Doctors Alexander Papanastassiou, MD, neurosurgeon at UT Health San Antonio, and Gabriel de Erausquin, MD, PhD, neurologist, and psychiatrist at UT Health San Antonio, talk about a new treatment for slowing down Alzheimer’s.
Interview conducted by Ivanhoe Broadcast News in April 2022.
I’ve done stories on DBS – Parkinson’s stimulation, DBS depression, DBS pain and now Alzheimer’s. How does this differ?
DR PAPANASTASSIOU: Well, besides that it’s a different disease, and Alzheimer’s being the most common cause of dementia, that’s the main difference. It’s funny. In terms of other differences, the other main difference is the target. The target for Alzheimer’s disease is the fornix whereas the targets for other things such as movement disorders are other parts of the brain, like the subthalamic nucleus or the thalamus or the globus pallidus. The surgery can be done awake or asleep. We prefer to do it awake for a couple of reasons. We do like to have the intraoperative confirmation and we feel like that’s helpful. And we like to avoid anesthesia because sometimes after anesthesia, people with mild Alzheimer’s will notice a decrement in their cognition that often comes back. But rarely, it feels like it is a long-term problem. So, there are a couple of good reasons to do it awake, but there are certainly centers who are doing it asleep as well.
So, how does it work?
DR PAPANASTASSIOU: When we’re talking about neurosurgery, one of the most basic concepts that has been around since the late 19th century is the idea of a stereotactic frame. So, those are the fancy medical words for when we put something rigid and metal and attach it to someone’s head, usually with screws that go into the bone. And of course, you need to have local anesthetic for that to work or to not have pain with that. But it’s very tolerable awake with some local anesthetic. Once you have a rigid relationship between that frame and the person’s head, then you can image it. And then you can use that frame with whatever the instrument may be. In our case, it’s the Renishaw neuromate® robotic system for stereotactic neurosurgery owned by University Hospital. That’s the tool we use, based on that frame, to get where we’re going.
DR DE ERAUSQUIN: One of the earliest structures that is abnormal or affected by the process of Alzheimer’s disease is the hippocampus. This is a tiny structure in the depths of the brain that has connections, both with the part of the brain that receives information from the world and from the part of the brain that receives information from its internal state. By joining those two, it creates new memories. It makes what we call episodic memory, which is our ability to track events on a day-to-day basis. It’s the most recent information that comes in, and we all organize that information according to its emotional value. That’s why the emotional component is important.
Is it our short-term memory?
DR DE ERAUSQUIN: People do refer to that as short-term memory. But short-term memory may also mean our ability to retain a phone number. And that’s slightly different in mechanism. If we’re trying to retain it online, so to speak, as we’re dialing it. Now, if we want to retain it from one day to the next, that will be episodic memory. And that’s what the hippocampus does. It also helps navigate spatially. And that’s why people with early Alzheimer’s sometimes have trouble orienting themselves. The point is that the biggest outflow of information from the hippocampus to the rest of the brain happens through a fiber track called the fornix. And that fiber track is where we put the wires to treat the early symptoms of Alzheimer’s disease. The original notion was that by increasing the flow of information in that tract, we might improve the ability of a person to retain new information. Now, that needed to be tested. And the original tests were done by a number of smaller groups on what we would call case reports, or anecdotal cases. They looked very promising. So, ADvance I happened, which was the first phase of this trial that compared two small groups of 20-odd people. All of them received implants in the fornix. All of them had early Alzheimer’s disease documented very thoroughly. And half of them got the stimulation turned on right away. The other half waited for about a year and then were turned on and waited and followed up for another 12 months. So, some people had 24 months of stimulation, and some had 12. The purpose of this trial was not to prove if memory was held so much as to make sure that the stimulation didn’t cause any trouble, any serious side effects. So, it was a feasibility trial. It was to make sure that people could tolerate the surgery without getting worse, wouldn’t suffer significant side effects, and hopefully to see if there was a signal in terms of memory retention or memory improvement in the optimal case. The remarkable thing is that even though it was a feasibility trail and was not really intended to prove efficacy, these patients did very well. About half of them got turned on right away, they had two years of stimulation, and had an essentially flat progression curve, meaning that they did not get worse in 24 months. Now, in that period of the disease, 24 months without worsening is quite good. It’s better than anything we have right now. The people who got turned on 12 months later also did fairly well and stayed reasonably flat. Now, a handful of people got even better, and a handful of people got somewhat worse. And literally, I mean, a handful, like four or five. So, obviously, it was a striking result. And that’s what gave rise to the second trial, the ADvance II trial. This is really a much larger effort with the same model. We are going to turn the stimulation on in half the people right away and then half the people after the year and follow them for a total of 24 months. But the intent is to have enough people that we can make a very strong case of efficacy. Because if the early data from the feasibility trial turn out to be true, this is the best treatment we have.
Can you tell us about the robot?
DR PAPANASTASSIOU: I love the robot, and in neurosurgery, one of the things that we care about a lot is accuracy. This robot allows us to be even more accurate than we were with the traditional frames. With the traditional frames, you had dial-in sets of coordinates to get where you were going. It was limited by the accuracy of what you could do with dialing those in. And then, the robotic arm is much more rigid. So, when you’re doing things like drilling a hole or inserting something, the rigid arm increases your accuracy. So, this has been studied, and we found the robot that has the best accuracy. We’ve been tracking it in our patients, not just with this study but across the other things that we use it for, like epilepsy surgery and deep brain stimulation for movement disorders. The accuracy is phenomenal. It just gives us a lot of pleasure to plan where the electrode is supposed to go. And then if you look at your post-op image and it’s right there, that feels good.
How do you know exactly where to put it and how do you get the electrodes in?
DR PAPANASTASSIOU: You start with the anatomy, like all of surgery and a lot of medicine. And we start with a very high-resolution MRI scan and have collaborated with the radiology group, with UT Health San Antonio and with University Hospital to develop sequences that are ideal for doing stereotactic surgery and for doing this study. So, we have a sequence called the FGATIR. That allows us to see white matter bundles, like the fornix, more easily. And if you’ve studied your anatomy, you can pick it out. And then once you know where that is, then you have to pick a trajectory. So, first you pick your target and say, “Here’s where we’d like to stimulate. Here’s where we want our active contacts to be — the little pieces of metal that are going to deliver the current.” Once you’ve decided where that is, then you ask yourself, “What’s the best way to get here?” And you want to go through parts of the brain on your way there so that it won’t cause any problems or deficits. You also want to avoid critical structures in the brain, including arteries and veins, to minimize the chances of causing a problem with a stroke or a hemorrhage. That’s what it’s all for and that’s why the accuracy matters so much, because you can make your plan and then if you can execute it and avoid all the critical things and just get the electrodes to where you want to stimulate, then you’re in good shape.
Is it a constant stimulation?
DR DE ERAUSQUIN: Yes. Originally, when the brain stimulation was developed to treat tremor and then Parkinson’s disease, the concept was that you were creating a transient lesion of a tissue by driving enough current through it that the cells would not be able to fire. So, they were tired out of fighting. The idea there is that in previous surgical trials — and those go back 60 or 70 years before the onset of DBS — people had shown that for movement disorders causing lesions in some parts of the brain, damaging the tissue had beneficial effects. So, the notion behind the brain stimulation was we can do the same without causing damage to the tissue. We can inhibit the activity of the cells without killing or breaking anything. And so, if things happen that are bad, we can always take it out then, no harm, no foul. Everything’s the same as it was before. Over the course of the past, from 1991 to 2022, if you were to take 30 years of experience with DBS, we have learned that we can detect the activity of the local cells and correct it in more specific ways. We’re still in the infancy of doing that. And that’s with diseases that we know well, that we have been treating for 30 years. So, the possibility that we might do that for Alzheimer’s is far away. For now, what we’re doing is just running current through at a fixed rate and hoping for the best. And that seems to be good enough, interestingly.
DR PAPANASTASSIOU: This is a constant stimulation and with most deep brain stimulation, it is. There are other types of devices for the brain that have closed loop stimulation or responsive stimulation. But in this case, it’s continuous stimulation.
What delivers that simulation?
DR PAPANASTASSIOU: The way it works is the electrodes go down into the brain near the fornix and the entry sites are up on the top of your head. Then, you tunnel the wires underneath the skin behind the ear and underneath the skin down by the neck and down to the chest wall. And then we have a little battery pack there. It’s a lot like a pacemaker. The battery for deep brain stimulation is a little bit bigger than a pacemaker. But that’s where it sits and that’s what generates the stimulation.
How long can that last?
DR PAPANASTASSIOU: It depends on the stimulation settings and the device and a lot of factors, whether it’s rechargeable or not. But on average, they last somewhere between three and five years.
So, was it a little surprising when your first patient had a very vivid memory when you were using the electrodes for the first time?
DR PAPANASTASSIOU: I have to say, I was a little bit surprised. Maybe it’s the pessimist in me, but of course, you don’t always have that response. So, I honestly wasn’t expecting her to. I was certainly expecting to see a response with her blood pressure and heart rate, which were the main things we were monitoring. But I was a little bit surprised, and it was a pleasant surprise.
How is that patient doing now?
DR PAPANASTASSIOU: She’s doing great. She recovered well from surgery. There were no problems or complications. It’s interesting because on the one hand, this is considered a major brain surgery because we’re implanting electrodes in the brain. On the other hand, that doesn’t mean that it causes a lot of pain or needs a long recovery. So, she stayed in the ICU for monitoring for one night and left the next morning and was back on her feet and doing normal activities right away. Most people just need to take pain medicines, sometimes even just Tylenol for a week or two. So, she recovered well from surgery, came back for her programming appointment, and then was randomized to have her stimulator turned on or not. And of course, it’s a blinded study. So, we, as the investigators, both Dr. de Erausquin and I, we don’t know if her stimulator is on or not.
How long will her study last?
DR PAPANASTASSIOU: It’s a 13-month study where there’s 12 months of blinded monitoring. At the end of that one year of monitoring, where we take the formal neuropsychological scales to see whether the Alzheimer’s disease has progressed or not, at that point, the patient can be unblinded and all the patients who were not turned on can be turned on at that point. So, people often wonder that. Well, am I going to be randomized to have this brain surgery and then not ever be turned on? And that’s not the case — just not during the randomized period of a year.
Will they be turned on for the rest of their lives?
DR PAPANASTASSIOU: Usually yes, but it depends, because this is a clinical study, and we don’t know if it’s going to work or not. That’s why we’re doing the study. If it does work, then we would hope that it would lead to an FDA approval, and that would allow you to have your generator replaced. But if it doesn’t work, then, we probably would taper people off the treatment. We wouldn’t replace a generator for a therapy that didn’t work.
Is this the second study that we’re talking about?
DR PAPANASTASSIOU: This is. Yeah, exactly.
Do you have the final numbers for the first study?
DR PAPANASTASSIOU: Well, so the first study was a pilot and a safety trial. So, those results are published and available. And the second phase is not yet available. At this point, 58 patients have been implanted. So, there’s still quite a way to go to get to the full number.
How many are you looking for?
DR PAPANASTASSIOU: I believe it’s 210.
Can you change the frequency and are you going to change the frequency in patients?
DR PAPANASTASSIOU: Yes. So, the first part of the study is to look at a certain number of patients with a low frequency versus a higher frequency and see if one of those sets of parameters works better. And then, for the remainder of the patients in the study, we will use the one that worked better from the first part.
Are all the patients going through here?
DR PAPANASTASSIOU: Oh, no. There are 20-some sites around the United States and around the world. We’re just one of the sites.
Are you hoping to stop it, delay it, cure it, or reverse Alzheimer’s?
DR PAPANASTASSIOU: I think that what we’re hoping to do is stop progression or delay progression at one year. We do not think that stimulation of the fornix should address the underlying disease. We don’t think that we’re offering a cure for this by any means. But if we’re able to slow or stop the progression, that’s our main goal. And of course, it’s a wide-open question. What would happen beyond a year? Because we just don’t have a good sense of it yet because it hasn’t been studied yet. But we do have, from our preliminary data from the safety trial, an idea that there’s a pretty good chance of delaying progression for at least a year.
DR DE ERAUSQUIN: I’m hoping to reverse it. But that’s not what necessarily will happen, of course. What we know from the feasibility trial is that in most of the people who are implanted, the disease was stopped and that would be quite a result. I would be exceedingly happy if that happened. Now, in a few it got better. And maybe we can learn enough about how to use this tool to make it better for more people. That’s in the future.
Nothing else out there does that, right?
DR PAPANASTASSIOU: That’s true. But there are some drugs that offer symptomatic relief. That’s one of the things that makes the trial exciting. In medicine, it can be difficult. As doctors, we get so used to there being lots of very large problems for which we have little or nothing to offer. So, we’re very used to that. And it’s a very exciting time in medicine where we’re about to start being able to offer more for diseases like Alzheimer’s and others, as well.
Is it exciting for you to be at the beginning of this, where you could be in the first phase of stopping something that we’ve all been told we’re going to get sooner or later?
DR PAPANASTASSIOU: It is. It’s very exciting to be a part of it. And most of us who have gone into medicine, we really take great pleasure in helping people and seeing good outcomes and being able to be part of generating information to allow a new type of good outcome. It’s just a pleasure seeing each patient respond to it. And there’s also other parts of medicine, too, that a big part of it for us is getting to know people. And either way, hope is very important. So, we have to come into this even-minded in recognizing that the study may or may not work. On the other hand, it does provide people hope in a situation with a disease that is slowly but progressively very devastating.
Were there any bad side effects for any of the people in the first trial?
DR DE ERAUSQUIN: No, and to be honest with you, I don’t remember off the top of my head how many were seen or the side effects that you can have from any other implant of a device, a foreign device into the brain. Meaning you can have an infection, you can have a small hemorrhage, because as they’re putting the wire in, they may accidentally pop a small blood vessel. But those are rare or infrequent, as infrequent as they would be for Parkinson’s or for tremor or for any other application of DBS, which, as in the preliminary conversation, we were pointing out is quite common these days. We have tens of thousands of patients implanted all over the world, and it’s a very well-established and safe treatment. And perhaps the biggest highlight is that the technology we know is exceedingly safe. So, if we can prove efficacy for the disease that doesn’t have any effective treatments now, it would be a massive improvement in our armamentarium, as they say, in our toolbox to treat the disease.
How much current is it? Is there anything comparable?
DR DE ERAUSQUIN: It’s a very tiny amount of current. Depending on exactly the settings, it’s about 5 milliamps of current.
Do people ever say they feel anything?
DR DE ERAUSQUIN: Of course, depending on where you put the current. But for instance, with the treatment for deep brain stimulation, we actually test the location of the wire because you can always be a few millimeters away from where you intend to be based on the imaging. So, with very careful planning, using MRI, we make sure that we see the structure on the brain of the person. But of course, that’s a static image. We’re not seeing the brain as we drop the wire in. So, if the brain moves because the person is breathing or because of changes in pressure or any other reason, you may miss. So, we have to confirm where we are. And we confirm where we are by running the electricity up to about seven milliamps inside the operating room.
Are the patients awake?
DR DE ERAUSQUIN: The patient is awake, and we are asking them questions and looking at the monitor because in this case, two things happen. One of them is that the blood pressure or the heart rate or both go up as we’re running the current through if we’re in the right place. The second thing, and that’s not always the case, but it’s quite interesting, is that they have a very strong reminiscence of old memories. So, in the case with her, she was suddenly flooded by a memory of her sister and her playing on the beach in, I think she said, South Padre Island when they were young. And they were playing with the sand. This was a very vivid, intense memory. She produced this spontaneously. We were not asking her or inducing her. We’re just looking at the monitor, looking for blood pressure changes or heart rate changes. And she volunteered that she was having this very intense memory. She was very surprised although I had warned her. But it’s not the same to be told that you’re going to have a memory than to experience the memory. It’s quite a moving experience for some people.
So, how is this clinical trial going? Are you just doing it here?
DR DE ERAUSQUIN: It’s in 28 centers, several of them in Europe, several in Canada, and many in the United States. We are just one of those centers. We are responsible for also taking pictures of the brain after the surgeries in the sense that we took PET scans, or positive emission tomography. So, this is a technique that allows many things. But amongst them you can measure the amount of blood that hits specific parts of the brain during rest or after specific activity. So, one of the things that we are doing is we’re measuring the response of the blood flow of the brain to the stimulation.
What do you know now about that?
DR DE ERAUSQUIN: Practically little. We’re in the early stages, so it’s too early to tell. But that’s one of the things that we’re interested in trying to understand. And we are one of the few centers that are doing that part of the trial. Most of them are just implanting and looking at the patients.
Do you expect that more blood will be flowing to that area?
DR DE ERAUSQUIN: We expect that more blood will be flowing to the areas that are affected by Alzheimer’s, which are primarily the temporal lobes and the parietal lobes.
Is this not intended for people in late-stage Alzheimer’s?
DR DE ERAUSQUIN: No, unfortunately not. We are looking for people who are in what’s called the clinical demonstrating score of 0.5 to 1, which is the early-stage surveillance.
Is there anything else you would want people to know?
DR DE ERAUSQUIN: What I like about this technology, and the reason we have been so successful in using it over the past three decades, is that, as I was mentioning, it’s minimally invasive. You have to have a wire in your head, and you have to have a pacemaker. But many people have pacemakers for heart reasons, as well. And this is not harmful to the body. And anything that we do can be undone. Of course, you can have complications from the surgery, and those cannot be undone. But those are rare, 1 to 2 percent, maybe. For the overwhelming majority of people who have it, anything that we do can be undone. And we don’t cause any harm, which is the first and foremost goal of a physician. So, I really like that aspect of it.
END OF INTERVIEW
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