand the number of patients to 30, and provide additional safety data of focused ultrasound blood-brain barrier opening in Alzheimer’s.
The pursuit of a safe and reversible means of temporarily and safely overcoming the blood brain barrier has been a major goal for clinicians and scientists for decades. We can now, with sub-millimeter accuracy, choose in which part of the brain we want to open the blood brain barrier and so safely and efficiently. For patients, it can mean a safe strategy to deliver potentially effective treatments to the brain down the road.
Dr. Black: The phase 2 study will involve focally opening the blood-brain barrier at the same time in several brain regions affected by Alzheimer’s disease. If that goes well, the next step would be to introduce large molecules, such as antibodies against plaques and tangles, the toxic brain deposits associated with Alzheimer’s disease. Only a small percentage of such antibodies infused through a vein would otherwise get into the brain, so periodic openings could more effectively remove these deposited proteins.