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A new noninvasive procedure is safe and effective for treating patients with mild Alzheimer’s disease (AD), new research suggests.

The approach uses MRI-guided low-intensity focused ultrasound (FUS) and injected microbubbles to temporarily open the blood-brain barrier (BBB).

In a small group of patients, the procedure was significantly associated with reduced amyloid plaque and cognitive decline.

Being able to cross the BBB “on demand” and in a safe way opens up numerous frontiers for treating not only AD but also other neurodegenerative disorders, co-investigator Ali R. Rezai, MD, executive chair, Rockefeller Neuroscience Institute, West Virginia University, aborto de 5 semanas con cytotec Morgantown, West Virginia, told Medscape Medical News.

And the possibilities don’t end there; the technique may have a role in treating brain tumors and perhaps certain psychiatric conditions, Rezai added.

The findings were presented at the American Association of Neurological Surgeons (AANS) 2021 Annual Meeting, which was held online.

Targeted Brain Treatment

An estimated five million Americans live with AD, “and the numbers are rapidly growing,” said Rezai. There is no cure or effective treatment for the condition despite more than 1000 clinical trials, he added.

However, that could change with a technique that transiently opens the BBB to allow targeted treatments to the brain. The BBB normally limits transport of most substances from the blood to the brain.

The new approach involves low-intensity ultrasound. High-intensity FUS is approved by the US Food and Drug Administration for treating tremors in patients with Parkinson’s disease and essential tremor.

Low-intensity ultrasound, combined with an intravenous microbubble contrast agent, has been shown in animal studies to temporarily disrupt the BBB and increase permeability to the brain with substances that normally do not cross this barrier.

As well, this approach was associated with a reduction in plaques and improved behavior in AD preclinical trials. Researchers are now testing this procedure in humans.

For the treatment, patients wear a helmet that has ultrasound probes. Surgeons use MRI to visualize areas of the brain that have amyloid plaques.

“The ultrasound waves travel wirelessly through the scalp, the skin, and converge at the location in the brain we target with MRI that has a high degree of plaques,” Rezai reported.

The tiny spherical microbubbles that are injected into the bloodstream oscillate or “shake” in areas targeted with ultrasound, resulting in a temporary structural opening of the BBB. The treatment takes about 2 hours. Patients undergo three treatments, each 2 weeks apart.

The study is currently enrolling patients aged 50 to 85 years who have mild AD, have a Mini–Mental State Examination (MMSE) score of 18 to 26, and whose results on positron-emission tomography (PET) are positive for amyloid beta ( Aβ) .

Immune System Activation?

Preliminary findings for six participants were published online in October in Frontiers in Human Neuroscience. Safety data for three participants were published online in January in Radiology.

At the AANS meeting, Rezai presented data on 15 participants who had undergone 45 FUS treatments. Follow-up was 3 to 32 months.

In all 15 patients, the BBB was opened without hemorrhage or other adverse events. The BBB opening was “transient, reversible, and resolved in 24 to 48 hours,” said Rezai.

For 10 patients, PET imaging at about 60 days 1 week after their third treatment session showed an average reduction of amyloid plaques in the hippocampus/entorhinal cortex and the parietal and frontal lobes of about 26%.

In eight patients who underwent cognitive assessment at 1 year, there was less decline compared with participants matched for age, sex, and clinical features from the Alzheimer’s Disease Neuroimaging (ADNI) cohort. Rezai said ADNI is the best comparator “short of doing a randomized clinical trial.”

The relative change for MMSE was 2.2 for the FUS group, vs 3.8 for the ADNI cohort. Change in score on the Alzheimer’s Diusease Assessment Scale–Cognitive was 4.6 for FUS vs 5.6 for ADNI.

Rezai said that because the sample was small, they can only say that “there was no meaningful cognitive or behavioral worsening with FUS compared to the ADNI comparator group.”

Another study limitation was that the amount of Aβ varied among participants; some had low amounts at baseline.

The exact mechanisms involved in this technique are not clear and are “under investigation,” Rezai noted. They are likely multifactorial and may involve activation of the immune system and ultrasound breakdown of plaques into smaller pieces, he added.

Encouraging Signs

Overall, the researchers are “cautiously optimistic” about these new “encouraging signs” for the procedure for patients with early AD, said Rezai.

“The benefit, in my opinion, is that it’s a noninvasive technique. We’re not doing brain surgery; we’re not cutting the scalp,” he noted.

However, he stressed that “this is early on,” and more patients, more long-term follow-up, and a sham controlled trial are needed.

Still, the approach might extend beyond AD, Rezai noted. “This opens a whole new opportunity for being able to reduce brain metabolites or pathological proteins that accumulate in, for example, Parkinson’s, in Lewy body dementia, in all brain degenerative conditions,” he said.

Some researchers are investigating this approach to deliver chemotherapy for brain tumors. Others are investigating its use in transporting viral vectors or antibodies. In addition, low-intensity ultrasound that targets the brain’s reward system may be useful for treating addictions, said Rezai.

During his presentation at the meeting, several attendees used the virtual chat function to praise the research. Some called it “superb,” and some said it signifies “exciting possibilities.”

Following the presentation, Elizabeth C. Tyler-Kabara, MD, PhD, associate professor, Department of Neurosurgery, University of Texas at Austin Dell Medical School, Austin, Texas, provided a commentary. In it, she congratulated the investigators, saying the study demonstrates a “potential treatment” for early AD.

“This study is significant because it’s the first to identify that low-intensity focused ultrasound can be used to open up the BBB up to 33 cc of volume,” said Tyler-Kabara, who was not involved with the research.

She added that the study “provides the potential for delivery of biologics and other medications to the brain.”

The study was funded by the Rockefeller Neurological Institute and Insightec. Rezai and Tyler-Kabara have reported no relevant financial relationships.

American Association of Neurological Surgeons (AANS) 2021 Annual Meeting: Plenary Session 3, presented August 25, 2021.

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