Technique That Opens Blood-Brain Barrier May Help Target Treatment, Study Says

A new non-invasive technique that can temporarily “open” the blood-brain barrier may make it easier for promising therapies to enter the brain of people with Alzheimer’s disease, a study reports. 

The study, “Noninvasive hippocampal blood−brain barrier opening in Alzheimer’s disease with focused ultrasound,” was published in the journal Proceedings of the National Academy of Sciences. 

The blood-brain barrier is made of a “wall” of cells tightly bound together by protein structures called tight junctions that act like a kind of “cement.”

This barrier surrounds blood vessels in the brain and spinal cord (central nervous system or CNS) to separate the bloodstream from the tissues within the CNS and prevent the passage of cells, particles, or microbes that might disrupt the normal function of the CNS.

However, when it comes to therapies to treat brain disorders, the blood-brain barrier also limits the use of potentially effective medicines, immunotherapy, gene therapy, and other treatments, which may not be able to enter the brain in the necessary amounts. 

“The blood brain barrier has long presented a challenge in treating the most pressing neurological disorders,” Ali Rezai, MD, executive chair of the West Virginia University Rockefeller Neuroscience Institute, said in a press release.

The hippocampus and entorhinal cortex are areas of the brain that play a major role in memory processing. They are especially vulnerable to damage at the early stages of Alzheimer’s disease. 

For this reason, the hippocampus is a key target for new therapies for Alzheimer’s. However, the presence of the blood-brain barrier has meant that high doses of a given medication or invasive procedures were often required for therapies to be effective.

“The ability to non-invasively and reversibly open the blood brain barrier in deep brain areas such as the hippocampus, offers a new potential in developing treatments for Alzheimer’s disease,” Rezai said.

In recent years, scientists have developed a technique called magnetic resonance-guided focused ultrasound (MRgFUS), that would allow a non-invasive, reversible “opening” of the blood-brain barrier in precise areas of the brain. 

To do this, doctors inject microscopic bubbles into the patient’s bloodstream, which are then exposed to a focused ultrasound through a treatment helmet attached to a magnetic resonance imaging (MRI) table. This causes the bubbles to start oscillating and open small “holes” in the “cement” that joins together the cells of the blood-brain barrier. 

In a previous Phase 1 clinical trial (NCT02986932), the MRgFUS technique was shown to safely open the blood-brain barrier in Alzheimer’s patients. In this trial, the targeted brain area was the dorsolateral prefrontal cortex, important for short-term memory and switching attention.

Now, researchers at the institute, in partnership with the Weill Cornell Medical Center, are conducting a multicenter Phase 2 clinical trial (NCT03671889) with the goal of evaluating the safety and feasibility of using MRgFUS to temporarily open the blood-brain in the hippocampus and the entorhinal cortex in people with early-onset Alzheimer’s disease.

Although the trial is still ongoing and recruiting, the team has now reported on results from six patients with early Alzheimer’s disease (five women and one man between 55 and 73 years old) who participated in the study.

Each MRgFUS session was administered two weeks apart, with each patient receiving two to three sessions, for a total of 17 treatment sessions.

In all sessions, there was an immediate opening of the blood-brain barrier that corresponded to an average 29% of the overall hippocampus volume. The barrier was seen to close again within 24 hours without any adverse events. 

Cognitive assessments 30 days post-treatment showed no clinically meaningful changes linked to the procedure. In addition, no adverse effects or neurological changes related to MRgFUS were found up to 15 months after the treatment. 

Importantly, MRIs taken immediately after MRgFUS and at a later follow-up showed no signs of bleeding in the brain.

MRgFUS “provides a noninvasive method for time-limited, precise, and large [blood-brain barrier] BBB opening, providing an exciting opportunity for research coupling FUS with targeted delivery of medications, immunotherapy, gene therapy, or stem cells into various complex and deep brain structures, including the hippocampus,” the researchers wrote.

The therapy may help deliver meaningful volumes of a therapy to “essential brain structures in [Alzheimer’s disease] and other neurological conditions,” they added.

“Our demonstration that we can safely and precisely open the blood-brain barrier over most of an important structure in the brain … suggests that we may be able to deliver restorative therapies for complex brain disorders without invasive surgery as an outpatient procedure,” said Michael Kaplitt, MD, PhD, professor of neurological surgery at Weill Cornell Medicine.

“Given recent events, the potential to treat major brain disease without using inpatient hospital resources could not only be preferable for patients but could provide important options when circumstances limit access to invasive surgery,” he added.

The trial is sponsored by Insightec, the developer of the technology and manufacturer of the focused ultrasound device, called Exablate Neuro.

“By working with leading clinicians, researchers, and hospitals, we are gaining tremendous insight and experience on how our MR-guided focused ultrasound platform can help to treat devastating diseases like Alzheimer’s,” said Maurice R. Ferre, MD, chairman and CEO of Insightec.