An ultrasound experiment tackles a huge problem in brain medicine

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

Researchers wondered if they could improve that grim result by trying something different: They would open the blood-brain barrier for a short time while delivering the drug. Their experimental method was to use highly focused ultrasound pulses along with tiny gas bubbles to pry open the barrier without destroying it.

The researchers at the Rockefeller Neuroscience Institute at West Virginia University, reported their 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 didn’t measure the amount of antibody that entered — that would require the drug to be radioactively labeled — but in animal studies, opening the barrier allowed 5 to 8 times more antibody to enter the brain, said Dr. Rezai.

The early-stage experiment, which was only attempted in three patients with mild Alzheimer’s, was funded by the university and the Harry T. Mangurian, Jr. Foundation.

It was a preliminary safety study – the first phase of the study – and not intended to measure clinical outcomes.

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

Researchers said it was an innovative but difficult approach to a problem created by Dr. Walter Koroshetz, director of the National Institute of Neurological Disorders and Stroke, considered one of the most challenging in treating brain diseases: how do you get drugs into the brain?

Antibodies such as the Alzheimer’s drug aducanumab, which the company Biogen sells under the name Aduhelm, are extremely expensive; Aduhelm’s listed price is $28,000 per year. One reason for the high price, said Dr. Koroshetz, is that only 1 percent of antibodies injected into the bloodstream slip past the blood-brain barrier.

However, it took more than a decade to find a safe way to open that barrier. Researchers understood how the barrier worked, but if you opened it without causing any damage, you only had to keep it open for a short time, due to its role in protecting the brain. It is a delicate part of the circulatory system and not what many people imagine based on the name.

“Many people think of it as something that is wrapped around the head,” like a turban for the brain, said Dr. Alexandra Golby, a professor of neurosurgery and radiology at Harvard Medical School.

Instead, the barrier is located at the ends of several large blood vessels that supply blood to the brain. As they enter the head, the vessels branch and divide until they form narrow capillaries with extremely tight walls at the ends. This barrier keeps large molecules out and allows small molecules such as glucose and oxygen to enter.

The challenge was to pry open those walls without tearing apart the capillaries.

The solution turned out to consist of two components. First, patients are injected with tiny microbubbles of perfluorocarbon gas. The bubbles reach inwards mate from 1.1 to 3.3 microns (a micron is approximately 0.000039 inches). Pulses of low-frequency ultrasound are then focused on the area of ​​the brain to be treated. The ultrasound pulses cause waves in the fluid in the blood vessels; the microbubbles expand rapidly and contract with the waves. This opens the blood vessels without damaging them, allowing access to the brain.

Microbubbles, said Dr. Golby, are routinely used in ultrasound studies of the heart and liver because they light up and reveal blood flow. They are filtered from the body by the kidneys and liver.

“They have 20 years of experience in safety,” she said.

For the experiment described in the new paper, researchers used ultrasound on one side of the brain, but not the other, for comparison, and then performed brain scans to check the results.

Although the focused ultrasound approach proved successful as an experiment, all was not rosy. The device is designed to deliver ultrasound to a small target area, but in Alzheimer’s disease, amyloid-containing plaque is everywhere in the brain.

“If you want to get amyloid out of the brain, you have to go in with a paintbrush, not a pencil,” said Dr. Koroshetz.

The researchers deliberately targeted brain areas involved in memory and reasoning, but it remains to be seen whether the treatment improves outcomes. That will require a larger investigation.

The Alzheimer’s study is just one of many studies opening the barrier to delivering drugs to patients with a variety of brain diseases.

They are all in early stages and so far all show that the method works; blocked medications come in.

One group, led by Dr. Nir Lipsman, a neurosurgeon at the University of Toronto’s Sunnybrook Research Institute, and his colleagues opened the barrier to delivering a chemotherapy drug to the brains of four breast cancer patients whose cancer had spread to the brain. The concentration of the drug, trastuzumab, increased fourfold, they said reported.

That work was funded by the Focused Ultrasound Foundation and sponsored by Insightec, which manufactures the ultrasound machine used.

Dr. Lipsman and his colleagues have now treated seven breast cancer patients and are expanding the study. They also conduct preliminary studies on a variety of brain diseases, including cancer, Parkinson, And IF.

Dr. Golby of Harvard Medical School and her colleagues have used the method to treat patients with glioblastoma, a deadly brain cancer.

One of the few chemotherapeutic agents that can enter the brain is temozolomide. But even this is largely blocked; only 20 percent cross the blood-brain barrier.

That’s why the medical center of Dr. Golby and several others received approval from the Food and Drug Administration to conduct a clinical trial, using focused ultrasound with microbubbles to deliver a larger portion of chemotherapy. It was funded by Insightec.

The patients did well, but the purpose of the study, which has not yet been published, was to assess the safety of the technique, not its efficacy, she said.

“I would love to see a trial of a drug that doesn’t normally get into the brain,” said Dr. Golby. There are many drugs that look good in laboratory studies but, she said, “complete failures” because they are blocked by the blood-brain barrier.

For the time being, however, questions remain, such as where in the brain the therapies should be targeted.

But, says Dr. Jon Stoessl, a Parkinson’s expert and professor of neurology at the University of British Columbia, says the method “resolves what has historically been a problem for anyone treating central nervous system disorders.”

Kullervo Hynynen, vice-president for research and innovation at Sunnybrook Research Institute in Toronto, is hopeful.

“If this works and is safe, it will open doors to a completely new way of treating the brain,” he said.