Preliminary results of a small study involving a new Alzheimer’s therapy have shown potential in the first human trials, and been described as “intriguing” by experts, who say the findings point to a need for larger, longer trials.
Researchers at the West Virginia University Rockefeller Neuroscience Institute (RNI) in the US found that by pairing focused ultrasound in combination with antibody therapies, they were able to accelerate the removal of amyloid-beta plaques from the brains of patients with Alzheimer’s disease.
The findings were published in the New England Journal of Medicine.
An abnormal build-up of amyloid-beta proteins is one of the hallmarks of Alzheimer’s, the proteins clumping together to form plaques that interfere with neurons in the brain.
Anti-amyloid-beta monoclonal antibody treatments, such as aducanumab and lecanemab, have proved effective in clearing these plaques and slowing disease progression.
But until now the drugs have been limited by the blood-brain barrier (BBB), designed to keep harmful substances from reaching the brain, reports Fox News.
More than 98% of drugs are blocked by the barrier, meaning patients require higher doses and more frequent therapies, the researchers noted.
In this study, scientists used a focused ultrasound (FUS) system to temporarily open the blood-brain barrier, allowing the antibodies to have greater access to areas of the brain with high amyloid-beta plaques.
After six months of antibody treatment, the study participants had an average of 32% more reduction in amyloid-beta plaques in areas where the BBB was opened compared with areas where the drug was used without the ultrasound.
“This was a first in human safety and feasibility study in three participants demonstrating that the BBB opening can accelerate clearance of beta amyloid plaques,” study lead Dr Ali Rezai, director of the RNI, said.
“Non-invasive focused ultrasound is an outpatient procedure that allows for targeted delivery of therapeutics to the brain that can potentially accelerate the benefit of the antibody treatment in Alzheimer’s,” he added.
For the study, three patients, aged between 59 and 77, all with mild Alzheimer’s disease, received six monthly infusions of the aducanumab antibody.
After each treatment, the focused ultrasound was used to open the BBB at the sites of the highest plaque build-up.
While there are some potential risks associated with ultrasound use, such as brain swelling and haemorrhage, Rezai said those effects were not observed in this study.
“We verified with MRI scans that the BBB opening was temporary, and it closed 24 to 48 hours after the FUS procedure,” he said.
The reductions in amyloid plaques were verified in PET scans.
This was the first step toward larger studies; in those, researchers will be able to evaluate more patients and larger areas of the brain, Rezai noted.
In the next phase of the clinical trial, the ultrasound therapy will be paired with lecanemab, another anti-beta amyloid antibody.
Dr James Galvin, director of the Comprehensive Centre for Brain Health at UHealth, the University of Miami Health System, who was not involved in the research, said the study was important “because it demonstrates there may be safe ways to increase drug delivery to the brain without any serious adverse effects”.
"Focused ultrasound has been used in other treatment paradigms for brain diseases, like Parkinson’s and brain tumours,” he said, but also cautioned that this research was conducted with only three patients and was not a placebo-controlled study.
“It was also designed as a safety study and not appropriately powered to detect significant clinical changes,” he added. “It is still too early to make any specific recommendations, but I am excited to see if there are planned follow-up studies with a larger number of patients.”
Rebecca Edelmayer, PhD, senior director of scientific engagement at the Alzheimer’s Association, who was also not involved in the study, called the results “very intriguing”.
She said while it was a “very small study of relatively short length”, it was a worthwhile way to test a “cutting-edge idea” for improving the effectiveness of Alzheimer’s medications, and that the results pointed to the need for larger-scale, longer trials.
Study details
Ultrasound Blood–Brain Barrier Opening and Aducanumab in Alzheimer’s Disease
Ali Rezai, Pierre-Francois D’Haese, Victor Finomore, et al.
Published in New England Journal of Medicine on 4 January 2024
Summary
Antiamyloid antibodies have been used to reduce cerebral amyloid-beta (Aβ) load in patients with Alzheimer’s disease. We applied focused ultrasound with each of six monthly aducanumab infusions to temporarily open the blood–brain barrier with the goal of enhancing amyloid removal in selected brain regions in three participants over a period of 6 months. The reduction in the level of Aβ was numerically greater in regions treated with focused ultrasound than in the homologous regions in the contralateral hemisphere that were not treated with focused ultrasound, as measured by fluorine-18 florbetaben positron-emission tomography. Cognitive tests and safety evaluations were conducted over a period of 30 to 180 days after treatment.
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