Ep 63: Dr. Suzanne LeBlang – Focused Ultrasound Technology and Alzheimer’s Treatment (part 1)

A ground-breaking, but still experimental non-invasive procedure for treating those newly diagnosed with Alzheimer’s disease, has attracted widespread media attention. Featured on CBS 60 Minutes, focused ultrasound can target and treat tissue deep within the brain, enhance drug delivery, and facilitate the removal of amyloid plaques without the need for surgery. Dr. Suzanne LeBlang, Director of Clinical Relations at Focused Ultrasound Foundation (www.fusfoundation.org), discusses this new non-invasive technology with BrainStorm host Meryl Comer that could transform care and quality of life for patients suffering Parkinson’s to Alzheimer’s.  You won’t want to miss this episode!

Transcript

Susie LeBlang (00:01):

I am a big advocate of liquid biopsies for diagnosing disease early and following disease, right? It's much cheaper than a neuroradiology scan, whether it's an MRI or a PET scan. So a lot of work is being done in the liquid biopsy space for cancers and for neurodegenerative diseases, Alzheimer's disease. And there's actually something very exciting about focused ultrasound and liquid biopsy. So think if we could possibly open the blood-brain barrier in specific areas of that person's amyloid and test a blood sample before and after. And maybe there are differences in each person that will allow us to give the precise medicine that's best for that type of amyloid plaque.

Introduction (00:42):

Welcome to BrainStorm by UsAgainstAlzheimer's, a patient-centered nonprofit organization. Your host, Meryl Comer, is a co-founder, 24-year caregiver and Emmy Award-winning journalist and the author of the New York Times bestseller Slow Dancing with a Stranger.

Meryl Comer (00:59):

This is BrainStorm and I’m Meryl Comer. Welcome to a glimpse into a promising and experimental treatment for Alzheimer's disease. The use of focused ultrasound. This rapidly evolving technology as featured on CBS 60 Minutes showcased its potential to treat the brain minus invasive surgery, to open the blood-brain barrier for enhanced drug delivery and to transform care and quality of life for patients suffering from everything from Parkinson's to Alzheimer's disease. Joining us is Dr. Susie LeBlang, a neuroradiologist and director of Clinical Relations for the focused ultrasound Foundation. Dr. LeBlang, thank you so much for joining us. Can you share with our audience what focused ultrasound is?

Susie LeBlang (01:50):

First of all, thank you so much for having me. Focused ultrasound is a very unique technology where you can deliver an ultrasound beam just like the ultrasound you have when you're pregnant or looking at the gallbladder. But instead of using it for diagnosis, you can actually treat tissue deep inside the body. So I'm going to tell you how we do that. It's almost like when you were young and you were outside and you took a magnifying glass and you made all the sun's rays converge at a focal spot on the leaf and that leaf would catch on fire. We can do the same thing with an ultrasound beam, but instead of the sun's rays, you use an ultrasound beam, you make the beam converge at a focal spot deep inside the body, let's say in the brain somewhere. And you can cause a lot of things to happen at that focal spot. You can open the blood-brain barrier if you use it at a certain energy. You can do thermal ablation, you could even do mechanical ablation of tissue. But the important thing is that it's completely noninvasive. It goes right through the skull, right through normal brain tissue to get to the area that you want. And nothing happens along the path, only at the focal spot.

Meryl Comer (02:53):

So is this the next generation of the MRI scans that most of us have experienced for one condition or another?

Susie LeBlang (03:01):

You know, I think there's a couple of analogies with MRI scan. MRI scan really revolutionized the way that we did diagnosis in the body, especially in the brain with the amazing contrast resolution. And it really changed the way we did medicine. And I think focused ultrasound has the same ability to really change the way we do treatment inside the body. So in that way, they're analogous. Now, when you do a focused ultrasound procedure in the brain, which we'll talk about with Alzheimer's disease, it can be performed inside an MRI scanner where you use the actual pictures from the MRI scan to delineate your target. But you're really using an ultrasound beam around the head or on the head to deliver the beam of energy to cause the therapeutic effect. So you can use an MRI scan to figure out the target. You can use a previously performed MRI scan loaded in a computer and have the patient sitting in your office and use neuro navigation to lead that therapeutic beam to your target. And maybe in the future there'll be some other imaging modalities. So right now you can do it inside an MRI machine. You can do it outside an MRI machine. And there's even a company that puts a little indwelling focused ultrasound transducer inside the skull flap itself to deliver the ultrasound beam itself. So it doesn't have to be performed in an MRI scan.

Meryl Comer (04:17):

Now as a neuroradiologist, can you contrast how the technology has evolved from when you first entered the field? What excited you about the field then to what's happening today?

Susie LeBlang (04:29):

In 2003, this concept of focused ultrasound was getting very close to commercial approval, at least here in the United States. So where I worked at the time, we all sat in on some in-service exams to learn about focused ultrasound because we were slated to buy the first FDA approved machine to treat uterine fibroids in 2004. So in 2003, my coworkers and I sat in on the in-service to learn about this focused ultrasound technology. And I sat there with my mouth a gait I could not believe here I was 10 years out of training and there's this new technology where you could treat inside the body without doing any incisions. So from when I started medical school, it was general surgery. You took out a gallbladder with cholecystectomy and then it went to minimally invasive surgery with laparoscopic techniques, right? More minimally invasive. And now you're saying that we can treat tissue inside the body without even any holes or any incisions. No scalpels at all. And it was like something out of Star Trek. I'm like, this is incredible. I was so fortunate to be involved with this technology starting back in 2004, just waiting for it to get into the brain because I could already foresee the tremendous implications that I would have that day. When I heard the in-service for the first time about this technology, I just couldn't believe in that my lifetime I would be able to see this and use it.

Meryl Comer (05:48):

When you say it's not invasive, it also seems to eliminate the need for general anesthesia, which is not advised for aging brains. Is that the case?

Susie LeBlang (05:58):

That's such a great point to bring up. You know, when we talk about noninvasiveness, I think I'd like to clarify that a little bit. We're talking about an incisionless procedure. No scalpel, no cutting of the skin at all. No catheters, no electrodes, no surgical equipment. Are we changing brain tissue? Yeah, we're tending to change brain tissue, so it's invasive in that we're changing brain tissue, but it's incisionless.

Meryl Comer (06:23):

Can you explain the significance of that first clinical trial conducted with focused ultrasound in patients with Alzheimer's disease?

Susie LeBlang (06:32):

I'd like to give a little bit of background if that's okay. It turns out the focused ultrasound foundation really tries to keep our pulse on everything that's happening in the focused ultrasound community around the world. Back in 2007, there were some reports coming out every year that focused ultrasound was able to open the blood brain barrier in preclinical animal models. So little by little more papers were being published that they could open the blood brain barrier, they could deliver therapeutics to the brain. And then in 2014, 2015, there were two independent labs, one in Canada and one in Australia. They didn't know each other. And about the same time, they both published papers on the use of focused ultrasound to treat mice with Alzheimer's disease and we're getting some improved clinical benefit, some clinical improvement in the memory. So two independent labs at the same time.

Susie LeBlang (07:23):

So we said, let's get these groups together, let's convene the community. So the focused ultrasound foundation had a workshop in September, 2015 where we had those two labs as well as neurologists, neurosurgeons, specialists in the field sit in a room and we said, what do we need to do to move this from preclinical animal studies to the first in human clinical trial? Which is a big step, right? The parameters that you use in the ultrasound beam are very different in animals than in humans. Physiology of the brain is different. So we needed these great minds to really strategically think how we could safely move this into the first in human clinical trial. And after sitting for hours and having endless conversations, we were finally able to do the first in human clinical study shortly after that workshop. And it was a little scary. I'm, I'm not going to lie, we're opening the blood-brain barrier in a very specific area of the brain.

Susie LeBlang (08:15):

In someone with Alzheimer's disease, we know they may have fragile vessels to begin with. Amyloid angiopathy, are we going to cause a bleed or we going to improve the amyloid and tau plaques like they showed in the preclinical animal models. So when we were doing that first son at Sunnybrook Hospital in Toronto, there were about 10 people in the room. And I think everyone was holding their breath and they turned the machine on in a small area in the right frontal woe where we knew there was some amyloid plaque, took a deep breath, heard the machine, injected the microbubbles to open the blood-brain barrier, patient was awake on the table. We confirmed with gadolinium, which is a contrast agent, that we opened the blood-brain barrier where we wanted it to go. The patient did fine. We all took a deep breath and we're like, okay, it's going to be okay. We're doing what we wanted to do and we did it safely. It was quite a memorable moment.

Meryl Comer (09:05):

What is the potential to actually improve cognition?

Susie LeBlang (09:08):

That's a great question. So I think there have been probably five to 10 studies now in clinical patients with the use of focused ultrasound for Alzheimer's disease. And basically little by little we go from opening small volumes of the blood-brain barrier opening where there's amyloid deposited that we can see on amyloid scans to opening larger areas, more areas in the frontal lobe, in the hippocampus where we know there's amyloid deposition and we know that Alzheimer's disease is affected. So over all of these studies over the last few years, we're opening larger areas of the brain. And in doing so, we're slowly starting to get some sense that there may be a clinical benefit if we're opening the proper areas of the brain and enough areas of the brain. So we're still in clinical trials with that, but it's very exciting that little by little we're showing decreased amyloid in the regions where we're opening the blood-brain barrier compared to the areas where we're not.

Susie LeBlang (10:04):

And again, larger areas seem to make more of a difference. In fact, in a study that's coming out of South Korea, which has been presented at meetings but not published yet, they opened a substantial area of the frontal lobes and they even found some decrease in amyloid. Not only where we open the blood-brain barrier, but in other areas. So we're thinking that we're activating some kind of immune effect or activating some microglia cells that are being signaled to not only digest the amyloid where we're opening the blood brain barrier, but they're like scavengers and they'll go to other areas of the brain and look for the amyloid as well. So we think it's going to be an issue of how much volume you open up as part of the puzzle.

Meryl Comer (10:45):

What happens when you look at the difference in sex and gender? Because we're now discovering their differences between men and women when it comes to their brains.

Susie LeBlang (10:54):

We're very different brains, right? <Laugh>. So yes, that's a great point. And I don't think we have enough data yet, but that's very interesting. And we really hope to incorporate some artificial intelligence techniques to help us figure out where are the default mode networks, where are the amyloid loads different that are causing problems in cognition, different in men and women? And then we can start looking at that issue and tailoring the treatment not only the specific patient, but by gender as well. So I think those are really important studies we have to do moving forward. Once we get enough patients under our belt.

Meryl Comer (11:24):

There are an estimated 7.1 million undiagnosed Americans walking around with MCI or mild cognitive impairment. How important is it to be diagnosed early to take advantage of focused ultrasound?

Susie LeBlang (11:39):

So when we started doing that first in human clinical trial, one of the questions came up was, should we include patients with only mild cognitive impairment? Because they can actually give informed consent to be part of the study. However, the risk is if we actually have a side effect or an adverse event, we're taking someone with only mild cognitive impairment, it could possibly make them worse. On the other hand, if we take someone with advanced cognitive impairment, is the disease too far along for us to make a difference? So we ended up going with the former and doing more mild cognitive impairment. And as I mentioned before, everything is fine. But it's very interesting that you say that because I think there are biomarkers coming out now that liquid biopsy markers like a blood test that's going to be able to inform us a little bit earlier.

Susie LeBlang (12:23):

If someone has mild cognitive impairment and the ability to intervene earlier in the disease may not only stop progression but also may potentially reverse it. So these are other questions that we have to answer with, including different types of studies with different patients and different levels of involvement with Alzheimer's disease. Right? So let's say someone with mild cognitive impairment, maybe they would benefit from just doing focused ultrasound blood-brain barrier alone 'cause they don't have a huge amyloid load. Maybe someone with a bigger amyloid load and more cognitive impairment may need a drug given like Leqembi or something else that will also help get rid of that amyloid and or tau antibodies or some other drug. So I think that that's a spectrum and we're going to have to start to learn which patients could benefit from which type of focused ultrasound intervention.

Meryl Comer (13:09):

Susie, as a highly skilled neuroradiologist, our blood tests becoming as good as PET scans in diagnosing Alzheimer's.

Susie LeBlang (13:17):

Even though I'm a neuroradiologist and I love imaging. And now we have not only atomic imaging and we can look at connectomics and see how different networks of the brain connect, right? How does the frontal lobe connect with the hippocampus and other areas in Alzheimer's disease? But we have these amyloid scans and tau scans where we can actually visualize the amyloid in tau. I mean, that was a huge increase. Even though I'm a neuroradiologist, I do want to say that I am a big advocate of liquid biopsies for diagnosing disease early and following disease, right? It's much cheaper than a neuroradiology scan, whether it's an MRI or a PET scan. So they're cheaper, they're potentially faster to get it and potentially more specific. So a lot of work is being done in the liquid biopsy space for cancers and for neurodegenerative diseases, Alzheimer's disease. There's a ton of literature coming out now on liquid biopsies, and there's actually something very exciting about focused ultrasound and liquid biopsy.

Susie LeBlang (14:12):

We're talking about the fact that we intentionally want to open the blood-brain barrier. We wanna open the blood-brain barrier to get certain cells, certain medications into the brain activate things in the brain. But remember when we open the blood-brain barrier, there's a potential of bidirectional flow. You can get stuff into the brain, but stuff that previously was in the brain and couldn't get into the blood because of the blood-brain barrier is now able to flow in that direction back into the peripheral circulation so we can detect it in a biopsy. So there's a lot of research going on now with focused ultrasound and liquid biopsy for brain tumors. So now you're going to say, well, how does this apply to Alzheimer's disease? I'm going to suggest to you the possibility that everyone's amyloid and t load is different and the resulting protein or metabolic changes within or around the amyloid and tau plaques could be different.

Susie LeBlang (15:03):

So think if we could possibly open the blood-brain barrier in specific areas of that person's amyloid and test a blood sample before and after. And maybe there are differences in each person that will allow us to give the precise medicine that's best for that type of amyloid plaque. I'm not saying we're there yet, but I think the potential is there to do a spatially targeted, non-invasive biopsy of that person's amyloid. And one person's amyloid is probably slightly different than someone else's. So there's tons of particles we can look at microRNAs, extracellular vesicles, neurofilament lights stuff. So there's tons of things that we could interrogate and look at in that specific part of the brain for that specific person. It's an exciting field. There's very early work being done on liquid biopsy in Alzheimer's disease, and we're very excited about the prospect of formulating some hypotheses and looking at where that's going to go.

Meryl Comer (16:00):

Our guest, Dr. Suzie LeBlang, a neuroradiologist and director of clinical relations for the focused ultrasound foundation in part two, Dr. LeBlang shares the most common inclusion exclusion criteria for these non-invasive clinical trials and her ethical concerns about this evolving technology.

Susie LeBlang (16:21):

This was really a landmark trial. It was the first time a drug was combined with the blood-brain barrier opening. You give aducanumab, some of it crosses the blood-brain barrier. Some of it helps to dissolve some of that amyloid clearly in the frontal lobe of the brain that received the focused ultrasound therapy compared to the side of the brain that didn't receive the focused ultrasound therapy. The amount of amyloid decrease in the focused ultrasound treated side was markedly decreased compared to the side that didn't receive the focused ultrasound.

Meryl Comer (16:53):

You won't want to miss it. That's it for this edition. I'm Meryl Comer. Thank you for braintorming with us. With us on brainstorm. We interview top experts in dementia research and brain health, but we know you are the experts on the Alzheimer's journey, which is why we invite your participation in our A list. By joining and taking periodic surveys, you're helping inform healthcare providers, policy makers, and other leaders in the field about your experience and what matters most to you. It only takes a few minutes of your time. Join the A-list and see how it feels to be heard.

Closing (17:35):

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