Combination of Ultrasound Blood-Brain Barrier Opening and Aducanumab Significantly Reduces Amyloid-β in Alzheimer Disease


In a recent open-label trial, utilization of focused ultrasound to open the blood–brain barrier combined with infusions of aducanumab decreased amyloid-β levels.

 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

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.

"The main findings of this proof of concept study were that opening the blood-brain barrier with noninvasive focused ultrasound can be done safely in patients with AD undergoing anti-Aβ antibody treatment, and that opening the blood-brain barrier accelerated the reduction of Aβ plaques in the brain compared to antibody treatment alone in 3 participants," 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 told NeurologyLive®. "Specifically, at 6 months since the beginning of aducanumab anti-Aβ antibody treatment, we observed an average of 32% more reduction in standardized uptake value ratio Aβ plaques (53% centiloid units) in brain areas with blood-brain barrier opening compared to the homologous brain areas with no blood-brain barrier opening."

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.

"This initial study demonstrates the safety and feasibility of combining anti-Aβ antibody treatment with focused ultrasound blood–brain barrier opening. This first in human proof of concept study shows the potential for focused ultrasound technology blood–brain barrier opening to improve drug delivery to the brain in AD, and offers promise for further investigations combining blood–brain barrier opening with other brain therapeutics.” Rezai told.

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.

"We will continue the follow up observation of patients with focused ultrasound blood–brain barrier opening and aducanumab treatment. We are also recruiting patients for the next step study combining the FDA approved anti-Aβ monoclonal antibody lecanemab (Leqembi) with focused ultrasound blood-brain barrier opening," Rezai added. "This study will further explore safety and how to further accelerate Aβ plaque removal. In addition, we need to further increase the volume of blood brain barrierB opening to determine if this combination therapy can impact cognitive decline in patients with AD in addition to reduction of Aβ plaques."

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.
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