Aducanumab (Aduhelm) infusions combined with focused ultrasound led to lower cerebral amyloid-beta levels in Alzheimer’s disease, a proof-of-concept trial showed.
The investigational treatment involved creating an opening in the blood-brain barrier with MRI-guided focused ultrasound to boost drug delivery.
In each of three participants who received aducanumab infusions, amyloid reduction was greater in brain regions targeted with focused ultrasound than in regions not exposed to focused ultrasound, said Ali Rezai, MD, of West Virginia University in Morgantown, and co-authors in a New England Journal of Medicine brief report.
From baseline to the 26-week assessment, PET scans showed that focused ultrasound combined with aducanumab led to a drop in amyloid levels from 224.2 to 115.2 centiloids in participant 1, from 185.6 to 104.6 centiloids in participant 2, and from 251.5 to 84.9 centiloids in participant 3. Contralateral brain regions that did not have focused ultrasound showed little change in amyloid levels from baseline to 26 weeks.
“We observed an average 32% reduction in SUVR [standardized uptake value ratio] for the three participants combined after 26 weeks in the regions that had received treatment to open the blood-brain barrier and six combination treatments,” Rezai and colleagues wrote.
Headaches were the most common adverse events and were mild except for one moderate headache. One participant had two severe adverse events during the focused ultrasound treatment due to discomfort with head and neck positioning; this resolved immediately after the procedure. No amyloid-related imaging abnormalities were seen.
Low-intensity focused ultrasound has reversibly opened the blood-brain barrier in people with Alzheimer’s disease or other neurologic disorders, including Parkinson’s disease, brain tumors, and amyotrophic lateral sclerosis.
Previous work by Rezai’s group showed that focused ultrasound alone — without a therapeutic agent like aducanumab — slightly reduced amyloid-beta levels, noted Kullervo Hynynen, PhD, of the University of Toronto in Canada. “The reduction observed in the current trial was numerically greater than in the previous studies,” he wrote in an accompanying editorial.
“The blood-brain barrier safeguards the brain from harmful substances while allowing essential nutrients to pass through,” Hynynen said. “However, it also impedes the delivery of drugs to the brain.”
The three participants were a 77-year-old man (participant 1), a 59-year-old man (participant 2), and a 64-year-old woman (participant 3). All received a diagnosis of Alzheimer’s disease within the year before enrollment. None had previously received aducanumab therapy and none carried an APOE4 allele.
For 6 months, participants received monthly intravenous aducanumab, escalated up to 6 mg/kg rather than the on-label dose of 10 mg/kg, as a risk mitigation strategy.
Opening the blood-brain barrier with focused ultrasound started 2 hours after each infusion. The blood-brain barrier closed within 24 to 48 hours after the procedure.
Focused ultrasound was applied to areas with high beta-amyloid in the frontal or temporal lobe or the hippocampus. In the contralateral hemisphere, homologous brain regions that were not exposed to focused ultrasound served as controls.
Participants 1 and 2 had no neurologic, cognitive, or behavioral changes at their last follow-up visit. At day 30 of follow-up, participant 3’s cognitive test scores declined, but she showed no neurologic change or change in activity of daily living scores.
These findings are consistent with those of mouse studies that demonstrated increased penetration of aducanumab when combined with focused ultrasound to open the blood-brain barrier, Rezai and colleagues noted.
“However, our trial did not quantify monoclonal antibody penetration, and therefore enhanced delivery of the monoclonal antibody was not directly shown,” they acknowledged.
The study involved small tissue volumes in one side of the brain of only three patients, Hynynen pointed out. Larger trials are needed and expanding treatment to both sides of the brain is crucial to determine efficacy, he observed.
“That all being said, the results spark optimism that this approach to treatment, together with agents that remove [amyloid-beta], could eventually slow the progression of Alzheimer’s disease,” he wrote.
Judy George covers neurology and neuroscience news for MedPage Today, writing about brain aging, Alzheimer’s, dementia, MS, rare diseases, epilepsy, autism, headache, stroke, Parkinson’s, ALS, concussion, CTE, sleep, pain, and more. Follow
Disclosures
This study was funded by the Harry T. Mangurian, Jr. Foundation and the West Virginia University Rockefeller Neuroscience Institute.
Rezai had no disclosures.
Co-authors reported relationships with Insightec, AbbVie, Genentech, Neurocrine Biosciences, Teva Pharmaceuticals USA, and Taylor & Francis Group.
Hynynen is a founder of FUS Instruments and holds patents related to focus ultrasound methods.
Primary Source
New England Journal of Medicine
Source Reference: Rezai AR, et al “Ultrasound blood–brain barrier opening and aducanumab in Alzheimer’s disease” N Engl J Med 2024; DOI: 10.1056/NEJMoa2308719.
Secondary Source
New England Journal of Medicine
Source Reference: Hynynen K “Sounding out the blood–brain barrier” N Engl J Med 2024; DOI: 10.1056/NEJMe2311358.
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