Scientists Are Harnessing Sound Waves in Hopes of Treating Alzheimer’s
Researchers at Columbia University are testing an experimental treatment for Alzheimer's that uses ultrasound waves and "microbubbles."
In 2010, a 67-year-old former executive assistant for a Fortune 500 company was diagnosed with mild cognitive impairment. By 2014, her doctors confirmed she had Alzheimer's disease.
As her disease progressed, she continued to live independently but wasn't able to drive anymore. Today, she can manage most of her everyday tasks, but her two daughters are considering a live-in caregiver. Despite her condition, the woman may represent a beacon of hope for the approximately 44 million people worldwide living with Alzheimer's disease. The now 74-year-old is among a small cadre of Alzheimer's patients who have undergone an experimental ultrasound procedure aimed at slowing cognitive decline.
In November 2020, Elisa Konofagou, a professor of biomedical engineering and director of the Ultrasound and Elasticity Imaging Laboratory at Columbia University, and her team used ultrasound to noninvasively open the woman's blood-brain barrier. This barrier is a highly selective membrane of cells that prevents toxins and pathogens from entering the brain while allowing vital nutrients to pass through. This regulatory function means the blood-brain barrier filters out most drugs, making treating Alzheimer's and other brain diseases a challenge.
Ultrasound uses high-frequency sound waves to produce live images from the inside of the human body. But scientists think it could also be used to boost the effectiveness of Alzheimer's drugs, or potentially even improve brain function in dementia patients without the use of drugs.
The procedure, which involves a portable ultrasound system, is the culmination of 17 years of lab work. As part of a small clinical trial, scientists positioned a sensor transmitting ultrasound waves on top of the woman's head while she sat in a chair. The sensor sends ultrasound pulses throughout the target region. Meanwhile, investigators intravenously infused microbubbles into the woman to boost the effects of the ultrasound. Three days after the procedure, scientists scanned her brain so that they could measure the effects of the treatments. Five months later, they took more images of her brain to see if the effects of the treatment lasted.
Promising Signs
After the first brain scan, Konofagou and her team found that amyloid-beta, the protein that clumps together in the brains of Alzheimer's patients and disrupts cell function, had declined by 14%. At the woman's second scan, amyloid levels were still lower than before the experimental treatment, but only by 10% this time. Konofagou thinks repeat ultrasound treatments given early on in the development of Alzheimer's may have the best chance at keeping amyloid plaques at bay.
This reduction in amyloid appeared to halt the woman's cognitive decline, at least temporarily. Following the ultrasound treatment, the woman took a 30-point test used to measure cognitive impairment in Alzheimer's. Her score — 22, indicating mild cognitive impairment — remained the same as before the intervention. Konofagou says this was actually a good sign.
"Typically, every six months an Alzheimer's patient scores two to three points lower, so this is highly encouraging," she says.
Konofagou speculates that the results might have been even more impressive had they applied the ultrasound on a larger section of the brain at a higher frequency. The selected site was just 4 cubic centimeters. Current safety protocols set by the U.S. Food and Drug Administration stipulate that investigators conducting such trials only treat one brain region with the lowest pressure possible.
The Columbia trial is aided by microbubble technology. During the procedure, investigators infused tiny, gas-filled spheres into the woman's veins to enhance the ultrasound reflection of the sound waves.
The big promise of ultrasound is that it could eventually make drugs for Alzheimer's obsolete.
"Ultrasound with microbubbles wakes up immune cells that go on to discard amyloid-beta," Konofagou says. "In this way, we can recover the function of brain neurons, which are destroyed by Alzheimer's in a sort of domino effect." What's more, a drug delivered alongside ultrasound can penetrate the brain at a dose up to 10 times higher.
Costas Arvanitis, an assistant professor at Georgia Institute of Technology who studies ultrasonic biophysics and isn't involved in the Columbia trial, is excited about the research. "First, by applying ultrasound you can make larger drugs — picture an antibody — available to the brain," he says. Then, you can use ultrasound to improve the therapeutic index, or the ratio of the effectiveness of a drug versus the ratio of adverse effects. "Some drugs might be effective but because we have to provide them in high doses to see significant responses they tend to come with side effects. By improving locally the concentration of a drug, you open up the possibility to reduce the dose."
The Columbia trial will enroll just six patients and is designed to test the feasibility and safety of the approach, not its efficacy. Still, Arvantis is hopeful about the potential benefits of the technique. "The technology has already been demonstrated to be safe, its components are now tuned to the needs of this specific application, and it's safe to say it's only a matter of time before we are able to develop personalized treatments," he says.
Konofagou and her colleagues recently presented their findings at the 20th Annual International Symposium for Therapeutic Ultrasound and intend to publish them in a scientific journal later this year. They plan to recruit more participants for larger trials, which will determine how effective the therapy is at improving memory and brain function in Alzheimer's patients. They're also in talks with pharmaceutical companies about ways to use their therapeutic approach to improve current drugs or even "create new drugs," says Konofagou.
A New Treatment Approach
On June 7, the FDA approved the first Alzheimer's disease drug in nearly two decades. Aducanumab, a drug developed by Biogen, is an antibody designed to target and reduce amyloid plaques. The drug has already sparked immense enthusiasm — and controversy. Proponents say the drug is a much-needed start in the fight against the disease, but others argue that the drug doesn't substantially improve cognition. They say the approval could open the door to the FDA greenlighting more Alzheimer's drugs that don't have a clear benefit, giving false hope to both patients and their families.
Konofagou's ultrasound approach could potentially boost the effects of drugs like aducanumab. "Our technique can be seamlessly combined with aducanumab in early Alzheimer's, where it has shown the most promise, to further enhance both its amyloid load reduction and further reduce cognitive deficits while using exactly the same drug regimen otherwise," she says. For the Columbia team, the goal is to use ultrasound to maximize the effects of aducanumab, as they've done with other drugs in animal studies.
But Konofagou's approach could transcend drug controversies, and even drugs altogether. The big promise of ultrasound is that it could eventually make drugs for Alzheimer's obsolete.
"There are already indications that the immune system is alerted each time ultrasound is exerted on the brain or when the brain barrier is being penetrated and gets activated, which on its own may have sufficient therapeutic effects," says Konofagou. Her team is now working with psychiatrists in hopes of using brain stimulation to treat patients with depression.
The potential to modulate the brain without drugs is huge and untapped, says Kim Butts Pauly, a professor of radiology, electrical engineering and bioengineering at Stanford University, who's not involved in the Columbia study. But she admits that scientists don't know how to fully control ultrasound in the brain yet. "We're only at the starting point of getting the tools to understand and harness how ultrasound microbubbles stimulate an immune response in the brain."
Meanwhile, the 74-year-old woman who received the ultrasound treatment last year, goes on about her life, having "both good days and bad days," her youngest daughter says. COVID-19's isolation took a toll on her, but both she and her daughters remain grateful for the opportunity to participate in the ultrasound trial.
"My mother wants to help, if not for herself, then for those who will follow her," the daughter says. She hopes her mother will be able to join the next phase of the trial, which will involve a drug in conjunction with the ultrasound treatment. "This may be the combination where the magic will happen," her daughter says.
Urinary tract infections account for more than 8 million trips to the doctor each year.
Few things are more painful than a urinary tract infection (UTI). Common in men and women, these infections account for more than 8 million trips to the doctor each year and can cause an array of uncomfortable symptoms, from a burning feeling during urination to fever, vomiting, and chills. For an unlucky few, UTIs can be chronic—meaning that, despite treatment, they just keep coming back.
But new research, presented at the European Association of Urology (EAU) Congress in Paris this week, brings some hope to people who suffer from UTIs.
Clinicians from the Royal Berkshire Hospital presented the results of a long-term, nine-year clinical trial where 89 men and women who suffered from recurrent UTIs were given an oral vaccine called MV140, designed to prevent the infections. Every day for three months, the participants were given two sprays of the vaccine (flavored to taste like pineapple) and then followed over the course of nine years. Clinicians analyzed medical records and asked the study participants about symptoms to check whether any experienced UTIs or had any adverse reactions from taking the vaccine.
The results showed that across nine years, 48 of the participants (about 54%) remained completely infection-free. On average, the study participants remained infection free for 54.7 months—four and a half years.
“While we need to be pragmatic, this vaccine is a potential breakthrough in preventing UTIs and could offer a safe and effective alternative to conventional treatments,” said Gernot Bonita, Professor of Urology at the Alta Bro Medical Centre for Urology in Switzerland, who is also the EAU Chairman of Guidelines on Urological Infections.
The news comes as a relief not only for people who suffer chronic UTIs, but also to doctors who have seen an uptick in antibiotic-resistant UTIs in the past several years. Because UTIs usually require antibiotics, patients run the risk of developing a resistance to the antibiotics, making infections more difficult to treat. A preventative vaccine could mean less infections, less antibiotics, and less drug resistance overall.
“Many of our participants told us that having the vaccine restored their quality of life,” said Dr. Bob Yang, Consultant Urologist at the Royal Berkshire NHS Foundation Trust, who helped lead the research. “While we’re yet to look at the effect of this vaccine in different patient groups, this follow-up data suggests it could be a game-changer for UTI prevention if it’s offered widely, reducing the need for antibiotic treatments.”
MILESTONE: Doctors have transplanted a pig organ into a human for the first time in history
A surgeon at Massachusetts General Hospital prepares a pig organ for transplant.
Surgeons at Massachusetts General Hospital made history last week when they successfully transplanted a pig kidney into a human patient for the first time ever.
The recipient was a 62-year-old man named Richard Slayman who had been living with end-stage kidney disease caused by diabetes. While Slayman had received a kidney transplant in 2018 from a human donor, his diabetes ultimately caused the kidney to fail less than five years after the transplant. Slayman had undergone dialysis ever since—a procedure that uses an artificial kidney to remove waste products from a person’s blood when the kidneys are unable to—but the dialysis frequently caused blood clots and other complications that landed him in the hospital multiple times.
As a last resort, Slayman’s kidney specialist suggested a transplant using a pig kidney provided by eGenesis, a pharmaceutical company based in Cambridge, Mass. The highly experimental surgery was made possible with the Food and Drug Administration’s “compassionate use” initiative, which allows patients with life-threatening medical conditions access to experimental treatments.
The new frontier of organ donation
Like Slayman, more than 100,000 people are currently on the national organ transplant waiting list, and roughly 17 people die every day waiting for an available organ. To make up for the shortage of human organs, scientists have been experimenting for the past several decades with using organs from animals such as pigs—a new field of medicine known as xenotransplantation. But putting an animal organ into a human body is much more complicated than it might appear, experts say.
“The human immune system reacts incredibly violently to a pig organ, much more so than a human organ,” said Dr. Joren Madsen, director of the Mass General Transplant Center. Even with immunosuppressant drugs that suppress the body’s ability to reject the transplant organ, Madsen said, a human body would reject an animal organ “within minutes.”
So scientists have had to use gene-editing technology to change the animal organs so that they would work inside a human body. The pig kidney in Slayman’s surgery, for instance, had been genetically altered using CRISPR-Cas9 technology to remove harmful pig genes and add human ones. The kidney was also edited to remove pig viruses that could potentially infect a human after transplant.
With CRISPR technology, scientists have been able to prove that interspecies organ transplants are not only possible, but may be able to successfully work long term, too. In the past several years, scientists were able to transplant a pig kidney into a monkey and have the monkey survive for more than two years. More recently, doctors have transplanted pig hearts into human beings—though each recipient of a pig heart only managed to live a couple of months after the transplant. In one of the patients, researchers noted evidence of a pig virus in the man’s heart that had not been identified before the surgery and could be a possible explanation for his heart failure.
So far, so good
Slayman and his medical team ultimately decided to pursue the surgery—and the risk paid off. When the pig organ started producing urine at the end of the four-hour surgery, the entire operating room erupted in applause.
Slayman is currently receiving an infusion of immunosuppressant drugs to prevent the kidney from being rejected, while his doctors monitor the kidney’s function with frequent ultrasounds. Slayman is reported to be “recovering well” at Massachusetts General Hospital and is expected to be discharged within the next several days.