Study: Focused ultrasound improves Alzheimer’s drug delivery

Amyloid Plaque Alzheimer2 Social

Alzheimer’s disease researchers have reported promising results from using aducanumab infusions combined with focused ultrasound to reduce levels of cerebral amyloid-beta (Aβ) plaques.

The MRI-guided focused ultrasound temporarily opened up the blood–brain barrier to increase access to targeted areas of the brain for delivery of aducanumab, an amyloid-binding monoclonal antibody.

The results have sparked hope that this approach to treatment, combined with agents that remove Aβ, could “eventually slow the progression of Alzheimer’s disease”, says one expert.

Scientists from West Virginia University Rockefeller Neurology Institute (RNI) have reported their findings from a proof-of-concept trial on three patients in the New England Journal of Medicine (NEJM).

The investigational treatment involved the MRI-guided focused ultrasound combined with infusions of aducanumab in selected brain regions over a six-month period.

Researchers say there was a greater reduction in the level of Aβ than aducanumab therapy alone in homologous regions that were not treated with the focused ultrasound.

“We observed an average 32% reduction in SUVR (standardized uptake value ratio) in the three participants combined, after 26 weeks in the regions that had received treatment to open the blood–brain barrier and six combination treatments,” say the authors, who were led by Ali Rezai, executive chair of the RNI.

“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,” they add.

The blood−brain barrier—a physical and biochemical boundary between the bloodstream and the parenchyma of the central nervous system (CNS)—safeguards the brain from harmful substances while allowing essential nutrients to pass through. However, it also impedes the delivery of drugs to the brain.

Focused ultrasound has previously been shown to safely open the blood−brain barrier in the absence of drug delivery in patients with Alzheimer’s disease and to deliver antibodies into brain metastases.

Ultrasound waves pass through the skin and skull to reach the brain target via a transducer helmet encircling the patient’s head.

The three study patients, who had mild cognitive impairment due to Alzheimer’s disease or mild Alzheimer’s disease dementia, had not previously received aducanumab therapy.

Headaches were the most common adverse events and were mostly mild, say researchers.

“The trial did not quantify monoclonal antibody penetration, and therefore enhanced delivery of the monoclonal antibody was not directly shown,” the authors wrote.

An accompanying NEJM editorial describes how Rezai and colleagues quantified the effect of treatment on cerebral Aβ load by comparing 18F-florbetaben positron-emission tomographic scans before and after the treatment series, assessing the difference between the volume of Aβ in the treated region and that in the analogous region of the other hemisphere.

“Previous studies by this group, however, showed that focused ultrasound alone slightly reduced Aβ levels. The reduction observed in the current trial was numerically greater than in the previous studies,” writes editorial author Kullervo Hynynen, who is vice president of research and innovation and a senior scientist at Sunnybrook Research Institute and holds the Temerty Chair in Focused Ultrasound Research.

The West Virginia University study involved small tissue volumes, which were not systematically chosen, in one side of the brain.

 Hynynen says expanding treatment to clinically significant volumes on both sides of the brain is “crucial for assessing its efficacy in slowing disease progression,” while further studies are needed to establish long-term safety and efficacy.

“That all being said, the results spark optimism that this approach to treatment, together with agents that remove Aβ, could eventually slow the progression of Alzheimer’s disease”, he writes.

The ultrasound device manufacturer was Insightec, whose CEO and chairman Maurice R. Ferré, MD said in a statement, “The ability to disrupt the blood–brain barrier to effectively deliver treatment demonstrates the power and potential of using focused ultrasound technology when addressing complex neurological conditions.”

The study was funded by the Harry T. Mangurian Jr. Foundation and the West Virginia University RNI.

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