Key Points
- The trial used focused ultrasound plus microbubbles to open the blood-brain barrier (BBB) in patients with Alzheimer’s disease.
- The procedure was safe, and researchers identified several positive relationships between the BBB opening and levels of serum-derived AD biomarkers.
The research team at Columbia University led by Elisa Konofagou, PhD, recently published the final data from their clinical trial (NCT04118764) using focused ultrasound plus microbubbles to open the blood-brain barrier (BBB) in patients with Alzheimer’s disease (AD). The trial was co-led by Lawrence Honig, MD, PhD, a neurologist at the Taub Institute of Alzheimer’s Disease and Aging at Columbia. The study made the cover of the current issue of Theranostics.
Six participants with mild-to-moderate AD (2 males and 4 females with an average age of 69.7 ± 7.2 years) were enrolled in this phase I pilot study. Each patient underwent one session of focused ultrasound sonication followed by an MRI scan approximately 2 hours later to assess safety and efficacy. Positron emission tomography (PET) scans were also used to assess beta amyloid levels in the brain, cognitive function tests were used to evaluate any potential treatment effects, and blood was collected before and 3 days after the treatment to for analysis of AD-based biomarkers.
This study was unique in that it used Columbia’s single-element, neuronavigation-guided portable device. With this portable device, treatments take place with the participant sitting upright in a chair with the system wheeled to the point of care. The focused ultrasound sonication lasted 2-minutes, with the Definity microbubbles being intravenously injected 3 seconds after treatment for 10 to 20 seconds after the start of the sonication.
“We are very excited about what we have accomplished with this study” said Dr. Konofagou, the Robert and Margaret Hariri Professor of Biomedical Engineering, Radiology, and Neurosurgery at Columbia University. “Not only were we able to demonstrate that a portable and single-element device can safely open the BBB in the human Alzheimer’s brain, but the device also performed the treatment within minutes in both cortical and subcortical brain regions pertaining to the disease. The real-time transcranial 2D cavitation mapping and dose monitoring was found to be correlated with the safety and efficacy in beta amyloid reduction detected on PET a few weeks later (without any pharmacological treatment).
When asked about potential cognitive improvements, Dr. Konofagou said, “Cognitive amelioration was not the goal here, but we did find a minute increase in mini mental state examination score. We believe, however, that treating larger volumes of the brain in each session – as well as over multiple sessions – would incur cognitive improvement, because we have seen it in our preclinical studies.”
During the study, the portable focused ultrasound system safely performed BBB opening in the frontal lobe of the brain at volumes ranging from 278 to 2,013 cubic mm. The average contrast-enhanced volume (a measure of BBB opening volume) was 983 ± 626 cubic mm. There were no serious adverse events, but the first participant had mild skin erythema that resolved within 3 days and asymptomatic cerebral edema with a superficial hemorrhagic component that resolved by day 15.
Cognitive function tests revealed no clinical changes after the treatments, but the PET scans did show a lower amyloid-beta load increase in the treated frontal lobe region when compared with the contralateral region. Interestingly, the researchers also identified several positive relationships between the amount of BBB opening and the level of serum-derived AD biomarkers that were detectable with higher accuracy within the first hour after portable focused ultrasound.
These results now join other international studies demonstrating safe BBB opening in people with AD.
“An important feature of BBB opening is the possibility of repeated treatments,” said Tim Meakem, MD, a managing director at the Foundation and co-director of the research and education team. “This portable system, which does not require intraprocedural MRI or complete head shaving, could be advantageous as this technology moves toward providing care for patients.”
The study was funded by two National Institutes of Health grants, the Focused Ultrasound Foundation, and the Alzheimer’s Disease Research Center. “We wish to wholeheartedly thank the Foundation for supporting our study throughout the past few years,” said Dr. Konofagou.
The article, “Transcranial blood-brain barrier opening in Alzheimer’s disease patients using a portable focused ultrasound system with real-time 2-D cavitation mapping,” was published in Theranostics. (Open Access)
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