Ali Rezai, MD
Credit: West Virginia University
Newly published in The New England Journal of Medicine, a prospective, open-label, single-group, single-institution, proof-of-concept trial of 3 patients showed that a combination of focused ultrasound to open the blood–brain barrier and administration of aducanumab (Aduhelm; Biogen), a recently discontinued treatment for Alzheimer disease (AD), resulted in significant reductions in amyloid-β (Aβ) levels.1,2
The reduction from baseline to 26 weeks was greater with focused ultrasound than without by 107.5 centiloids (difference, 48%) in participant 1 (a 77-year-old man), 87.6 centiloids (49%) in participant 2 (a 59-year-old man), and 158.1 centiloids (63%) in participant 3 (a 64-year-old woman). Participants 1 and 2 had no neurologic, cognitive, or behavioral changes at the last follow-up visit. Notably, participant 3 had cognitive decline at day 30 days after follow-up but no neurologic changes were observed.
Top Clinical Takeaways
- The combination of focused ultrasound and aducanumab demonstrated a significant reduction in amyloid-β levels, showing promise in Alzheimer disease treatment.
- The trial's safety profile indicates a few adverse events, mainly mild headaches, supporting the feasibility of the combined treatment approach.
- The trial's unique design, utilizing focused ultrasound on one hemisphere, provides a controlled comparison and strengthens the reliability of the observed results.
“We observed an average 32% reduction in standardized uptake value ratio (for the 3 participants combined) after 26 weeks in the regions that had received treatment to open the blood–brain barrier and 6 combination treatments,” lead author Ali Rezai, MD, executive chair and director of the Rockefeller Neuroscience Institute; and associate dean and John D. Rockefeller IV tenured professor in neuroscience at West Virginia University, and colleagues wrote.1 “There was also a greater reduction in Aβ levels in the regions of the brain that had received treatment to open the blood–brain barrier than in the homologous regions in the contralateral hemisphere that were not treated with focused ultrasound.”
READ MORE: Phase 3 Trials of Aducanumab Highlight High Risk of Amyloid-Related Imaging Abnormalities in APOE Carriers
Investigators applied focused ultrasound with each of 6 monthly aducanumab infusions to temporarily open the blood-brain barrier in participants with AD over a 6 month treatment period. The levels of Aβ were measured with a PET scan and assessments of neurologic, cognitive, and behavioral outcomes were performed. MRI of the participants were conducted at baseline and before, during, immediately after treatment initiation, and 24 and 48 hours after the focused ultrasound treatment. Investigators also performed cognitive tests and safety evaluations in the participants over 30 to 180 days posttreatment.
“In our trial design, focused ultrasound was applied to 1 hemisphere only, allowing comparison between homologous brain regions in each participant. This design controls for several variables, such as antibody infusion, disease progression, and brain targets, and provides an appropriate comparator between homologous brain regions,” Rezai et al noted.1 “In the 3 participants, brain regions with high levels of Aβ were treated with the use of focused ultrasound, and the Aβ results were averaged for comparison with those in homologous regions on the contralateral hemisphere of the brain.”
One serious adverse event was reported in the follow-up phase, having passive thoughts of death, that was not related to the trial treatment. The most common adverse events were mild headache except for 1 moderate headache. There were 2 severe adverse events during the focused ultrasound treatment in the same participant owing to head and neck positioning discomfort, which resolved after the procedure. There were no amyloid-related imaging abnormalities or neurologic changes observed except for 2 instances of mild pronator drift of the left arm in participant 2, which was present before the trial. Authors observed a mild increase in behavioral symptoms, characterized by elevations in agitation, sleep disturbances, and appetite fluctuations, in participant 3.
“In this proof-of-concept trial involving 3 participants, combining aducanumab infusion therapy with regional focused ultrasound to open the blood–brain barrier in participants with mild AD was associated with few adverse events (mainly headache), and, during the 6-month combination-treatment phase, resulted in a greater reduction in the level of Aβ than aducanumab therapy alone in homologous regions that were not treated with the use of focused ultrasound,” Rezai et al noted.1
1. Rezai AR, D'Haese PF, Finomore V, et al. Ultrasound Blood-Brain Barrier Opening and Aducanumab in Alzheimer's Disease. N Engl J Med. 2024;390(1):55-62. doi:10.1056/NEJMoa2308719
2. Biogen to realign resources for Alzheimer’s disease franchise. News release. Biogen. January 31, 2024. Accessed January 31, 2024. https://finance.yahoo.com/news/biogen-realign-resources-alzheimers-disease-123000872.html