Investigating the Use of MRI-Guided Focused Ultrasound in Alzheimer Disease

Ali Rezai, MD

Early results from a study (NCT03671889) on the safety and efficacy of using MRI-guided focused ultrasound (FUS) to reversibly open the blood-brain barrier (BBB) in patients with mild Alzheimer disease (AD) were presented at the 14th Clinical Trials on Alzheimer’s Disease Conference (CTAD), November 9-12, 2021. The study is the first to demonstrate opening of the BBB in a manner that was safe and reversible in patients with early AD, as well as reduction of ß-amyloid plaques seen on PET scans. 

Ten participants with mild AD and positive amyloid-ß PET completed a total of 30 sessions of FUS, with 6 participants receiving treatment in the hippocampus/entorhinal cortex and the remaining 4 receiving additional treatment of the frontal and parietal lobes. Despite the small sample included in the study, investigators concluded that FUS was well-tolerated in this patient population, and all subjects had immediate opening of the BBB and closure within 24 to 48 hours. 

Ali Rezai, MD, executive chair, Rockefeller Neuroscience Institute; vice president, neuroscience; and associate dean and John D. Rockefeller IV tenured professor in neuroscience, West Virginia University, sat down with NeurologyLive® to discuss the mechanisms of FUS treatment and clinical findings. Noting that results are early and FUS is not yet a definitive therapy, Rezai provided his opinion on the encouraging aspects of the technology and processes. 

NeurologyLive®: Can you provide background on the ultrasound technology and how it is used?

Ali Rezai, MD: The technology that we've used is MRI-guided focused ultrasound, or FUS for short, and that's really an emerging technology in neurology, neuroscience, and neurosurgery, where we're doing noninvasive targeting [of] our brain structures. [It is] an outpatient procedure, there is no incision or opening in the skull. We use MRIs to target different structures in the brain, anywhere in the brain—the superficial parts of the brain, or deep parts of the brain—with millimeter precision. You lie in the MRI, a helmet comes over your head—the helmet has over 1000 ultrasound probes that are beamed, and they go through the scalp, through the skull, and they converge to a point that you've targeted based on MRI in the brain. It can be frontal lobes, parietal lobes, brainstem, hippocampus—anywhere can be targeted with this technology, and it's a converging technology. There are 3 applications of this technology, 1 is using high intensity ultrasound, so higher doses for lesioning the brain, and that's FDA-approved and Medicare reimbursed for the treatment of Parkinson's [disease] and essential tremor. In that case, we converge the beams into the tremor part of the brain, the thalamus, and [with] increased intensity, it will make a small lesion and you see the benefits live on the table. So that's the first application. 

There have been 3000 patients who've had this procedure worldwide, with multiple randomized controlled trial published studies that are showing the long-term benefit for improvements of tremor and control of tremor. That's the most common application. The second most common application, which was the focus of our study, involves opening up the blood-brain barrier and using focused ultrasound.

With regards to opening the blood-brain barrier, it’s a new technology. As many know, the blood brain barrier is a diffusion barrier, limiting the access of most substances from the blood vessels into the brain tissue, and essentially substances that are larger than 400 Dalton molecular weight do not cross the blood-brain barrier readily. This includes many pharmaceuticals, medications, antibodies, and other therapies. So, in the neurosciences, a big problem has been the noninvasive opening of the blood-brain barrier, and focused ultrasound allows that.

How is the BBB opened in this process?

We inject intravenously a solution of microbubbles that's used for cardiac imaging, and the microbubbles are traveling across the bloodstream, through the rest of the entire body, and in the brain—the areas where they're traveling, if we deliver the ultrasound dose to that area, these microbubbles in the blood vessels oscillate, and they open the blood-brain barrier temporarily. This is noninvasive, focal, on-demand, and the blood brain barrier closes within 24 to 48 hours. The Alzheimer study stemmed from a decade of research into animal models of Alzheimer's that showed that there were improvements in the animals' behavior and cognitive function with focused ultrasound that opens the blood-brain barrier, and the beta amyloid plaques also were reduced.

The first human studies were done in 2018 for Alzheimer's in Sunnybrook, Toronto, where they opened the blood-brain barrier in 5 patients in frontal lobe. Subsequently, our team opened the blood-brain barrier in the hippocampus—the memory part of the brain—in 6 patients that we published in PNAS [Proceedings of the National Academy of Sciences in the United States of America] in 2020, in collaboration with our colleagues at Cornell and West Virginia University, where we demonstrated we can open the blood-brain barrier with precision and reversibility in 6 subjects. 

This current study was a continuation of the safety and efficacy clinical trial. The objective was to look at what happens long-term when we open the blood-brain barrier in the hippocampus, the frontal lobes, and the parietal lobes of individuals with mild Alzheimer's disease. The clinical trial is ongoing and reporting the outcomes of the first 10 subjects for the long-term, reporting the impacts for safety of opening up the blood-brain barrier and closure, as demonstrated by intravenous contrast extravasation into the brain tissue, and then closure demonstrated by no contrast enhancement in brain tissue. We looked at safety, which was a primary goal of this study. Second was looking at the effects on cognition and memory, looking at ADAS-Cog [Alzheimer’s Disease Assessment Scale–Cognitive Subscale] and MMSE [Mini-Mental State Examination] and longitudinally following our subjects. Third was looking at the effects on amyloid-ß biomarker in the brain, in the areas that we treated focally with focused ultrasound.

There's a lot of research still ongoing [regarding mechanisms of opening the BBB]. There are concepts of immunological activation in the region and focal inflammation, which demonstrated neutrophil and microglia recruitment to the ultrasound-targeted region. Intravascular proteins also gain access to the brain and seem to be activating the immune mechanism of clearance. The other mechanism seems to be an enhanced brain removal clearance pathway in the brain. We published a study in 2021, early this year, in Radiology, demonstrating that the glymphatics seemed to be activated, and a glymphatic-mediated clearance mechanism seems to be in place, based on this early preliminary study. Others have also shown that ultrasound can break down these plaques into smaller components and maybe make them more soluble for clearance. So, [those are] the potential mechanisms, but it's still under active investigation.

Transcript edited for clarity. For more coverage of CTAD 2021, click here.

REFERENCE
Rezai A, Ranjan M, Haut M, et al. Longitudinal safety, clinical, and beta amyloid PET outcomes of a multi-center clinical trial of focused ultrasound blood brain barrier (BBB) opening of the hippocampus, front, and parietal lobes in early Alzheimer’s disease. Presented at CTAD; November 9-12, 2021; Virtual & Boston, MA. Abstract OC26.