How Focused Ultrasound is Changing Alzheimer’s Treatment

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NANCY KEACH: Welcome, everybody. Good morning. Good afternoon. I’m Nancy Keach. I’m with BrightFocus Foundation, which is a 51-year-old nonprofit that funds scientific research globally to understand and treat Alzheimer’s disease, macular degeneration, and glaucoma. And to date, we have funded just over $310 million in research globally.

We’re delighted to bring this presentation to you today and also want to thank the program’s educational sponsors, that is, Biogen, Lilly and Genentech. And today, I also want to give a shout-out to the Focused Ultrasound Foundation, which is an organization that is co-funding a couple of grants with BrightFocus Foundation right now that are using this technology. So they’ve been very helpful to us, and we’re very grateful that they are also supporting research in this area.

Also, some of the questions that were submitted were not on the topic of focused ultrasound, but we want you to know that we have been doing hour-long episodes on lots and lots of different research topics to do with Alzheimer’s and related dementias. So if your question is not answered today, all these episodes that you’re seeing on the screen right now are on our website and free for you to access. So please feel free to use this resource.

And now I’m going to jump in with great delight to introduce Dr. Ali Rezai, who is a functional neurosurgeon dedicated to advancing the treatment of people with neurological and mental health conditions. He is the executive director of the West Virginia University Rockefeller Neuroscience Institute, John D. Rockefeller IV Neuroscience Chair, Associate Dean of Neuroscience, and professor of Neurosurgery at West Virginia University. Since 2018, he has built the Rockefeller Neuroscience Institute into a global leader in patient care, education, and research. And I’m sure many of you have seen him on TV on 60 Minutes or The Today Show. And Dr. Rezai focuses his clinical practice on neuromodulation treatments for movement disorders, chronic pain, brain and spinal cord injury, obsessive-compulsive disorder, Alzheimer’s, and drug addiction. His research focuses on rapid cycle innovation and first-in-human clinical trials of new approaches. Welcome, Dr. Rezai. We are absolutely thrilled to have you here today.

ALI REZAI: Thank you, Nancy. My pleasure. And also, I appreciate everybody on the call and the work that BrightFocus Foundation does to advance innovations that help people with Alzheimer’s and eye conditions.

NANCY KEACH: Thank you so much. All right. So I’m going to jump right in. And I’m going to start with the very basic basics here. I’m going to ask you three questions. What is focused ultrasound? What is the blood-brain barrier? And what is neuromodulation? Let’s just get some of those terms straight. And if you want to show a video, we can do that. You let us know in very lay terms what those terms mean.

ALI REZAI: Thank you, Nancy. So focused ultrasound. Many of you know what ultrasound is. You deal with it routinely. It has transformed the way diagnostics is done in medicine. So very common to look at a baby in a womb. You’ve all seen the pictures. That’s from an ultrasound or imaging into heart echocardiogram or a number of other applications. We’re using ultrasound to diagnose various aspects of human disease.

But now we’ve had significant engineering advances and technological innovations that allows us to use higher energy focused ultrasound energy to various parts of the brain to treat a number of conditions. For example, it can be from addictions to Alzheimer’s to dementia to brain tumors and many others. And fundamentally, what is ultrasound? Sound waves. Normally, humans can hear energy sound waves from 20 Hertz– that’s cycles per second of sound to 20,000. Ultrasound is anything above 20,000, so it’s just higher frequency. And the ultrasound technology that’s emerging is transforming the way we’re treating a number of conditions. So imagine you have 1,000 ultrasound probes, not one that you use to look at a baby in a womb, but 1,000 of them, that you can deliver the ultrasound energy to different parts of the brain, for example, areas involved in cognition or memory or anxiety, or areas in the brain that have an accumulation of beta amyloid proteins and plaques that are one of the hallmarks of Alzheimer’s to really open the blood-brain barrier, to accelerate the delivery of drugs, to clear the plaques, or to activate the areas of the brain that are not as active, involved in cognition or anxiety or memory, or for brain tumors to open the blood-brain barrier to deliver more chemotherapy.

So it is transforming the way we are treating various brain conditions, from addictions and Alzheimer’s to brain tumors to epilepsy to Parkinson’s and tremor.

NANCY KEACH: So it’s a sound wave. Ultrasound is sound waves that you’re able to put into the brain. And I will show the video, potentially, but the blood-brain barrier. Well, let’s have you described just simply the blood-brain barrier, because what we’re going to be talking about today is that the use of this focused ultrasound technology, it’s used a couple of different ways, and one of them involves opening the blood-brain barrier to allow therapeutic drugs to get in more easily to the brain. So let me have Dr. Rezai describe that.

ALI REZAI: And Nancy, that blood-brain barrier is very important. So basically, all of us have a blood-brain barrier. What does that mean? All of your vessels, the blood vessels in your brain, have an additional protective layer barrier that’s important for preventing other– Brain is very sensitive to drugs and other substances that are harmful. So you don’t want it to get in. So it’s a naturally interfacing barrier that prevents substances to get into the brain. And that’s good for safety. But the problem is that many drugs and antibodies, and other medications are too large, and they cannot get into the blood-brain barrier easily. As a result, you have to take larger doses of medications, more infusions if you’re getting antibodies, long-term treatment to really allow some of that drug to seep into the brain to overcome the blood-brain barrier or that gate in the brain.

So I think that’s an area in medicine, in neuroscience, for the past 30 years that people have been strategizing how to open the blood-brain barrier in the areas where it needs to be to deliver the medications better. Because imagine if now you have 10 times the dose of the medication getting into the area in the brain that is problematic and needs that medication, the effect can be more significant.

For example, it’s being used for brain tumors and chemotherapy, where now we can deliver 8 to 10 times more concentration of the chemotherapy agent into the brain to treat the cancer in the brain. And that’s the application of the blood-brain barrier opening. So maybe we can play that first video that talks about what the blood-brain barrier is, please.

[VIDEO PLAYBACK]

– Deep inside the brain is a shield that protects against invaders. It’s called the blood-brain barrier. It allows nutrients to reach brain cells from the bloodstream while filtering out germs and other harmful substances. But there’s a downside– drugs needed to treat brain diseases, too often, can’t get through, either.

The blood-brain barrier is made up of cells that line most of the brain’s smallest blood vessels. Those endothelial cells are tightly packed together, so only small molecules slip by. Many drugs for cancer, Alzheimer’s, and other brain diseases are too big to easily pass through. But what if scientists could make the blood-brain barrier temporarily leak in just the right spot in hopes of one day helping those medicines sneak inside?

To try, they inject microscopic bubbles into the bloodstream. MRI scans pinpoint the desired brain location. Then, researchers beam what’s called focused ultrasound right at that spot. The ultrasound waves make the microbubbles vibrate, creating a temporary opening in the blood-brain barrier. An experiment with a handful of Alzheimer’s patients shows the barrier opened, let some harmless dye seep in, and then sealed back up.

Similar small safety tests are getting underway with brain tumor patients and people with Lou Gehrig’s disease.

[END PLAYBACK]

ALI REZAI: Thank you. So basically, this is a new technology that allows us to open the blood-brain barrier because you cannot keep it open always. So it temporarily opens it. So now you have a window of time where you can deliver more drugs to the area where the problem is. So it’s very focused therapy. And so there’s two applications of blood-brain barrier opening that has relevance for Alzheimer’s. There are many studies going on for brain tumors and others that we can talk about that as well if there’s an interest.

But regarding Alzheimer’s and dementia, by opening the blood-brain barrier, we want to deliver more drugs to the parts of the brain that have, for example, higher concentration of beta amyloid protein and plaques to allow them to impact those plaques or allow the drugs to get in the higher penetration. So you don’t need to give as much drugs potentially in the future, and you can reduce the dose. I want to be careful to caution that this is all research still. It is not FDA-approved for treatment, so this is an important point. There’s active research going on worldwide using blood-brain barrier opening with focused ultrasound technology. But the beauty of this is that now, for the first time, we can selectively open the blood-brain barrier on demand anywhere in the brain with a pathology, see what the problem is and link it up to a therapeutic agent to hopefully accelerate or increase the penetration of that drug or therapeutic agent to the brain to clear the plaques more or treat more.

The second major application is now we can do what’s called a liquid biopsy. That’s a brain biopsy without doing surgery. So imagine now if the blood-brain barrier is open. Now you can get more drugs to get into the brain, the area where it’s open. But at the same time, the biomarkers or proteins that normally does not get into the blood because the barrier is not open, they can get into the blood, and you just get a venous sample, a blood sample, and potentially be able to diagnose these conditions years ahead of time because now you’re seeing the biomarkers that typically stain the brain more and do not get into the bloodstream are now getting in. So the application would be a diagnostic by opening the blood-brain barrier, so we can have earlier diagnosis potentially. And also monitor treatments to see if some of these biomarkers, for example, plaques, beta amyloid, or tau that are associated with Alzheimer’s, if their levels are decreasing. So it can have a diagnostic and monitoring capabilities and the second is treatment capabilities. But all very active and ongoing research. It’s a technology that allows tremendous opportunity for the future.

NANCY KEACH: It is so exciting for Alzheimer’s and many other conditions. And I’m grateful that you said it is not really generally available today. We had a tremendous number of questions about availability. There are clinical trials going on which we are going to post and let people know about it, but it’s not at a stage where you can walk into your doctor’s office and request a focused ultrasound procedure yet. But I think the pace of research has been incredible in the last number of years. I don’t know to what extent cuts in federal funding will affect that, as I’m sure everybody is aware. And that’s why I would say private foundations like ours, who rely on private donations, and so on, are more important than ever to keep this research going.

And what’s really fascinating to me, and we’re going to talk about it related to Alzheimer’s today, though, is that there are applications to what Dr. Rezai is doing in so many untreatable, currently untreatable or hardly treatable conditions like OCD and anxiety and depression and then these other kinds of diseases. But I’m going to go for this moment back to the work that was profiled. So you did a small trial of patients that enabled the blood-brain barrier to be opened, and you administered some Aducanumab, which, if you guys are following the treatments, the new treatments on the market, Aduhelm was the first one that was FDA approved. And then that was followed Leqembi first and then Kisunla. And for those of you that don’t know what I’m talking about, we have there are episodes on our website, full hour-long episodes explaining those drugs at the moment they got approved and how they were to be used. And they can be used in early-stage cognitive impairment or very mild Alzheimer’s disease to remove those sticky protein plaques that Dr. Rezai was mentioning. So you did a trial then with Aducanumab. Aduhelm is the market name. Do you want to just talk a little bit about what you found from that?

ALI REZAI: Exactly. So I think for your audience, as many of you know, we have now excitement. And as you were saying, Nancy, the Kisunla and Leqembi, for the first time, we have what we call disease-modifying therapies, which are exciting for Alzheimer’s disease, where these antibodies directed against the beta amyloid protein clumps in the brain are able to clear the beta amyloid in the brain. And that’s really exciting to do that. And these antibody treatments involve every other week or once a month, going into the infusion suite of getting an IV and then sitting down and having the antibody infuse over the next hour. And for the next couple of weeks, three weeks, it is circulating in your bloodstream, slowly gets across the blood-brain barrier, and that’s what opportunity is. And then over time, it clears these plaques.

And what’s really exciting is that it’s not a cure, but it’s showing that we now have a way to clear these beta amyloid plaques with antibody infusion. And that has resulted in a reduction in the progression of the disease. And that is the first time we’re seeing a reduction in progression. So there’s a very large number of centers across the country who are giving the antibody treatment.

And our study was to say, OK, we’re delivering the antibodies, and you have to give it every other week. At that time, aducanumab was FDA-approved and available; it is no longer available. So the only two drugs that are available are Kisunla and Leqembi are called lecanemab and donanemab, provided by Biogen, Eisai, and Eli Lilly, FDA-approved. So what we said is that can we combine the two treatments. Meaning that the antibodies are normally circulating in your bloodstream when you get an infusion.

What we want to see if the ultrasound can open the blood-brain barrier and accelerate the delivery of the antibodies. And a lot of animal studies that were done are doing this combination therapy have shown that the ultrasound, when it opens the blood-brain barrier, can increase the delivery of the antibody to the brain by seven to eight-fold. So we want to demonstrate that in the proof-of-concept study. And that was a study that was published in The New England Journal of Medicine. And we showed that we can actually increase the removal of these beta amyloid plaques further by opening the blood-brain barrier. And on average, we’re able to reduce by 50% more the plaques in the brain when combined to antibody with the blood-brain barrier opening.

So it was a proof of concept, but it shows a potential capability for the future where the ultrasound can now open the blood-brain barrier, for example, in an area with a high density of beta amyloid plaques, maybe in the frontal part of the brain, parietal part back of the brain, or areas that are devastated with a lot of plaques in the brain for Alzheimer’s like areas involved in thinking and memory, like hippocampus, the frontal lobes, behavior, personality, parietal lobes involved in visual spatial orientation, finding your way around. So depending on what part of the brain is impacted, usually large parts of the brain, you have a manifestation clinically in language abilities, attention, concentration, memory and behavior. So that was the concept. And perhaps, Nancy, we can just play the video that shows the ultrasound technology of how it’s applied.

So there’s application one is doing a lesioning where you can stop the tremor of Parkinson’s. Application two is the blood-brain barrier opening. And application three is what we do with neuromodulation, that we can talk about as well, that activates the parts of the brain involved in thinking and memory and reduces the anxiety in the brain.

[VIDEO PLAYBACK]

– Focused ultrasound has three main treatment applications– one, high-intensity focused lesioning, two, low-intensity opening blood-brain barrier for targeted drug delivery, three, low-intensity neuromodulation. The blood-brain barrier is a key element of our brain. The blood-brain barrier is comprised of tightly knit endothelial cells that form a protective lining along the majority of all the brain’s blood vessels. This acts as a shield that protects the brain, allowing essential nutrients to enter the brain but preventing harmful substances from entering the bloodstream.

This barrier also prevents larger molecules from entering the brain, such as many essential drugs and therapeutics used to treat diseases like brain tumors, Parkinson’s, and Alzheimer’s disease. Inside an MRI scanner, ultrasound waves are focused on precisely targeted regions of the brain. This is achieved by using an array of ultrasound sources inside the helmet covering the head.

Microscopic bubbles are then injected into the bloodstream, and the ultrasound waves activate the microbubbles, making them vibrate and expand. This creates a tiny temporary opening in the blood-brain barrier. The temporary ultrasound-guided opening of the blood-brain barrier allows for therapeutics, such as drugs and antibodies, to increase their entry into the brain. These antibodies then attach and reduce the Alzheimer’s plaques in the surrounding brain tissue.

After the focused ultrasound procedure, the blood-brain barrier will reseal and regain its protective functionality within 48 hours.

[END PLAYBACK]

ALI REZAI: And if you go to the next slide, that shows the outcome of this study published in The New England Journal of Medicine. And you can see here when you combine the two treatments, and here’s a picture that shows–The green on the bottom is the reduction that you see in the brain plaques when you combine the ultrasound with the antibody, and the yellow shows just the area of the brain receiving the antibody alone. So you can see the areas that have received the ultrasound antibody on the right panel at 26 weeks. The red is a PET scan that shows beta amyloid concentration in the brain. And you can see when you add the ultrasound, that area essentially cleared of beta amyloid much faster. So the goal is to be able to clear the plaques within three to six months versus waiting two to three years with the antibody infusion alone.

NANCY KEACH: And that’s a very dramatic– I love that slide because it shows a dramatic difference in how quickly the drug works when it can get through the blood-brain barrier more easily. So I’m going to ask one question about this. And then, thanks to those of you that are starting to put questions into the chat. I’m going to get to those. But I’m just going to ask you one thing first. So you’ve shown that the amyloid was reduced much more quickly and very effectively. Did you follow this group of patients to see whether there was actual improvement in cognition or daily functioning, or memory? Do we know that yet, or is that still an unknown?

ALI REZAI: That’s a great question. That’s still unknown. The numbers are very small. It’s only a handful of patients that we did with lecanemab and Leqembi, the other antibody. So we need much larger studies and more patients. So we can see how this combination therapy can accelerate the impact of the drug, meaning that maybe it can help reduce the progression of disease faster than the antibody alone. But we don’t have that answer, hence why this is still research. It’s important research that allows that shows that you can deliver the drug faster and more penetration. But we need much more studies. So that is to be determined.

The good news is that the antibody by itself, over time, clears the plaques and also can reduce the progression of disease. So our goal is to see if we can accelerate that. So people with Alzheimer’s, you want to have a running start against Alzheimer’s. So imagine if you can clear the plaques in three months, in six months. Why not do that if you can do that in three to six months versus waiting two years?

So antibodies are excellent therapies. This is a way to maybe augment the impact of the antibodies. But again, it’s research. We need to be careful and cautious, and it is performed in a handful of centers, but it’s about an exciting opportunity leveraging ultrasound for Alzheimer’s and blood-brain barrier opening.

NANCY KEACH: Holly and Maria both asked about how does this affect the risk of ARIA? So we know that in the use of those monoclonal antibodies, Leqembi and Kisunla, there is a side effect, which we describe as small brain bleeds, that’s called ARIA, and that has been a risk. So is there a similar risk, or does this eliminate that risk?

ALI REZAI: So we ARIAs are very serious, and we should always monitor them. So for the audience, ARIAs stands for Amyloid Related Imaging Abnormalities. And you can have edema, or you can have a hemorrhage. So ARIA-E is for edema. ARIA-H is for hemorrhage, microhemorrhages. And what happens is that that’s associated with patients receiving this antibody therapy. And usually, it’s without symptoms and is fine and is monitored and treated with steroids or medications to resolve before resumption of the antibody. But sometimes, it can cause headaches, confusion or other neurological deficits. So these ARIAs are important side effects for people with antibodies. So in our studies, we did not see the ARIAs associated with blood-brain barrier opening. But again, the numbers are small.

NANCY KEACH: Can I ask you what the numbers are? How many patients were in your trial?

ALI REZAI: We’ve done five patients in the trial in this combination, so it’s a small number. And it’s got a long way to go. So there are sites also in Canada and Europe, and other sites in the US starting these trials not only with Kisunla or Leqembi rather, but also other treatments, IgGs or other combination therapies for Alzheimer’s. And also people are looking at it for Parkinson’s treatments, looking at ALS treatments. So it really is opening up a whole new frontier for delivery of agents into the brain. And some of these drugs from pharmaceuticals cannot get into the brain enough, and that’s why you have to have higher doses, that can have side effects. So, potentially down the line with more research, you can reduce the dose of the drug if you’re opening the blood-brain barrier. So maybe some of the drugs that have a large side effect. Profiles may now be more beneficial with ultrasound if they’re delivered to a smaller dose.

NANCY KEACH: Makes sense, perfect sense. So if you had a crystal ball, we have Jim on YouTube asking when is full FDA approval most likely to occur? Let’s take your crystal ball guess.

ALI REZAI: Yes, so this is going to take at least several years. We need much more studies. It’s a very complex study and trial. But for blood-brain barrier opening by itself, diagnostically, that’s FDA-approved. So you can do liquid biopsy or biopsy of the brain for brain tumors, for example, using ultrasound, which is exciting by opening the blood-brain barrier. But for Alzheimer’s and dementia, they are not FDA-approved and it still requires years of research. Obviously, looking at safety, which is the first and foremost and then the benefit and longevity. But we think this actually augments and provides additional opportunities for the drugs to be more safe and effective.

But the blood-brain barrier opening, Nancy, the diagnostic part is really, I think, important because just the doing of being able to do a brain biopsy without actually opening the blood-brain barrier is opening up many possibilities of earlier detection of Lewy body disease, or chronic traumatic encephalopathy or frontotemporal degeneration, or these other elements, diseases that cause dementias. So that’s an exciting opportunity to study more and use that with the evolution in blood biomarkers, which is fantastic area of evolution with tau and others that you’re detecting in your blood. Perhaps the combination of all of these can really make us much more precise and having a better window about time in the future if somebody has a higher risk of or getting diagnosed earlier, which means that you can intervene earlier and help patients.

NANCY KEACH: So a lot of people are asking how they can get into your study or get into a study. The Focused Ultrasound Foundation has on their website a link to several active clinical trials.https://search.app/QMuk9WBZCswjnLTq8 These are early-stage trials, so that you all know. But what I saw, and there may be more, so this may not be comprehensive. But when I looked at it yesterday, I saw that trials were available in Utah, West Virginia, Toronto, Los Angeles, and then 10 locations in Florida, New York, and Ohio, and Texas, and one in Japan. So for those of you that are writing in, how can I participate you can click on the link above.

We had several questions sent in earlier about whether people who are, and I know there’s the now and then there’s in the future, but people who are in moderate or later stages, whether this will benefit them or is this similar to the monoclonal antibodies, only something that works if you’re in a mild cognitive impairment.

ALI REZAI: Yes. So right now, for these studies with focused ultrasound in Alzheimer’s, it is for people that are very early on in the disease. So Mild Cognitive Impairment or MCI or early Alzheimer’s. And also people who do not have the APOE4, which is a biomarker, also, so that’s a contraindication. But right now, it’s for very early stage of Alzheimer’s disease at this point.

NANCY KEACH: And why is being APOE4 positive or homozygote, why is that not work with this technology?

ALI REZAI: So the APOE4 individuals that have APOE4, their brains are more sensitive and their brains are more sensitive for ARIAs and their brains are more sensitive for having hemorrhages and more problems. So because this is a safety study, first and foremost, we need to make sure that we’re able to show demonstrate benefits. So in the future, I think we can expand. But APOE4 people can still get the antibodies with it. But somebody who has an APOE4 positive carriers, they’re eligible for the antibodies but not for the ultrasound. So they’re excluded right now. And APOE4, in general, your brain is much more sensitive and much more susceptible for swelling or edema or hemorrhage.

NANCY KEACH: So, for now, it’s not that this will never work for those people, but for now, because we’re in such an early stage and we’re looking at safety and we’re erring on the side of caution, so to speak.

ALI REZAI: Exactly, it’s for early stage and also people with early stage or mild cognitive impairment due to Alzheimer’s or MCI.

NANCY KEACH: I want to read Elizabeth’s question. “How does liquid biopsy work? I feel stupid, but I don’t understand how the sample is obtained noninvasively. Can you explain that?”

ALI REZAI: Yeah, so first of all, there’s no stupid questions. All questions are valid. So it’s just understanding technology. So if you open the blood-brain barrier, now it’s a bidirectional opening, meaning if you have biomarkers or plaques or proteins that are normally in the brain that do not get into the bloodstream because that barrier is bidirectional. It doesn’t allow things from getting in. Also, it doesn’t allow things from getting out as much. And now imagine if now that barrier gate is open temporarily. So biomarkers in the brain can now get into the bloodstream. And then after you open the blood-brain barrier, you can do a simple blood test, venipuncture blood test. And then sample that blood like we do for all biomarkers. But in this case, you would have a higher concentration of that biomarker that normally is in a very low concentration in the blood because the blood-brain barrier prevents it.

So that’s where the opportunity is, where we can, perhaps, with other technologies that are emerging– and it’s really an exciting time, in my opinion, for Alzheimer’s and dementia. So in my opinion, tremendous progress and we need to accelerate the research. And Nancy, you mentioned that what you’re doing at BrightFocus Foundation and others is critical because a lot of the work that we’ve done was funded by generous donors or foundations like yours that are trying to advance innovation. And now the NIH funding can be more limited or challenging. So, without the generosity of the donors, individuals, or foundations, we cannot advance the science, whether it’s for ultrasound for other things. So that’s mission-critical.

But the advantage of now this liquid biopsy. So it’s a liquid. You have a biopsy in your blood from the brain. It’s not blood in the brain, but the brain biomarkers get into the blood, and that’s why it’s called liquid biopsy. And it’s noninvasive, so you’re not doing surgery, whereas normal biopsy in the brain requires surgery. And what happens is that you can detect perhaps the conditions earlier. Many of these conditions, as you know, as some audience knows, you can have Alzheimer’s or dementia for a decade or more, growing in your brain, accumulating with these proteins and these mediators, and you’re not aware of it. And it takes 10 years or longer, even for Parkinson’s, same thing, before it reaches a tipping point of accumulation at which time, in that tipping point, you have clinical manifestations, a persistence or a pattern of recurrent memory loss. So finding your way around and/or for Parkinson’s, tremors or all those. Once it happens, it’s already too late because it’s been going on for a decade or longer. Imagine now using this technology, plus all the other great research being done worldwide, to do an analysis and being able to detect things 10 years before they are first manifesting clinically. And that’s an exciting potential. And also, we can monitor treatments. So we can do perhaps do a liquid biopsy to see if there’s an amyloid protein reduction in the brain or tau reduction. So we can also monitor disease. All research right now, but it provides a tremendous potential for the future.

NANCY KEACH: That’s very interesting and that was one of the questions I was going to ask, because there are several research projects right now being done looking at people who are in their 50s or before they have any outward symptoms of cognitive decline, but you can tell on imaging or with a PET scan or through blood tests now, which we’ve talked a lot about on these programs, can see that they have amyloid in the brain, even though they haven’t developed symptoms yet.

So there are actually trials happening now where you can get an infusion of those drugs before you are symptomatic, and there’s a lot of questions about that. But do you foresee a time potentially in the near future, where there would be trials where focused ultrasound and neuromodulation would be used in those trials, in those presymptomatic trials, like for our kids, who if we’re worried that they’re going to get it?

ALI REZAI: And you’re bringing a very important point. Just the antibody alone that’s FDA-approved. Many individuals here at the Rockefeller Neuroscience Institute we’re doing more than 5,000 infusions this year. And a lot of patients very active area. But many people are saying, I have a history. My family, my loved one, my parents, they had Alzheimer’s or Lewy body or frontotemporal degeneration or other conditions. And I’m fine now in my 50s, 40s, 60s, and I want to know what’s going on. These days, people in the 70s and 80s and 90s, they should live full lives. Live life. So this day age 80 is the old 60. So 80s 90s, we do procedures on people in the 80s and 90s routinely. So, Nancy, we’re seeing a lot of people are saying they don’t have the diagnosis of Alzheimer’s, but they want to get a PET scan earlier on. And they’re saying, if it’s positive, like, wow, I have it in my brain, and they’re opting in to getting the antibodies.

It’s not FDA-approved for that, but people are doing that more and more because these disease-modifying drugs can clear out or remove these proteins in the brain and give you a head start, potentially. And yes, indeed, with regards to combining this with the antibodies, I think in the future, as more research is done and approvals are obtained, people are discussing coming in, if there’s one part of the brain based on a brain scan, has a very high concentration of a plaque. Maybe you can target that one part and clear the plaque right away.

So there’s many options emerging for the future. But the key thing is to detect it earlier on PET scan, and other things, as you outlined, are allowing us to see these plaques and see images even before people have clinical symptoms or manifestations externally. So it’s providing a window into the future. That’s very exciting because it provides us with many opportunities to help people.

And as Nancy and the BrightFocus Foundation knows very well, you can try healthy brain habits, exercise, Mediterranean diet, social engagement to improve mental acuity, hobbies, reduce alcohol, reduce stress, better sleep, less exposure to pollution and controlling blood pressure, diabetes, and obesity. All these simple things that we can integrate into our daily lives. Like we practice heart health, practice brain health. So if you know you’re more susceptible for a brain condition based on a family history, or if you know earlier on that you have plaques but you don’t have problems, then it can be very aggressive in doing these healthy brain habits to help get ahead of this problem.

NANCY KEACH: Thank you. Thank you for that. And I’m excited. I think that one of our grantees who’s using focused ultrasound technology is on the call. Yes, Sharon, Dr. Rossi is shaking her head yes. So welcome, and we’re so glad that you’re with us.

The mechanism– I don’t want to get too scientific, but since we’re talking about these grants and research, the mechanism that focused ultrasound, the effect it has on different cell types, we don’t fully understand why it’s able to do what it is doing, correct? And so I know that some of the grants that we’re funding, and Focused Ultrasound Foundation is funding, and I’m sure you’re involved in this research, is looking at how these waves affect different types of cells and how it’s working. So if we, like the young man, I think, who’s on here that’s received a grant from us, if we start to understand how it affects this type of cell or the myelin, what will that mean for us in the relatively near term future meaning 10, 20 years?

ALI REZAI: Yes. So we need to understand how ultrasound impacts the brain, and we need to do more studies, basic neuroscience studies. And you’re very correct. Only understanding how this– So we’re talking about energy waves. So neuromodulation is modulating the nervous system, whether it’s the neurons or the axons that connect the neurons or synapses.

Neuromodulation involves using electrical energy or mechanical energy, in this case, ultrasound, which is a mechanical energy that can disrupt the abnormal functioning of the brain cells. Or you can use light energy or magnetic energy to modulate function. The most common element is electrical energy that’s used for deep brain stimulation, for example, that’s performed in quarter million people worldwide for Parkinson’s or epilepsy.

In the case of ultrasound, it’s very new. We’re trying to understand it, and that’s where more research is needed. But what we’re able to do in another study, for example, we’re delivering ultrasound, not opening the blood-brain barrier, but we’re delivering ultrasound to the part of the brain involved in addiction. It’s a small part of the brain that changes over time and becomes super sensitive, and is driving drug, alcohol, food addiction and gambling addiction. And in a study that we’ve done for the past four years, published now shows that a 20-minute ultrasound treatment can reset that part of the brain involved in addiction and result in very significant reduction in cravings and drug use. And so that opportunity is now being applied for the work that we’re doing for Alzheimer’s, because areas involved for memory and cognition, hippocampus is the part of the brain, temporal lobe, entorhinal cortex or the frontal lobes, we want to be able to increase the activity of those areas to facilitate attention, concentration, memory and improve cognition.

So we’ve done some early studies that shows promise where we can deliver ultrasound, not blood-brain barrier opening, but a different dose to further facilitate the function of those areas that are impaired in Alzheimer’s patients. And this is also being shown in Parkinson’s. So the technology is really very unique because it’s essentially noninvasive. It’s an outpatient two-hour procedure. You get the procedure in the morning. You go home in the afternoon. And that’s what’s transforming the potential. Because in the old days, we did a lot of brain surgeries, a brain implant for Parkinson’s, or tremor.

Now we do ultrasound. But that noninvasive or outpatient aspect of it really opens up the potential to open the blood-brain barrier for diagnosis, earlier disease, or monitoring treatment, opened the blood-brain barrier and combine it with therapeutics so more can get in, or do neuromodulation, which is not blood-brain barrier opening, but to activate the areas that are involved in thinking and cognition, or to reset the areas that are hyperactive for addiction and normalize them. So there are many different opportunities, but it’s an exciting time for the future.

NANCY KEACH: It’s so exciting. And folks are asking, Flora is asking. “I’m in a three-year acumen trial for Alzheimer’s. Could this help me?” Somebody else, “Could you participate in a trial with focused ultrasound potentially if you are on other drugs or in other drug trials?”, or someone asked I think they’d been through or are taking Leqembi. Can they potentially participate in these types of trials?

ALI REZAI: So these trials, again, very important to know that these are early clinical trials that are regulated by the Food and Drug Administration and other regulatory bodies. So no, unfortunately, to keep a clinical trial very clean, so we can understand what’s going on and not have variables that can confound our understanding of the safety and benefit, we cannot enroll people who are already in other trials. And that goes across all kinds of clinical research. You don’t want to create two different interventions that may confuse what’s going on with that one. So unfortunately, no. And that’s important to make sure the safety and the benefits are clear with respect to that intervention,

NANCY KEACH: I’m going to say for now, for now.

ALI REZAI: Yes.

NANCY KEACH: Because it’s so frustrating for people and families. But I’m really actually so excited about the way these technologies all seem to be coming together after decades of research, there’s a lot talk about GLP-1s, all the drugs that are now being used, Ozempic and Zepbound and Wegovy. And they’re now being used for weight loss because they have an effect of cutting cravings down. And you talked about that for addiction. And GLP-1s, we have a lot of Alzheimer’s scientists getting very excited that they think they’re going to have a positive effect potentially on Alzheimer’s. What do you see the intersection being here? Do you see a cocktail treatment that could involve all of these therapeutics and technologies?

ALI REZAI: Potentially, yes, 100%. I think we need to explore. Alzheimer’s is not going away, and it keeps on coming and getting stronger. And more people are having it. So we need to explore any and all possibilities to tackle Alzheimer’s and dementia in every different aspect of it. So indeed, the GLP-1s very, very interesting. And you said cravings. Yes, they’re being used for food noise, as it’s called and also is being used for diabetes. So very powerful drugs that are transforming the future landscape of management.

And interestingly, the ultrasound is acting on an area of the brain called cravings. There’s a craving center for addiction, and we’re seeing a dramatic reduction in cravings. So potentially in the future, you can have a combination as well, GLP-1s plus ultrasound, because what we’re seeing so far, the ultrasound impact on the craving center is dramatic, with the one ultrasound treatment can reduce cravings for the long term.

So I think combination of these treatments has to be explored 100%. Another area is using gamma wave, and that’s another exciting area. Using gamma brainwaves, too. Gamma waves are areas is a brain activity that’s involved in attention and concentration on memory. So there’s a clinical trial with a company called Cognito, really exciting, doing sensory stimulation. And that basically you expose the brain to coordinated sounds from an ear and a glass lights at a frequency called 40 Hertz. And 40 Hertz is important in neuroscience because it facilitates binding and cognition, and memory. And the results are very interesting clinical trials that shows this sensory stimulation with the eyeglass and the earpiece is actually also reducing beta amyloid, improving function.

So we have to tackle Alzheimer’s and dementias where there is ultrasound medication, sensory stimulation, everything the neuroscience is allowing to. But fundamentally, it needs to be based in science and proving safety and benefit. And that’s where the BrightFocus Foundation and others are critical because they’re funding these studies that enables additional trial, whether it’s basic science, animal studies or clinical trials. And we need to be open and explore any and all of these above. So I’m very enthusiastic about the future for Alzheimer’s, that decades has not had much enthusiasm because of the lack of impact. But now neuroscience is catching up and allowing us to combine neuroscience discoveries with technology. And then we’re off to the races for exploration.

NANCY KEACH: That’s very exciting. And I’m glad you mentioned the Cognito study. So the audience knows we do another series every other month, we feature a clinical trial. And I think Cognito may have been the second one that we featured because it is noninvasive. And so if you go on our website and Zoom In on Clinical Research archive, there is an episode on that Cognito trial. And I believe when we last we spoke with them, they were still just trying to recruit. The last patients and they were looking for moderate stage patients. So if you’re one of those people who armed the moderate stage, I believe they are still recruiting. And as we know, there is not a lot available for moderate stage patients except for lifestyle interventions, as Dr. Rezai was saying. And we are going to have Cognito back on to talk about the results because it is very exciting. Oh, thanks, Amanda. Amanda put it in the chat, the HOPE study. So if you’re in a moderate stage and interested in whether or not you can participate in that can click on that link in the chat.

I just want to mention that we have six minutes left. So if you have a burning question, throw it in the chat now, please. I’m just looking through them to see which ones I’ve missed. There was an interesting question when we were talking about liquid biopsy and opening the blood-brain barrier, which I thought was very interesting question. Could some of the proteins, let’s say the amyloid protein leak out? Could that cause some kind of a negative– I forget how she put it here– a danger of leaking toxic proteins into the bloodstream? So if you can put stuff in as bad stuff, potentially going to come out and cause any kind of an issue? Do we know?

ALI REZAI: These proteins are naturally removed by the brain’s lymphatic removal system. So no, not that we know of, but it needs to be studied more. But the goal is to accelerate. The brain has a natural clearance mechanism anyway.

So a lot of times when you’re sleeping, people may not know. Typically, your blood-brain barrier opens naturally to clear all the accumulation of proteins and toxins for day-to-day stressors to clear that up. And so by opening it, we’re just trying to facilitate the detection of it. But the brain has a natural clearance blood-brain barrier opening mechanism at night anyways when you’re sleeping. That’s why sleep is so restorative, and you get good quality sleep to have that blood-brain barrier open and clean out.

NANCY KEACH: So much more important than we understood, that getting a decent night’s sleep is extremely therapeutic and necessary. Kathy is writing some questions about do you know if there are any trials involving these technologies available for people with frontotemporal dementia?

ALI REZAI: Fantastic question. That’s a big problem. The FTD that’s ravaging so many families and people. The trials that we are looking at is doing a liquid biopsy to see if we can detect tau and other elements associated with FTD. And yes, we’re also looking at a study to look at how we can improve the behavioral aspects of it. A lot of times, anxiety, behavior, irritability, impulsivity due to frontal lobe behavior and personality areas. So we’re looking at how we can use the ultrasound to reduce that anxiety and the significant behavioral manifestations that also, people often don’t realize that Alzheimer’s not only attention and cognition and memory, but it can be associated with significant behavioral disruption that can be very problematic for families as well to deal with. So yes, we’re looking at an early study to look at its under development, to look to see if we can improve the function and reduce the anxiety and the impulsivity of people with FTD, and also to do blood-brain barrier opening to detect it earlier, if we can.

NANCY KEACH: And I’m going to do a shameless plug for a film that we just released with BrightFocus, presented with the Hilarity for Charity Foundation. It’s called Taking Care, and it’s available streaming. It’s a 38-minute documentary about Seth Rogen and his wife, Lauren Miller Rogen. Lauren’s mom had early-onset dementia, but she recorded her mom having a lot of very clear agitation symptoms, and in fact, she probably had either Lewy body or some combination. And one of the goals of that Lauren and Seth had in our making this film was to show that Alzheimer’s is not just, oh, losing your memory and forgetting where you left your keys, but have this array of very dramatic symptoms.

And Kathy, yes, frontotemporal– the AFTD is wonderful organization to follow.

ALI REZAI: Nancy, this irritability is a big problem that we see, really, irritability, anxiety, impulsivity. That’s a big problem with different types of dementia that we need to find better solutions for. Typically, we give medications that can also really reduce the alertness of individuals. So that’s where I think ultrasound may have an option to help as well.

NANCY KEACH: I know you have a patient, and I don’t want to let you go because we’re just almost at time. I was going to ask you what hurdles you see to this technology becoming accessible, but that’s too much of a downer to end on. I want to say– because we know there are hurdles and we know this. So people want to participate in clinical trials now, which is fantastic. So how do you see us overcoming some of these hurdles faster than we might have otherwise? What can people do to try to help make these technologies become more available more quickly?

ALI REZAI: I think, as you said, the key barriers are the cost, infrastructure, clinical trials. And also, we need specialized imaging and personnel and regulatory approvals. But scaling access, this is important to scale this, very important. As you said, multiple sites have to come on. We need better public awareness, foundation awareness, and better support from donors and foundations to accelerate the research and of course, NIH. That’s critical. And we need to get the word out so more people get interested in the research and innovations, and get more public, private, academia and foundation partnerships. And Nancy, only when we combine the partnership with the public, private industry, foundations, then we can really try to tackle these big problems that are impacting so many people, like dementia and Alzheimer’s.

NANCY KEACH: And that’s why we’re doing these shows too and why we thank you so much for giving us your time today, because we need the experts and the researchers who’ve been receiving those funding grants to come on and explain to people what’s happening and why this is so important, and keeping the general public and our donors in the loop. So I’m going to say thank you so much, and I hope I can get you to commit in front of all these people that you’ll come back because this is going to be rapidly evolving technology.

So thank you, and thanks for these comments in the chat. It’s very encouraging. Here are some resources. The clinical trials in ultrasound are listed. If you’d like free publications, you can email [email protected], and all of these resources are available for free. And all of the episodes that we’re doing are available at brightfocus.org/ZoomIn.

If there are topics you’d like us to cover, for those of you that are still on, please email us at [email protected]. I think we’re probably going to focus our next episode on agitation, symptoms and treatments. So we still have lots of topics to cover, and if you have something specific, please send it to [email protected]. And is there one more slide?

Yeah, the next episode, which will be on a clinical trial, potentially clinical trial on agitation, is Thursday, June 12. And then the next one of these episodes is in July. I’m going to close by saying, hold everyone you love close to you, and Dr. Rezai beat me to it, but I was going to tell you socialize, eat a healthy Mediterranean diet, get sleep, exercise regularly if you can, control your blood pressure, try to let go of stress, learn new things, get your hearing and your eyes checked.

These are all ways that you can really help your brain health at all stages of life, and your kids and your grandkids can. So thank you for attending, and we’ll look forward to seeing you next month. Have a great month.

ALI REZAI: Thank you, all. Bye-bye.

NANCY KEACH: Thank you, Dr. Rezai.

ALI REZAI: Bye-bye.

Resources:

• Learn about clinical trials that are investigating the use of focused ultrasound to treat Alzheimer’s Disease: https://search.app/QMuk9WBZCswjnLTq8
  Source: Focused Ultrasound Foundation

• The HOPE Study: https://www.hopestudyforad.com/

• Taking Care film: https://www.takingcarefilm.com/