Therapeutics

Focused Ultrasound – Blood-Brain Barrier

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Overview

Name: Focused Ultrasound – Blood-Brain Barrier
Synonyms: FUS-BBB, MRgFUS, MRI-Guided Focused Ultrasound, FUS+MB
Therapy Type: Procedural Intervention
Target Type: Amyloid-Related (timeline), Other (timeline)
Condition(s): Alzheimer's Disease, Amyotrophic Lateral Sclerosis, Mild Cognitive Impairment, Parkinson's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 1), Amyotrophic Lateral Sclerosis (Phase 1), Mild Cognitive Impairment (Phase 1), Parkinson's Disease (Phase 1)

Background

Focused ultrasound with microbubbles is a noninvasive procedure that transiently opens the blood-brain barrier (BBB) using low-intensity sound waves. The openings reseal within 24 hours. Using MRI to guide the ultrasound enables targeted opening of precise brain regions to facilitate drug delivery. In the case of Alzheimer’s disease, opening the BBB appears to promote amyloid removal.

More than 20 years ago, researchers discovered that low-energy ultrasound waves paired with intravenous microbubbles routinely used as contrast agents temporarily loosened the BBB in rabbits (Hynynen et al., 2001). The procedure has since been widely explored as a way to enable drug delivery to the brain. In mice, FUS-BBB was shown to elicit transient opening of the hippocampal blood-brain barrier, allowing entry of antibodies and larger molecules that normally would be excluded (Choi et al., 2007; Choi et al., 2010). Optimized parameters for sonication energy, time, and microbubble dose were studied in mice and rats, to maximize safety while minimizing tissue damage and hemorrhaging (Baseri et al., 2010; Choi et al., 2011; O’Reilly and Hynynen, 2012; Hsu et al., 2022). This led to studies in nonhuman primates (McDannold et al., 2012), and in pigs with human skull implants (Huang et al., 2017). In both, the ultrasound/microbubble combination appeared to cause no apparent tissue damage or long-term neurological effects. Work to optimize FUS-BBB protocols in humans continues (Meng et al., 2021).

A large body of preclinical work underpins the use of this intervention to treat neurodegenerative disease. In Alzheimer's mouse models, targeted ultrasound reversibly opened the hippocampal BBB similarly to normal mice (Choi et al., 2008; Raymond et al., 2008). BBB opening by itself, in the absence of adjunct drugs, was subsequently shown to activate microglia, stimulate neurogenesis, clear Aβ in targeted regions, improve synaptic long-term potentiation, and restore memory (Jordão et al., 2013; Burgess et al., 2014; Scarcelli et al., 2014; Kong et al., 2023).  In the rTg4510 amyloidosis mice, focused ultrasound reduced the levels of phosphorylated tau, when done before the onset of tau pathology (Karakatsani et al., 2019). A modified technique that uses scanning ultrasound to produce widespread BBB opening was found to activate microglia, reduce cortical plaques and improve cognition in APP23 mice (Mar 2015 news on Leinenga and Götz, 2015). Aging and amyloid pathology enhanced BBB opening, and delayed closing, in mice (Noel et al., 2023). The procedure is claimed to enhance glymphatic clearance of proteins from the mouse brain (Ye et al., 2023).

In a safety study using aged dogs with naturally occurring amyloid, four weekly treatments produced no changes on MRI, histology or neurologic exams. One adverse event of vomiting and bloody urine was possibly related to anesthesia or contrast agent injections (O’Reilly et al., 2017). 

Animal studies in tauopathy models gave inconsistent results. In K391I mutant tau transgenic mice, repeat ultrasound was reported to reduce tau pathology and improve motor and cognitive behaviors (Pandit et al., 2019). A different group reported no effect of ultrasound treatment on tau pathology in P301S tau mice (Geraudie et al., 2023).

In preclinical drug delivery studies, FUS-BBB was shown to increase brain concentrations and efficacy of amyloid and tau antibodies, neurotrophic factors, IvIG, a GSK-3 inhibitor, and viral vectors, in mouse models of AD and PD (Jordao et al., 2010; Samiotaki et al., 2015; Nisbet et al., 2017; Janowicz et al., 2019; Karakatsani et al., 2019; Hsu et al., 2018; Ji et al., 2019; Dubey et al., 2020; Xhima et al., 2021; Antoniou et al., 2023). One paper reported FUS-enabled transplantation of neural stem cells in rats (Burgess et al., 2011). FUS-BBB paired with an antibody to pyroglutamated Aβ resulted in fivefold higher brain antibody levels, greater plaque removal, synapse sparing, and improved cognitive function compared to antibody alone, in part due to enhanced recruitment of peripheral monocytes to plaques (Sun et al., 2021; Bathini et al., 2022). Ultrasound reportedly enhanced brain levels of a new tau monoclonal antibody, but not its efficacy (Bajracharya et al., 2022). FUS-BBB boosted delivery of GDNF gene therapy in a mouse model of Huntington’s disease and of edaravone in a model of ALS (Lin et al., 2019; Shen et al., 2023).

Several studies have examined the response to FUS-BBB at the tissue and cell level. Transcriptional analysis, including single-cell sequencing of brain tissue after the procedure, showed upregulated phagosome pathway genes, microglial proliferation, more of the disease-associated microglia phenotype, and recruitment of central nervous system macrophages in targeted areas (Kline-Schoder et al., 2023; Leinenga et al., 2023; Mathew et al., 2021). FUS-BBB enhanced aducanumab delivery, but did not change the endothelial cell transcriptome, endothelial or astrocyte viability, or inflammatory responses in an in-vitro BBB model generated from AD patient-derived cells (Wasielewska et al., 2022).

Most clinical studies to date use InSightec’s ExAblate® Neuro device. This helmet-mounted array of 1,200 probes is used with a stereotactic frame to deliver focused, low-intensity sound waves to defined brain regions while the patient is undergoing MRI. The device is approved in the U.S. and other countries for high-intensity surgical ablation of tissue, including to treat essential tremor and Parkinson’s disease. Temporarily opening the BBB requires 100-fold lower energy than tissue ablation. Other devices, including a frameless version, and an implantable sonicator, are in development (e.g. Epelbaum et al., 2022).

Findings

In 2016-2017, a feasibility trial in Ontario enrolled five people with mild Alzheimer’s disease for two rounds of focused ultrasound, spaced one month apart and targeting a small region of the frontal lobe. BBB opening was detected with the MRI contrast agent gadolinium. The procedure produced no adverse events, hemorrhages, or brain swelling, and BBB opening was reversed after 24 hours (Aug 2018 conference news; Lipsman et al., 2018). A transient decrease in functional connectivity occurred after BBB opening, which also resolved by 24 hours (Meng et al., 2019). This academic trial, using the ExAblate device, was sponsored by InSightec.

In September 2018, an InSightec-sponsored safety trial began at West Virginia University, enrolling 10 patients with mild AD for three serial treatments targeting the hippocampus/entorhinal cortex. The study was later expanded to two more sites, and enrollment increased to 50. Interim results on six patients were published, reporting rapid BBB opening in the targeted regions, which reversed in 24 hours (Rezai et al., 2020). Participants had no adverse events, and neither cognitive nor neurological worsening after the procedure. Opening of the BBB was seen in 95 percent of the targeted area the hippocampus, covering one-third of the hippocampal volume. Amyloid PET scans revealed an average 5 percent reduction in probe uptake one week after the third treatment (D’Haese et al., 2020). Published data on three women in this study reported no gadolinium contrast agent entering the brain parenchyma after 24 hours, consistent with BBB closure. However, contrast agent was detected in the perivenous space of the blood-meninges barrier, away from the target opening sites, for up to 48 hours. This blood-meninges opening resolved by one week, and no adverse effects were reported in these patients (Mehta et al., 2021, commentary by Klibanov, 2021). The perivenous appearance of contrast agent was proposed to be evidence of glymphatic efflux (Meng et al., 2019).

Additional data was published on 10 patients who had received three treatments targeting brain regions containing the highest amyloid loads, including the hippocampus/entorhinal cortex, and parietal and frontal lobes, and had at least six months of followup (Rezai et al., 2022). Patients were tested on cognition and memory using the ADAS-Cog and MMSE one week after treatment, and intermittently thereafter. Participants declined comparably to an ADNI reference group on the ADAS-Cog and MMSE after six months. Reduction in amyloid plaque averaged 14 percent in the targeted regions. Completion of this trial is planned by December 2024.

In December 2018, another safety trial began enrolling 30 patients to a course of three treatments. The endpoints are device- and procedure-related adverse events through six months, with secondary outcomes of BBB disruption and closure, change in ADAS-Cog, and amyloid tracer uptake by PET. The trial, sponsored by InSightec at the Sunnybrook Health Sciences Centre in Ontario, Canada, is anticipated to end in December 2024. Results on the first nine patients were published (Meng et al., 2023). All showed BBB opening in the targeted areas of the default mode network, which included the bilateral precuneus, anterior cingulate cortex, and the hippocampus, with no serious adverse events or deleterious cognitive effects. After treatment, patients had a modest reduction of amyloid on PET scans, and stable biomarkers of AD pathology and BBB integrity; they also had a transient elevation of NfL. 

From 2018-2021, the company sponsored pilot studies demonstrating the safety and feasibility of focused ultrasound to the primary motor cortex in eight patients with ALS, and to the posterior putamen in seven people with Parkinson’s disease and cognitive impairment (Abrahao et al., 2019; Pineda-Pardo et al., 2022). In the PD patients, there was a small but significant reduction in Aβ tracer uptake in the targeted region and no change in FDOPA PET. An additional company-sponsored pilot assessed the use of focused ultrasound-BBB disruption to deliver Cerezyme® β-glucocerebrosidase enzyme in four people with Parkinson’s disease. The trial was supposed to finish in December 2022; no further information has been made public. 

A 2020 pilot study in six mild AD patients in Korea found repeated opening of volumes up to 30 ml in frontal lobe regions was safe and tolerable (Park et al., 2021). In 2022, the same investigators began a new trial with six additional patients, offering a higher number and more frequent treatments. 

In August 2020, a Phase 2a trial at Columbia University began testing a portable ultrasound transducer that does not require patients to be immobilized in an MR machine (see Wu et al., 2018 and Pouliopoulos et al., 2020). This NIA-funded study plans to enroll six people with AD, and includes outcomes of successful opening of BBB, safety, and change in amyloid PET and MMSE scores. Completion was planned in December 2023. Results in a single patient were published, showing a 1.8 percent reduction in amyloid PET SUVr 3 weeks after treatment, but a 5.9 percent increase after three months (Karakatsani et al., 2023).

In July 2022, a Phase 1 trial began to test the effects of FUS-BBB opening in AD patients treated with an anti-amyloid antibody. Five participants with mild cognitive impairment or mild dementia will receive aducanumab infusions monthly for six months at a top dose of 6 mg/kg, below the effective dose of 10 mg/kg established in Phase 3 trials. After each infusion, participants will undergo BBB opening with the ExAblate protocol. The primary outcome is safety; secondary is change in brain amyloid, ADAS-Cog, and MMSE. According to interim results on three patients presented at the October 2023 CTAD conference, the procedure cleared about half of baseline amyloid in the targeted regions in six months (Nov 2023 conference news). Clearance in ultrasound-targeted regions was greater than in non-targeted areas. No ARIA was noted, but none of the patients carried the ApoE4 gene. The most common adverse event was headache, and one patient experienced cognitive worsening during follow-up. Results were published after peer review (Rezai et al., 2024). The study, at West Virginia University, is planned to run until summer of 2029.

Use of focused ultrasound for BBB opening is also being tested to improve delivery of chemotherapeutic agents to glioblastoma and other brain cancers (e.g., Carpentier et al., 2016).

Other studies are evaluating targeted low-intensity ultrasound, without bubbles, as a means of noninvasive neuromodulation of deep brain structures in the absence of BBB opening (for preclinical evaluation, see Jun 2021 news). This procedure in healthy adults has been shown to increase blood flow, neural activity and functional connectivity (Kuhn et al., 2023). An open-label trial is enrolling 100 patients with PD or AD with MCI or dementia, to receive short-term, transcranial focused ultrasound to the putamen and substantia nigra or the hippocampus, depending on their diagnosis. Preliminary results on 22 participants have been reported, claiming safety and possible cognitive improvements (Nicodemus et al., 2019). The trial is expected to end in early 2025. A 40-patient, sham-controlled trial of ultrasonic neuromodulation in people with cognitive impairment and confirmed AD biomarkers is registered to begin in April 2024. Two smaller studies are also registered, testing single sessions of neuromodulation for safety and cognitive effects in people with AD.

For details on focused ultrasound trials, see clinicaltrials.gov.

Last Updated: 16 Jan 2024

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References

News Citations

  1. Focused Ultrasound Breaches Blood-Brain Barrier in People with Alzheimer’s
  2. Unlocking Blood-Brain Barrier Boosts Immunotherapy Efficacy, Lowers ARIA
  3. No Breach Needed: Ultrasound Improves Memory in Mice
  4. Stop, Hey, What’s That Sound? ... Amyloid Is Going Down?

Paper Citations

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External Citations

  1. clinicaltrials.gov

Further Reading

Papers

  1. Zhou M, Fu X, Ma B, Chen Z, Cheng Y, Liu L, Kan S, Zhao X, Feng S, Jiang Z, Zhu R. Effects of low-intensity ultrasound opening the blood-brain barrier on Alzheimer's disease-a mini review. Front Neurol. 2023;14:1274642. Epub 2023 Nov 1 PubMed.
  2. Karakatsani ME, Blesa J, Konofagou EE. Blood-brain barrier opening with focused ultrasound in experimental models of Parkinson's disease. Mov Disord. 2019 Sep;34(9):1252-1261. Epub 2019 Jul 30 PubMed.
  3. Mooney SJ, Shah K, Yeung S, Burgess A, Aubert I, Hynynen K. Focused Ultrasound-Induced Neurogenesis Requires an Increase in Blood-Brain Barrier Permeability. PLoS One. 2016;11(7):e0159892. Epub 2016 Jul 26 PubMed.
  4. Liu X, Naomi SS, Sharon WL, Russell EJ. The Applications of Focused Ultrasound (FUS) in Alzheimer's Disease Treatment: A Systematic Review on Both Animal and Human Studies. Aging Dis. 2021 Dec;12(8):1977-2002. PubMed.