Alzheimer’s disease (AD) is a neurodegenerative condition that impacts 6 million Americans. According to the Alzheimer’s Association, this figure is expected to rise to 30 million by 2050 as the population ages.
Focused ultrasound is now being explored as a revolutionary therapy that could offer hope to patients. This innovative approach not only signifies a potential paradigm shift in treating a devastating disease, but its forward development also illustrates several incredible collaborative efforts and scientific advancements. In this blog, I summarize a presentation I shared with the Foundation’s Board and Council members to highlight the exciting work in this space, outlining the clinical milestones and the future direction of this promising treatment modality.
The Genesis of a New Treatment Paradigm
The discovery that focused ultrasound could open the blood-brain barrier (BBB) presented a breakthrough for the technology. As early as 2007, preclinical studies were suggesting that the technique was possible; subsequent studies began exploring focused ultrasound–induced BBB opening (FUS BBBO) in combination with delivering therapeutics to the brain – including anti-amyloid antibodies.
Around 2015, two independent laboratories in Canada and Australia reported that focused ultrasound – both with and without BBBO – could improve memory in preclinical models of AD. Due to these studies, the Foundation convened a group of multidisciplinary experts, including neurologists, neurosurgeons, neuroradiologists, and preclinical researchers, at its first AD workshop, marking a pivotal moment in collaborative research and clinical trial planning.
Clinical Milestones and Encouraging Results
Within three years, in 2018, a landmark study – the first in-human clinical trial of focused ultrasound for AD – was published in Nature Communications. The team at Sunnybrook Health Sciences Centre in Toronto had demonstrated that FUS BBBO in the right frontal lobe was feasible, safe, and reversible in patients with AD. Because the BBB also plays an important role in preventing unwanted pathogens from entering the brain tissue, researchers wanted to confirm that focused ultrasound only opened the BBB for a short time and that the BBB was able to close spontaneously.
Notably, the study also showed that there seemed to be a slight decrease in the amyloid plaques – a hallmark of AD pathology – in the part of the brain where the BBB was disrupted. These early results were encouraging and have been confirmed in subsequent FUS BBBO studies that decreased amyloid in other areas of the brain affected by AD (such as the hippocampus).
Beyond the research laboratory, further clinical studies continued to explore FUS BBBO and found that larger volumes of the BBB could be safely opened over multiple sessions a few months apart. Researchers continued to observe the reduction of plaques. Clinical studies spanning multiple countries and even using various focused ultrasound machines, confirmed the reproducibility and safety of FUS BBBO in patients with AD, providing a foundation for combining this technique with therapeutic drugs to enhance treatment efficacy.
An unexpected, yet promising finding from a recent clinical trial (in press) was recently described: researchers opened a larger area of the BBB than has been previously published and noticed that the amyloid plaques decreased not only in the areas treated with focused ultrasound, but in other areas of the brain not directly targeted with FUS BBBO. These results are notable because the focused ultrasound BBBO applied to larger areas may activate more microglia – cells that can clear plaques – enabling them to search and digest amyloid for excretion, not only where the BBB is opened, but also in nontreated regions of brain tissue. In addition, published preclinical studies (Lee, et. al., Mehta, et. al.) have reported that FUS BBBO enhances glymphatic clearance of abnormal protein aggregates, and clinical studies with FUS BBBO in patients with AD have confirmed prominence of the perivenular regions on MRI scans, which is consistent with activation of the glymphatic system.
Next Steps to Enhancing Drug Delivery and Efficacy
After it was accepted that FUS BBBO was potentially effective in clearing plaques by itself, the next major step for researchers was to combine the technique with a drug that by itself, cleared plaque. In 2021, a preclinical study revealed that combining FUS BBBO with drugs like aducanumab (Aduhelm) significantly decreased plaques and improved cognitive outcomes in Alzheimer’s models, more than with ultrasound alone or Aduhelm alone. These findings suggested that focused ultrasound not only facilitated increased drug delivery by nearly five-fold, but also enhanced the therapeutic impact, offering hope for more effective AD treatments.
Earlier this year, preliminary results from the initial three participants enrolled in a first-in-human clinical trial using FUS BBBO plus repeated administration of the drug Aduhelm (now using Leqembi) were published in the New England Journal of Medicine(NEJM). In this study, the team at West Virginia University Rockefeller Neuroscience Institute concluded that the combination therapy markedly decreased amyloid plaque in the areas of the brain treated with FUS BBBO compared with the other side of the brain (which received only the systemically administered drug) at the 26-week follow up. Jürgen Götz, PhD, a key researcher of focused ultrasound for AD, published a commentary on the NEJM article, and suggested that focused ultrasound may have various mechanisms of action that could contribute to the treatment of AD. His commentary suggested that FUS BBBO with drugs could increase drug delivery (as described above), that FUS BBBO alone (without a drug) may activate microglial cells that digest amyloid plaques, and that focused ultrasound without BBBO may have a neuromodulatory effect.
An Alternative to BBB Opening: Neuromodulation
Several clinical trials are now exploring the use of focused ultrasound neuromodulation in patients with AD. This technique does not open the BBB, but other effects could impact patient outcomes. These clinical studies are targeting multiple areas of the brain, including the hippocampus, and some are single-session treatments while others are using multiple sessions. Interestingly, neuromodulation has been shown to improve memory and recall, Mini Mental Status Exam scores, Alzheimer’s Disease Assessment Scale – Japanese subscale scores, as well as suppress cognitive decline in patients. According to Dr. Götz’s commentary, neuromodulation studies performed with focused ultrasound alone (without microbubbles) have been shown to be beneficial due to a mechanism of action using radiation forces that alter synaptic communications, change the extracellular matrix, release glutamate from astrocytes, and favorably alter neurotransmitters (similar to the FDA-approved drug memantine). Other neuromodulation studies also use focused ultrasound and microbubbles without opening the BBB, and similar mechanisms of action may be deployed. Interestingly, the various clinical benefits seen with neuromodulation studies compared to FUS BBBO studies may be because larger areas of the brain are treated with neuromodulation: up to almost 140 cm3 versus 40 cm3 with FUS BBBO (where clinical improvement has only been reported with the Caregiver Administered Neuropsychiatric Inventory score).
State of a Growing Field
To date, 15 studies have been completed or are ongoing exploring focused ultrasound for AD in the US, Canada, France, Germany, Korea, Japan, and Australia. In all, eight companies are testing their devices for this indication, and the devices are using a range of imaging modalities for targeting, including real-time MRI-guidance, neuronavigation with a previously performed MRI scan, and even an implantable focused ultrasound transducer within the skull.
The evolving landscape of focused ultrasound research is characterized by expanding clinical trials, the exploration of neuromodulatory effects, and integrating more drug therapies with FUS BBBO. Ample preclinical research is paving the way to explore the use of various classes of neurotherapeutics in clinical studies, such as newer anti-amyloid and anti-tau antibodies; glycogen synthase kinase-3 inhibitors (which also prevent amyloid formation); intravenous immune globulins (which decrease amyloid and promote neurogenesis); and tropomyosin receptor kinase A (which reduces plaque, enhances cholinergic function, and promotes neurogenesis).
Perhaps most exciting is the potential to use gene therapy to treat AD. The Foundation has a dedicated gene therapy program, and it has been shown that focused ultrasound can be used to spatially target the hippocampus and other brain networks affected by amyloid/tau deposits. It can also deliver higher gene concentrations to these areas, limit toxicity to the rest of the body, and enhance penetration of the gene vectors through the parenchyma into the cells.
The Foundation is committed to accelerating AD research because its treatment is a critical unmet need, and focused ultrasound could help so many patients. We have organized two workshops on the topic, held a special session at the 2022 Symposium, and hosted two webinars featuring experts in the field. To date, we have funded five preclinical studies and five clinical trials for AD. Additional ongoing studies aim to optimize FUS BBBO parameters, evaluate the effectiveness of combined treatments, and standardize outcome measures across studies. This year, we launched a dedicated $10 million fundraising campaign to fund research for neurodegenerative diseases like AD. Thus far, more that 170 patients with AD have been treated in clinical trials, and we are hopeful that focused ultrasound can impact countless more lives in the future.
Watch Dr. LeBlang’s Board Presentation
Suzanne LeBlang, MD, is a neuroradiologist and the Director of Clinical Relationships at the Focused Ultrasound Foundation. She started performing focused ultrasound procedures in 2004, and has treated uterine fibroids, adenomyosis, and pain from bone metastases. She now uses her expertise to advance focused ultrasound clinical trials and commercial treatments for various neurological diseases.