Breaching the Blood-Brain Barrier: A Potential New Treatment Modality


In a small, yet groundbreaking, clinical trial, MR-guided focused ultrasound (MRgFUS) (ExablateNeuro; Insightec, Miami FL) was used to open the blood-brain barrier (BBB) safely in 5 persons with mild-to-moderate Alzheimer’s disease (AD) who were also amyloid positive. Results were published in Nature Communications and presented at the Alzheimer’s Association International Conference (AAIC) in Chicago, Illinois. Investigators will continue studying the safety and efficacy of this technique in a larger group in a phase 2a trial beginning this fall.

Patients in the study, ages 50 to 85, had 1 or 2 noninvasive MRgFUS procedures. In the first, MRgFUS was used in a small area (5 x 5 x 5 mm3) to disrupt, or open, the BBB in 5 patients. Extravasion of gadolinium contrast seen on MRI during the procedure demonstrated permeability. Postprocedural MRI 24 hours later, the area of extravasion was no longer present, suggesting that the BBB had sealed.

In a second procedure, approximately a month later, MRgFUS was used in 4 of the patients to open the same area as before with a slightly larger margin. In addition, an adjacent and also larger area was also made permeable with MRgFUS.

This was a single-arm pilot designed to test the feasibility and safety of focally, reversibly, and repetitively opening the BBB. No drugs were administered to patients. No adverse events occurred. No radiologic evidence of intracerebral hemorrhage or swelling was seen. Patients experienced no change in neurocognitive test scores or activities of daily living.

During the study, 1 patient developed an unrelated respiratory infection and thus did not have the second procedure. Discrete round hypointensities were seen in 2 patients immediately after sonication, which could indicate microhemorrhage; however, these were not present on follow-up MRI 24 hours postprocedure.

The amount of energy used to open the BBB effectively was less than 1% of the power typically used for neuroablative procedures with MRgFUS. Based on preclinical experiments, it is thought that MRgFUS physically disrupts the connections between the endothelial cells of the BBB to make it permeable.  

Lead investigator for this study, Nir Lipsman, MD, PhD of the Sunnybrook Research Institute in Toronto, Canada, explained that, “The power of this technology is that it is neutral to whatever you want to deliver. We are pursuing a MRgFUS-alone track to see if opening the BBB alone could clear amyloid and be therapeutic for patients with AD. We are also exploring a therapeutic delivery track of MRgFUS plus a therapeutic agent, in which using MRgFUS to open the BBB is viewed primarily as a delivery method. If safe, that could be used to deliver a 'precision strike' of therapy for a variety of neurologic diseases.”


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