Opening Blood-Brain Barrier to Deliver Alzheimer’s Drug Shows Promise

— Focused ultrasound assisted aducanumab minimize amyloid-beta levels

by
Judy GeorgeDeputy Managing Editor, MedPage Today
January 3, 2024

Aducanumab (Aduhelm) infusions integrated with concentrated ultrasound resulted in lower cerebral amyloid-beta levels in Alzheimer’s illness, a proof-of-concept trial revealed.

The investigational treatment included producing an opening in the blood-brain barrier with MRI-guided concentrated ultrasound to increase drug shipment.

In each of 3 individuals who got aducanumab infusions, amyloid decrease was higher in brain areas targeted with concentrated ultrasound than in areas not exposed to focused ultrasound, stated Ali Rezai, MD, of West Virginia University in Morgantown, and co-authors in a New England Journal of Medicine short report.

From standard to the 26-week evaluation, PET scans revealed that focused ultrasound integrated with aducanumab caused a drop in amyloid levels from 224.2 to 115.2 centiloids in individual 1, from 185.6 to 104.6 centiloids in individual 2, and from 251.5 to 84.9 centiloids in individual 3. Contralateral brain areas that did not have actually focused ultrasound revealed little modification in amyloid levels from standard to 26 weeks.

“We observed a typical 32% decrease in SUVR [standardized uptake value ratio] for the 3 individuals integrated after 26 weeks in the areas that had actually gotten treatment to open the blood-brain barrier and 6 mix treatments,” Rezai and associates composed.

Headaches were the most typical unfavorable occasions and were moderate other than for one moderate headache. One individual had 2 serious negative occasions throughout the concentrated ultrasound treatment due to pain with head and neck positioning; this dealt with instantly after the treatment. No amyloid-related imaging irregularities were seen.

Low-intensity focused ultrasound has actually reversibly opened the blood-brain barrier in individuals with Alzheimer’s illness or other neurologic conditions, consisting of Parkinson’s illness, brain growths, and amyotrophic lateral sclerosis.

Previous work by Rezai’s group revealed that focused ultrasound alone– without a restorative representative like aducanumab– a little lowered amyloid-beta levels, kept in mind Kullervo Hynynen, PhD, of the University of Toronto in Canada. “The decrease observed in the present trial was numerically higher than in the previous research studies,” he composed in an accompanying editorial

“The blood-brain barrier safeguards the brain from damaging compounds while enabling necessary nutrients to go through,” Hynynen stated. “However, it likewise restrains the shipment of drugs to the brain.”

The 3 individuals were a 77-year-old male (individual 1), a 59-year-old guy (individual 2), and a 64-year-old lady (individual 3). All got a medical diagnosis of Alzheimer’s illness within the year before registration. None had actually formerly gotten aducanumab treatment and none brought an APOE4 allele.

For 6 months, individuals got month-to-month intravenous aducanumab, intensified approximately 6 mg/kg instead of the on-label dosage of 10 mg/kg, as a threat mitigation method.

Opening the blood-brain barrier with concentrated ultrasound began 2 hours after each infusion. The blood-brain barrier closed within 24 to 48 hours after the treatment.

Focused ultrasound was used to locations with high beta-amyloid in the frontal or temporal lobe or the hippocampus. In the contralateral hemisphere, homologous brain areas that were not exposed to focused ultrasound acted as controls.

Individuals 1 and 2 had no neurologic, cognitive, or behavioral modifications at their last follow-up go to. At day 30 of follow-up, individual 3’s cognitive test ratings decreased, however she revealed no neurologic modification or modification in activity of everyday living ratings.

These findings follow those of mouse research studies that showed increased penetration of aducanumab when integrated with concentrated ultrasound to open the blood-brain barrier, Rezai and coworkers kept in mind.

“However, our trial did not measure monoclonal antibody penetration, and for that reason boosted shipment of the monoclonal antibody was not straight revealed,” they acknowledged.

The research study included little tissue volumes in one side of the brain of just 3 clients, Hynynen mentioned. Bigger trials are required and broadening treatment to both sides of the brain is essential to identify effectiveness, he observed.

“That all being stated, the outcomes trigger optimism that this technique to treatment, together with representatives that eliminate [amyloid-beta]might ultimately slow the development of Alzheimer’s illness,” he composed.