Ultrasound experiment tackles giant problem in brain medicine

The effects of drugs that treat Alzheimer's disease, cancer and other diseases are often limited by the blood-brain barrier. Small study suggests a path forward.

There's a problem with the recently approved Alzheimer's drug, Aduhelm. It can remove some of the amyloid that forms the brain plaques characteristic of the disease. But most of the medicine is wasted because it hits an obstacle, the blood-brain barrier, which protects the brain from toxins and infections but also prevents many drugs from entering.

The researchers wondered if they could improve this dismal outcome by trying something different: They would open the blood-brain barrier for a short time while they administered the drug. Their experimental method involved using highly targeted pulses of ultrasound along with tiny gas bubbles to open the barrier without destroying it.

Rockefeller Neuroscience Institute investigators at West The University of Virginia reported its results last week in the New England Journal of Medicine. When the barrier was opened, 32 percent more plaque was dissolved, said Dr. Ali Rezai, a neurosurgeon at the institute, who led the study. The group did not measure the amount of antibodies penetrating – this would require radioactive labeling of the drug – but in animal studies, opening the barrier allowed 5 to 8 times more antibodies to enter the brain, Dr. Rezai said.

The early-stage experiment, which was only attempted on three patients with a mild form of Alzheimer's, was funded by the university and the Harry T. Mangurian, Jr. Foundation

This was a preliminary safety study — the first step in research — and not designed to measure clinical outcomes.

But when the results were presented at a recent meeting, “our mouths dropped open,” said Dr. Michael Weiner, an Alzheimer's disease researcher at the University of California, San Francisco, who was not involved in the study.

The researchers said it was an innovative but challenging approach to a problem that Dr. Walter Koroshetz, director of the National Institute of Neurological Disorders and Stroke, considered one of the most difficult in treating brain diseases: how to get drugs into the brain? Antibodies like the Alzheimer's drug aducanumab, which the company Biogen sells under the name of Aduhelm, are extremely expensive; Aduhelm's sticker price is $28,000 per year. One reason for the high price, Dr. Koroshetz explained, is that only 1% of antibodies injected into the bloodstream pass the blood-brain barrier.

Find a safe product However, it took more than a decade to open this barrier. Investigators understood how the barrier worked, but opening it without causing damage meant keeping it open for a short time, due to its role in protecting the brain. It is a fragile part of the circulatory system and is not what many people imagine based on its name.

“Many people view it as a thing that wraps itself around itself. the head,” like a turban for the brain, said Dr. Alexandra Golby, professor of neurosurgery and radiology at Harvard Medical School.

Instead, the barrier is at head level. ends of several major blood vessels that supply the brain. As they enter the head, the vessels branch and divide until they form, at their ends, narrow capillaries with extremely tight walls. This barrier prevents large molecules from entering and allows small molecules like glucose and oxygen to enter.

The challenge was to open these walls without tearing the capillaries.

The solution was found to have two components. First, patients are injected with tiny microbubbles of perfluorocarbon gas. Bubble sizes range from 1.1 to 3.3 microns (one micron is approximately 0.000039 inch.) Next, ultra low frequency pulses...