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In the Pipeline-Alzheimer's Disease
Focused Ultrasound Safely Opens Blood-Brain Barrier in AD Patients

ARTICLE IN BRIEF

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MRI DEMONSTRATION of blood–brain barrier opening and closure. (A) Axial T1-weighted gadolinium MR images of patient 5 at a baseline, (B) immediately after blood–brain barrier (BBB) opening, and (C) at 24 hours after procedure. Contrast extravasation within the volume in the right frontal lobe is seen immediately after the procedure, demonstrating increased BBB permeability. At 24 hours after the procedure, there is no significant extravasation of contrast in the area, suggesting BBB closure.

In a small study, researchers found focused ultrasound could safely open the blood–brain barrier, reversibly and repeatedly, in five patients with mild to moderate Alzheimer's disease.

Canadian researchers have used magnetic resonance imaging focused ultrasound to safely open and close the blood-brain barrier (BBB) in patients with mild to moderate Alzheimer disease (AD), demonstrating a potential way to monitor disease pathology and deliver targeted therapies in the future.

The study, published July 25 in Nature Communications, is the first peer-reviewed published report to demonstrate the safety and feasibility of opening and closing the blood-brain barrier in patients with AD using focused ultrasound.

Researchers at Sunnybrook Health Sciences Centre, in Toronto, Ontario, used magnetic resonance (MRI)-guided focused ultrasound in combination with intravenous microbubbles to safely and temporarily open the BBB in five patients with early to moderate AD. In animal models of AD, the technique has reduced amyloid-beta and tau pathology without any additional therapy.

The tiny bubbles adhere to large blood vessels of the BBB and expand and contract in response to ultrasound waves causing a transient opening large enough for large molecules, potentially even antibodies, to cross.

STUDY DETAILS

In the new study, the patients received two ultrasound procedures immediately after microbubbles were injected into the bloodstream, and the MRI contrast agent gadolinium was used to confirm that the barrier had in fact opened and later closed.

In the study's first stage, patients underwent the procedure, after which they were followed for 30 days. Each patient that did not experience any serious adverse events, such as brain edema, was eligible for the next stage where a larger volume area in a different part of the brain was targeted. They were then followed for an additional 60 days to evaluate adverse events and preliminary effectiveness.

The safety and feasibility of the technique was successful, said principal investigator and neurosurgeon Nir Lipsman, MD, PhD, director of the Center for Neuromodulation, at Sunnybrook Health Sciences Centre.

Dr. Lipsman presented the findings at the Alzheimer's Association International Conference on July 25, the same day it was published in Nature Communications.

“We are still very much in the early stages of investigating focused ultrasound in AD, and it is much too early for it to have any impact on actual clinical treatment. For clinicians, it means that an additional, perhaps more ‘outside the box’ approach is being investigated,” he told Neurology Today.

“For researchers, it means that the blood-brain barrier is, or should, no longer be considered a major obstacle to therapy development. There may now be a safe, effective, and reversible means of overcoming the BBB. Further, we have shown that opening the BBB in regions of the brain that are rich with amyloid is not associated with bleeding, swelling, or acceleration of amyloid deposition on brain imaging.”

He said the researchers used focused ultrasound to safely open the blood–brain barrier within the target volume, reversibly and repeatedly, in all five patients.

Amyloid-beta levels were measured before treatment using [18F]-florbetaben positron emission tomography (PET), and there were no group-wide changes in amyloid after treatment.

During treatment the investigators used different cycles of pressure to form thousands of microscopic vacuum bubbles in the solution. When these collapsed though a process known as cavitation, it enabled opening and closing of the BBB without any serious clinical or radiographic adverse events, or worsening of cognitive scores after three months compared to baseline.

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DR. CYNTHIA LEMERE: “The study is exciting because it is the first time focused ultrasound has been shown to safely and reversibly open the blood-brain barrier in AD patients during two treatments spaced a month apart... There is a lot more work to be done, but this is a major step forward for enhancing drug delivery to brain.”

“If you want to deliver a potential therapy, like an antibody to amyloid or tau, this appears to be a safe and temporary way of bypassing the BBB to allow a potential treatment to pass more effectively and increase the likelihood of binding to brain pathology and treating it,” Dr. Lipsman told Neurology Today. “Moreover, there is compelling animal data that suggests that using focused ultrasound to open the BBB alone, without delivering any therapy, may permit the body's own immune system to kick in and clear amyloid deposits.”

The next phase of the trial will investigate the safety and efficacy of focused ultrasound in a larger group of AD patients. This phase 2a trial is slated to start this fall.

The study was funded by the Ultrasound Foundation.

EXPERT COMMENTARY

“The study is exciting because it is the first time focused ultrasound has been shown to safely and reversibly open the blood brain barrier in AD patients during two treatments spaced a month apart,” said Cynthia Lemere, PhD, associate professor of neurology at Brigham & Women's Hospital and Harvard Medical School's Romney Center for Neurologic Diseases.

“I was skeptical a few years ago because many AD patients have vascular amyloid lining their blood vessel walls, which may make the vessels a bit more fragile. However, this Phase I safety study showed no adverse effects in 5 patients, setting the stage for the next clinical trial,” she told Neurology Today. “There is a lot more work to be done, but this is a major step forward for enhancing drug delivery to brain.”

Dr. Lemere chaired a featured research symposium on focused ultrasound for Alzheimer Disease at the recent AAIC meeting in Chicago in July were the study data were presented.

Stephen Salloway, MD, professor of Neurology and director of neurology and the Memory and Aging Program, at Butler Hospital, Alpert Medical School of Brown University, in Providence, RI, agreed that delivering medication across the blood brain barrier will be a major challenge.

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DR. STEPHEN SALLOWAY: “Of course this would need to be tested in a much larger sample that is more representative of AD patients, but if this provides positive results it may be possible to pair focused ultrasound with AD-targeted medications.”

In addition to potentially enabling delivery of experimental therapeutic agents, he told Neurology Today that this approach for opening the blood brain barrier might also be used to breakup aggregated proteins such as amyloid plaques.

“Of course this would need to be tested in a much larger sample that is more representative of AD patients, but if this provides positive results it may be possible to pair focused ultrasound with AD-targeted medications.”

THE SCIENCE EXPLAINED: FOCUSED ULTRASOUND

WHAT IT IS: Focused ultrasound uses real-time imaging to treat tissue deep inside the body without incisions or radiation. In addition to the ability to open and close the BBB, focused ultrasound beams can be used to create intracranial thermal ablative lesions.

HOW IT WORKS: The process uses multiple intersecting beams of ultrasound directed and concentrated on a target, much like a magnifying glass does with sunlight. Individual beams pass through tissue without any effect, but when brought together the beams can be used for ablation of tumors, and, depending on the energy of the beams, either collectively or alone, can be used to treat other conditions.

HOW IT IS USED: In 2016, the US Food and Drug Administration approved the Exablate Neuro device, the same one used in the current study, for treating essential tremor. Several other countries, including those in the European Union, have also approved the device for treating neuropathic pain and Parkinson's tremor. In the United States, efforts are underway to use focused ultrasound in patients with Parkinson's disease, hypertension, and brain tumors.

DISCLOSURES

Dr. Lipsman received an honorarium for serving on an expert steering committee on focused ultrasound in Alzheimer's disease. Drs. Lemere and Salloway reported no conflicts.

LINK UP FOR MORE INFORMATION:

• Lipsman N, Meng Y, Bethune AJ, et al. Blood–brain barrier opening in Alzheimer's disease using MR-guided focused ultrasound https://www.nature.com/articles/s41467-018-04529-6. Nature Commun 2018;9(1):2336.
    • Samiotaki G, Acosta C, Wang S, Konofagou EE. Enhanced delivery and bioactivity of the neurturin neurotrophic factor through focused ultrasound-mediated blood-brain barrier opening in vivo http://journals.sagepub.com/doi/abs/10.1038/jcbfm.2014.236. J Cereb Blood Flow Metab 2015;35(4):611–622.
      • Lipsman N, Mainprize TG, Schwartz ML, et al. Intracranial applications of magnetic resonance-guided focused ultrasound https://link.springer.com/article/10.1007%2Fs13311-014-0281-2. Neurotherapeutics 2014;11(3):593–605.