There are tough diseases to treat, and then there’s Alzheimer’s. After years of research, billions of dollars, and several hundred clinical trials, there are five FDA-approved drugs for Alzheimer’s, none of which can sustainably treat or reverse a patient’s inexorable decline. That has left Alzheimer’s researchers trying one drug candidate after another, and almost grasping for good news.
Finding a more effective drug is still imperative. It’s also essential to try novel approaches and leverage new technological innovations. Last week at the Rockefeller Neuroscience Institute at West Virginia University, we began testing a promising experimental therapy—one that involves no drugs and no surgery.
We have high hopes that the therapy, which uses a technique called magnetic resonance–guided focused ultrasound (MRgFUS), will one day help treat Alzheimer’s. We also think the technology will help the delivery of antibodies and medications to penetrate the blood-brain barrier, the biological seal that limits potential effective treatments from reaching their target tissue.
Forty-four million people worldwide, including 5.5 million Americans, currently have Alzheimer’s disease, and one in three people over 65 years of age will develop memory loss of some sort. That means the disease is becoming more common as our population ages, threatening a tidal wave of rising long-term care costs that could overwhelm families and swamp health care systems.
Thanks to yeoman’s work by the dedicated community of Alzheimer’s researchers, we have made significant progress in understanding the biology of the disease and improving the diagnosis of Alzheimer’s, but we have not seen commensurate progress for the treatment of this dreaded condition. There is an urgent need to find solutions. Fortunately, bioengineering and medical technology development are moving at lightning speed, creating exciting new opportunities to treat once intractable brain disorders.
Over the past two decades, our team and collaborators have conducted studies using new technologies such as a brain pacemaker to treat Parkinson’s disease, obsessive compulsive disorder and traumatic brain injury. MRgFUS is one of the most promising of these new advances that I have come across in my career. It’s already FDA-approved to treat tremors and is being actively tested on patients with a range of other neurological conditions, including obsessive-compulsive disorder, depression, Parkinson’s disease, epilepsy and brain tumors.
Opening the blood-brain barrier is one of the most encouraging applications of MRgFUS. The blood-brain barrier (BBB) allows small molecules to gain access to the brain and functions naturally to keep harmful substances out of the brain, while allowing nutrients to pass through and waste to be removed. Unfortunately, this protective function of the BBB also prevents the passage of larger molecules that compose or relate to medications, antibodies, the immune system and stem cells. Cracking the code to open the BBB safely and reversibly has been one of the most elusive quests for neuroscience researchers until now.
A growing body of studies is showing that MRgFUS can be a safe, reversible, and noninvasive method to open the blood-brain barrier. This technology uses over 1,000 ultrasound probes focusing their sound beams on a single point. Ultrasound beams penetrate the skin, the skull and the brain, as they do when examining a growing baby in a pregnant woman’s womb or evaluating the functioning of the heart. By using magnetic resonance imaging for guidance while holding a patient’s head still in an ultrasound helmet, we can focus the converging ultrasound waves precisely to a specific part of the brain. The tuning of the intensity of the ultrasound can also adjust its biological effects.
In earlier studies on mouse models with an Alzheimer’s-like condition, MRgFUS cleared up amyloid plaques and improved their memory. Last summer, researchers from Sunnybrook Health Sciences Centre in Toronto reported a phase I safety study in humans in Nature Communications. That trial focused on the frontal lobe of the brain and showed that MRgFUS was safe and reversibly opened up the blood brain barrier in six patients with Alzheimer’s.
Our procedures at WVU on October 16 and October 30 began the initial round of the first phase II trial of MRgFUS designed to test both the effectiveness and the safety of the therapy. Our patient, Judi, 61, had worked as a nurse and an educator in the neonatal intensive care unit until memory loss from early Alzheimer’s forced her to quit nursing. She is a pioneer in the treatment of Alzheimer’s who has bravely volunteered to be the first patient in the world to undergo focused ultrasound treatment in the hippocampus. She underwent MRI scans to target the hippocampus, the memory center of the brain, where Alzheimer’s plaques had accumulated.
We injected a solution of microscopic bubbles into her blood stream, then directed the focused ultrasound waves to her hippocampus. When the focused ultrasound hit the microscopic bubbles, they oscillated, temporarily opening the tightly connected endothelial cells that make up the blood-brain barrier. In Judi’s case, we showed that her BBB had in fact opened after the procedure; the following day, she returned home.
Although it’s clear MRgFUS improves memory in mice with an Alzheimer’s-like condition and reduces their plaques, the exact mechanism by which it does so remains unknown. Opening the BBB may allow the activation of the brain’s intrinsic immune system, or it may allow antibodies or cells to cross the barrier, or improve the efficiency of clearance out of the brain. Whatever the mechanism, we’re hopeful that the technique will prove effective for Alzheimer’s patients, though there is reason for caution because treatments that work in mice do not always work in people.
Applying technological innovations like MRgFUS to explore new treatment options is important for conditions such as Alzheimer’s for which there are no effective treatments or cures. Work at the intersection of modern health care and the latest technology should be done rapidly but responsibly. This is a complex endeavor and requires a multidisciplinary team of specialists. Preparing for last week’s procedure at the Rockefeller Neuroscience Institute tapped the skills and the collective efforts of more than 50 specialists, including engineers, neuroradiologists, MRI physicists, psychiatrists, neuroscientists and others. Developing this procedure into a standard treatment for Alzheimer’s will require much more research. Developing it into a standard treatment for other neurological disorders will require still more.
If the procedure works as we hope, physicians will be able to safely and noninvasively open the blood-brain barrier in targeted regions of the brain. This could usher in a wide variety of new therapies coupling ultrasound with targeted delivery of medications, antibodies and/or stem cells to significantly expand our armamentarium available to treat brain disorders. MRgFUS offers an exciting opportunity with great potential; however, more progress will be required to realize the full efficacy of opening the blood brain barrier.