Saturday, March 25, 2017
Focused Ultrasound Trialed for Alzheimer's Disease
Image Source: GIGAMEN
Aim is to modulate blood-brain barrier to make anti-amyloid drugs more effective
Researchers have successfully used focused beams of ultrasound to open the blood-brain barrier in patients with Alzheimer's disease, the first step in a study to see whether the technology can facilitate ablation of beta-amyloid plaques associated with the illness.
The aim is to make the blood-brain barrier more permeable so as to help amyloid-scavenging drugs such as antibodies reach the plaques.
"We treated the first two Alzheimer's patients yesterday, and things went well. We were able to open the blood-brain barrier successfully," the study's principal investigator, Nir Lipsman, MD, PhD, a neurosurgeon at Sunnybrook Health Sciences Centre in Toronto, said in an email Friday. "Both are doing well so far."
This is the first such use in humans of focused ultrasound to treat Alzheimer's disease, Lipsman said in an interview. The main objective of this phase I trial is to show that the technique is safe.
"If it is safe and technically feasible, subsequent study would combine focused ultrasound with an [anti-amyloid] agent that has trouble crossing the blood-brain barrier," he said. He cited a study in Nature last August that showed in mice that anti-amyloid antibodies can reduce amyloid and stabilize cognitive deficits. "Question is whether enhancing antibody delivery can improve on these results," he said in an email.
Alzheimer specialists not involved in the study were divided over whether this is an appropriate time to begin trials with humans, or whether more work should be done in animals first.
Samuel Gandy, MD, PhD, of Mount Sinai Hospital in New York City, said in an email that while focused ultrasound has been shown to be helpful in treating essential tremor, "brain regions involved in cognition, especially brain regions like the hippocampus that are performing poorly, may not tolerate the insult so well."
Such techniques are better at silencing overactive brain regions than improving function, he said. And he suggested that before moving to human trials, the technique should have been tested in dogs with an Alzheimer's-like condition called CCD (canine cognitive disorder) or in aged nonhuman primates.
Steven DeKosky, MD, of the University of Florida who has worked with Lipsman in the past, disagreed. "I don't think it's premature from the standpoint of the science," he said. Focused ultrasound has been approved for use in the treatment of essential tremor, he said, so "we know the technique can be used in humans safely." He described Lipsman's study as an "extraordinary clever" method of getting anti-Alzheimer medications to their target in the brain.
One concern is whether amyloid plaques could be removed in enough areas of the brain to affect symptoms. "The biggest problem is the cortex is big and the area of focus is small," he said.
David Knopman, MD, of the Mayo Clinic in Rochester, Minn., said he was not familiar with the Lipsman study, but he expressed similar reservations about human trials. Before studies are done in humans, he said, "there should be a clear understanding of what the target is and what the relationship is between the therapeutic target and the desired outcome -- which would be cognitive improvement or cognitive stability."
In this case, he pointed out, the target -- the amyloid plaques -- might have no relationship to the desired outcome.
Lipsman said his study "is the culmination of a few decades of research in animals," including some 200 studies on blood-brain barrier opening with focused ultrasound. "We felt it had reached the threshold where a phase I study was justified."
The study raises two important questions. One is whether it makes sense to go after amyloid when there are questions about the link between amyloid and Alzheimer's disease.
The so-called amyloid hypothesis in Alzheimer's has suffered a series blows in recent clinical trials of anti-amyloid drugs -- none of which have made any impact on cognition in patients with definitely Alzheimer's disease -- but opinion is divided over whether or not it should be abandoned. If the amyloid hypothesis is discarded, Lipsman's study would need to be re-evaluated.
"The amyloid hypothesis has more data by far than any other hypothesis," said DeKosky. "The problem is that there isn't any other hypothesis." Amyloid can appear in the brain years before patients begin showing symptoms. On the other hand, genetic studies have linked mutations in amyloid to Alzheimer's disease symptoms. And the failure of anti-amyloid drugs might simply mean "we have the wrong dose or the wrong drug."
The other question about Lipsman's study concerns the role of the Focused Ultrasound Foundation, based in Charlottesville, Va., which is dedicated to expanding uses of the technology. The group aggressively promotes the use of focused ultrasound for some 80 conditions, including Alzheimer's disease, Parkinson's disease, uterine fibroids, atrial fibrillation, congestive heart failure, depression, diabetes, obesity, cancers of the prostate, kidneys, pancreas, bladder, breast and dozens more illnesses, most at early stages of development.
The foundation is supporting Lipsman's phase I trial, which will include six patients. In the U.S., focused ultrasound has been approved by the FDA for essential tremor, uterine fibroids, pain from bone metastases, and ablation of prostate tissue in cancer or BPH, the foundation says.
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