A tightly packed assembly of cells including astrocytes (green) forms the barrier between blood vessels (black) and neurons (red).

A tightly packed assembly of cells including astrocytes (green) forms the barrier between blood vessels (black) and neurons (red).

C. J. GUERIN, MRC TOXICOLOGY UNIT/SCIENCE SOURCE

Ultrasound therapies target brain cancers and Alzheimer’s disease

From imaging babies to blasting apart kidney stones, ultrasound has proved to be a versatile tool for physicians. Now, several research teams aim to unleash the technology on some of the most feared brain diseases.

The blood-brain barrier, a tightly packed layer of cells that lines the brain's blood vessels, protects it from infections, toxins, and other threats but makes the organ frustratingly hard to treat. A strategy that combines ultrasound with microscopic blood-borne bubbles can briefly open the barrier, in theory giving drugs or the immune system access to the brain. In the clinic and the lab, that promise is being evaluated.

This month, in one of the first clinical tests, Todd Mainprize, a neurosurgeon at the University of Toronto in Canada, hopes to use ultrasound to deliver a dose of chemotherapy to a malignant brain tumor. And in some of the most dramatic evidence of the technique's potential, a research team reports this week in Science Translational Medicine that they used it to rid mice of abnormal brain clumps similar to those in Alzheimer's disease, restoring lost memory and cognitive functions. If such findings can be translated from mice to humans, “it will revolutionize the way we treat brain disease,” says biophysicist Kullervo Hynynen of the Sunnybrook Research Institute in Toronto, who originated the ultrasound method.

Some scientists stress that rodent findings can be hard to translate to humans and caution that there are safety concerns about zapping the brain with even the low-intensity ultrasound used in the new study, which is similar to that used in diagnostic scans. Opening up the blood-brain barrier just enough to get a beneficial effect without scorching tissue, triggering an excessive immune reaction, or causing hemorrhage is the “crux,” says Brian Bacskai, a neurologist at Massachusetts General Hospital in Boston who studies Alzheimer's disease and used to work with Hynynen.

Safely and temporarily opening the blood-brain barrier is a long-sought goal in medicine. About a decade ago, Hynynen began exploring a strategy combining ultrasound and microbubbles. The premise is that ultrasound causes such bubbles to expand and contract, jostling the cells forming the blood-brain barrier and making it slightly leaky.

EMMANUEL THÉVENOT/LAB OF ISABELLE AUBERT; COURTESY OF SUNNYBROOK RESEARCH INSTITUTE


That could help cancer physicians such as Mainprize deliver chemotherapy drugs into the brain. Hynynen also hypothesized that the brief leakage would rev up the brain's inflammatory response against β amyloid—the toxic protein that clumps outside neurons in Alzheimer's and may be responsible for killing them. Disposing of such debris is normally the role of the microglia, a type of brain cell. But previous studies have shown that when β amyloid forms clumps in the brain, it “seems to overwhelm microglia,” Bacskai says. Exposing the cells to anti bodies that leak in when the blood-brain barrier is breached could spur them to “wake up and do their jobs,” he says. Some antibodies in blood may also bind directly to the β-amyloid protein and flag the clumps for destruction.

Hynynen and others have recently tested the ultrasound strategy in a mouse model of Alzheimer's. In December 2014, for example, he and colleagues reported in Radiology that the method reduces amyloid plaques in a strain of mice engineered to develop the deposits, leading to improvements in cognition and spatial learning. Microglia consumed more β amyloid after the treatment, suggesting the cells do play a role in the effect, says neuroscientist Isabelle Aubert, who collaborates with Hynynen at Sunnybrook.

This week, neuroscientist Jürgen Götz of the Queensland Brain Institute in St. Lucia, Australia, and his Ph.D. student Gerhard Leinenga report that they have built on Hynynen and Aubert's protocol, using a different mouse model of Alzheimer's. After injecting these animals with a solution of microscopic bubbles, they scanned an ultrasound beam in a zigzag pattern across each animal's entire skull, rather than focusing on discrete areas as others have done. After six to eight weekly treatments, the team tested the rodents on three different memory tasks. Alzheimer's mice in the control group, which received microbubble injections but no stimulation, showed no improvement. Mice whose blood-brain barriers had been made permeable, in contrast, saw “full restoration of memory in all three tasks,” Götz says.

The team also found a two- to fivefold reduction in different types of β-amyloid plaques in the brain tissue of the treated group. The attempt to stoke microglia's appetite appeared to work; Götz and Leinenga found much more β-amyloid protein within the trash-eating cells of treated animals. Yet rousing microglia may not be the only mechanism responsible for the rodents' memory boost, Aubert notes. She and Hynynen recently reported in Brain Stimulation that ultrasound also boosts the birth and growth of new neurons in mice.

Götz and Leinenga next plan to test the whole-brain ultrasound scan method in larger animals with β-amyloid deposits, such as sheep. The approach, which could in theory be used for other brain diseases involving abnormal protein clumps, “is exciting,” says Gerald Grant, a neurosurgeon at the Stanford University School of Medicine in Palo Alto, California. “We've been thinking of opening up the blood-brain barrier as a way to get things into the brain, but this pays attention to getting things out.”

It's far from settled that eliminating β-amyloid deposits outside of neurons is the key to treating or stopping Alzheimer's disease, however. And Bacskai is skeptical that the mouse results say much about the technique's potential in humans. The range between a mouse that can learn and one that cannot learn “is pretty small,” so big gains in behavioral tests in mice may mean nothing in humans, he says. He adds that nonstandardized ultrasound equipment makes it hard to answer basic safety questions: “How long is the blood-brain barrier open? How big are the pores? What's the damage?”

Hynynen, who is working with a medical imaging company to commercialize the technique, notes that ultrasound application to the brains of animals including rabbits and monkeys has produced no negative side effects. And Mainprize's clinical trial may provide more safety data. He hopes to open the blood-barrier to increase chemotherapy delivery to a brain cancer patient just before he operates to remove the tumor. Using Hynynen's technology, he and colleagues will apply ultrasound and microbubbles to tissue in and around the tumor, as well as to several unaffected brain areas. Then they'll examine excised tissue for hemorrhages and to see if the treatment boosted the concentration of the drug. A similar trial is now recruiting participants in France.

If these phase I trials establish safety, “it opens the door for phase II trials looking to see if there's any benefit” to opening the blood-brain barrier, including for conditions beyond cancer, Mainprize says. Despite his doubts, Bacskai can't fully resist the dream driving this fledging field. “Imagine if your grandmother went to the clinic once per year, and it cleared amyloid β and that was all it took—no surgery, no drugs. It would be amazing.”