Crista Ellis 00:00:00
Hello and welcome to the Parkinson's Foundation's webinar series for veterans living with Parkinson's. I'm Crista Ellis, your host for today's webinar. Helping me behind the scenes are my colleagues Daniel Agpalo and Laura Cameron. More than 110,000 veterans with Parkinson's disease receive care through the U.S. Department of Veterans Affairs. Many U.S. military veterans with Parkinson's have access to specialized medical care and financial assistance through the VA. During this webinar, we will dive into an exploration of the latest advances in Parkinson's treatments.

This session is designed to empower veterans and care partners with up-to-date knowledge and tools for informed decision-making.

Today's webinar and the entire Veterans Webinar Series is presented with support from the Don and Lorraine Freeberg Foundation. The Parkinson's Foundation wants to take this moment to thank the Freeberg Foundation for helping to make these programs possible.

The mission of the Foundation is to make lives better for people with Parkinson's. Whether you are living with Parkinson's, caring for someone with Parkinson's, or working to end the disease, we are here to support you. To achieve our mission, the Foundation pursues three goals: to improve care for everyone with Parkinson's, to advance research toward a cure, and to empower and educate our global Parkinson's community. Today's program is a great example of one of the ways we are helping to meet these goals.

The Parkinson's Foundation hosts weekly education and wellness programs through our PD Health at Home virtual programming. Join us for Mindfulness Mondays, Wellness Wednesdays and Fitness Fridays. Most of the PD Health at Home programs are recorded and posted on the Parkinson's Foundation's YouTube channel. With your smart device, you can scan the QR code on the screen to connect to our YouTube channel and browse our archived videos. You can find out more and register to attend our live PD Health at Home programs at Parkinson.org/PDHealth.

Part of the Foundation's commitment is to reach every person living with Parkinson's. A critical way we do that is through our partnerships. With more than 110,000 veterans living with Parkinson's, the Foundation is proud to have established a formal partnership with the Veterans Administration. This partnership has the overarching goal to improve the quality of life for veterans living with Parkinson's disease and their care partners through greater access to education, resources and support. I'd like to invite you to visit our webpage and explore the resources offered by the Parkinson's Foundation that can support your navigation of living with Parkinson's as a veteran. That website is Parkinson.org/Veterans.

Today, it's my pleasure to introduce Dr. Vaswani. Dr. Vaswani is an assistant professor of clinical neurology at the University of Pennsylvania and an attending neurologist at the Philadelphia VA, where he specializes in Parkinson's disease and movement disorders. Dr. Vaswani has a particular focus on advanced therapies for Parkinson's and leads the deep brain stimulation program at the Philadelphia VA. He also serves as associate fellowship director for the Penn VA Movement Disorders Fellowship. Dr. Vaswani, we're grateful to have you here with us today to share your expertise. I'll pass the mic to you.

Dr. Pavan Vaswani 00:03:29
Good afternoon or good morning, depending on where folks are. Everyone, thank you all for joining. It's my pleasure to talk to you today a little bit about today's treatment landscape and how we are advancing care and new options for the treatment of Parkinson's. I want to start off by thanking the Parkinson's Foundation and the Freeberg Foundation for this invitation and for supporting this program. I think it's so important to be aware of your treatment options and know what's new and what's out there. It's a really important part of taking advocacy for your own care. Thank you all for joining, and with that, we'll get started.

I'll mention I have just a few disclosures. I do work with the companies that make deep brain stimulation devices. We're going to be talking about that a little bit later. I have worked with a number of foundations and work on some clinical trials. I am going to try to use the generic names for most of the medications as we go through this talk. We're going to be talking about a lot of medications today, or a few. But I will try to also include the brand name really for familiarity and for clarity, though many of the meds, some of the meds that we're going to talk about, do have generic equivalents that are essentially the same.

Stepping back for a moment before we dive into the cutting edge, the latest and greatest treatments, I just want to start by giving us a little bit of a big picture, which is that the holy grail in Parkinson's has been and remains finding a cure, something that reverses or slows down the progression of Parkinson's. We don't have that yet. Stay tuned to hear a little more of an update on that from my colleague in a few moments. But we do have, notably, many effective treatments. We have many treatments that we call symptomatic. They make the symptoms of Parkinson's, whether it be the slowness, the stiffness, the tremor, the cramping, the constipation, etcetera, better. We have a lot of medicines that can help those symptoms, and that's important because that's what helps people's quality of life. It helps you be more able to do the things you want to do every day.

We are fortunate that we have a lot of options for treatments of symptoms. Customizing that treatment approach for each person individually is, I think, a really, really important part of the care of people with Parkinson's disease. We are increasingly adjusting the approach that we take for each person. Having these options is wonderful, but also presents sort of a huge spread of choices, which can be daunting at times.

I want to start off with just a quick poll, just to get everyone engaged and awake and paying attention, and also for me to get a sense for what your biggest challenge right now is in managing Parkinson's disease. You can answer for yourself, or if you're here as a care partner, you can chime in as to your family member's challenges. I am not seeing the results, but I suspect Laura or Crista maybe.

Crista Ellis 00:06:40
Yeah, I can see them. We've got about 41% saying the most challenging is managing their motor symptoms. Twenty-seven are saying the biggest challenge is managing non-motor symptoms, and about 10% are talking to the challenge of medication and timing of off periods.

Dr. Pavan Vaswani 00:07:00
Perfect. I think that's a nice spread. I will mention that we are going to be focusing mostly on motor symptoms today, though we will talk a bit about non-motor symptoms as well. That's very, very helpful. As I was saying, we're going to talk about a few categories of treatments. Most of the updates in the last few years have really been on the medications for motor symptoms. That's what we're going to be focusing on for most of this talk. We'll just highlight a little bit about treatments for motor symptoms and then some updates in the surgical therapies, which I think actually have a couple of big updates that are important. Then we'll close with what is, in some ways, probably the most important part of the talk, which is the non-pharmacologic approaches, some things that we've known a lot about for a long time and an important part of the care of people with PD.

Just to give us a little bit of a refresher, like I said, the main focus of the talk is what's new, the cutting edge, but it's important to put that in the context of what we've known for a long time, the core medicines that we've had for Parkinson's for many, many years. Big picture, as I think this audience probably mostly knows, Parkinson's disease is caused by the loss of cells in the brain, neurons, which are the brain cells that talk to each other, that make a chemical called dopamine that the cells use to talk to each other. It's a chemical that, basically, they use for one cell to speak to the next.

Because in Parkinson's you lose those cells, a number of the treatments are focused on getting people that dopamine back. We've had a few options that have been around for many, many years. The main gold-standard workhorse medicine that we've had for 50 or 60 years is called carbidopa-levodopa or Sinemet. This gives you a precursor to dopamine back, so your body can convert it to dopamine and then use it to help you move and have more normal movements.

There are a few other classes of medicines that have also been around for a long time. There are medicines called dopamine agonists. These are medicines like pramipexole, which is Mirapex, or ropinirole, which is Requip, which can directly replace the dopamine. These tend to be a little more side-effect prone than carbidopa-levodopa but can be the right choice for some people. Then there are a few medicines, I think actually this is highlighted a little better on the next slide here, that instead of replacing the dopamine that's in the cell, prevent the breakdown of the dopamine that you have or that you're getting from these other agents and make it last a little longer. These are called the MAO-B inhibitors. These are medicines like rasagiline, or Azilect, or selegiline, or COMT inhibitors. This also prevents the breakdown of the dopamine you have, which these are medicines like entacapone and opicapone.

A few medicines we've had for a long time, and I think an important point to make is just because I'm going to be talking about new stuff, it doesn't mean that the old options are bad. In fact, I still find, and most of my colleagues find, that regular carbidopa-levodopa still remains the gold-standard, workhorse medicine, the first option I use for almost all of my patients and the one that I stick to for the majority of my patients, and still the gold standard used in many clinical trials. Most of these new agents sort of look at carbidopa-levodopa as their comparator in many cases. Just because it's new doesn't mean it's better, necessarily. It just really depends on your personal situation. We're going to talk a little bit about which situations these new options are good for.

Dr. Pavan Vaswani 00:10:32
Like I said, I usually start with regular carbidopa-levodopa. I think it's also helpful in context to think about the progression of Parkinson's disease and how these medicines work over time. Early on in Parkinson's, regular old carbidopa-levodopa is often an excellent choice. I'm going to orient you to this graph because understanding this idea, I think, is a big part about understanding some of the advances we've had in the last few years.

Early on in Parkinson's, folks have a pretty big window, this green area here, where you feel good. When you're in this window, that's what we call your on-time. Usually when you're above this window, that's when you have dyskinesias. Usually when you're below this window is when you're off or have tremor. Early on in Parkinson's, folks lose dopamine cells. Your dopamine level starts a little lower, lower than the green bar. You can see that in the morning here in the left panel. You take medicines to bring that dopamine level up in one way or another, and that puts you in the green range earlier in the day.

Now those levels go up and down a little bit, but early on, because that window is nice and big, folks stay in that green zone. They take another dose, shown by the next blue dot, and then another dose, usually taking the meds three or four times a day, and they stay in the green zone all day. If they're a little early or a little late, not such a big deal. Folks are able to feel good, that is, be on without side effects, for the majority of the day.

But unfortunately, Parkinson's is a progressive condition. One of the ways that it progresses, if we think about this figure, is that that green bar gets narrower and narrower. As you can see, it gets a little bit trickier to keep yourself in that green zone. A med might kick in a little well or get absorbed a little quickly, and you may overshoot a bit and get a little dyskinesia. You take another dose, the second blue dot in that middle panel, and then maybe it runs out a little early or you're a little late with the dose, and you turn a little bit off. You get a little bit more tremor or stiffness.

There are a few things you can do. You can take the meds a little more often or lower doses a little more often. You can adjust the regimen. But a number of the advances in the last few years have been really about trying to keep you in your green zone, to have you feel on without dyskinesias more hours of the day in a steadier way. That's been the main updates in the last few years, addressing what we call motor fluctuations, those ons and those offs, those ups and those downs that folks get from their Parkinson's disease motor symptoms.

The first few updates really have to do with extended-release versions of our current medications. You can imagine, if you're having ups and downs, having an extended-release version might smooth things out. One of the new extended, new-ish, I'm going to go in chronological order a bit here, extended-release versions is an extended-release version of a medicine called amantadine, which we've also had for many, many decades. The brand name of that extended-release version is called Gocovri. It was approved by the FDA in 2021, and it gives you more of those green hours shown in this figure from the paper, in this dark green box. The dark green box, the amount of time you're on without dyskinesia, goes up by, in this study, four or five hours for folks on average. This medicine can help smooth out your day, one of the extended-release versions of medicines to do that.

Dr. Pavan Vaswani 00:14:00
There was another extended-release version that was just approved now about a year and a half ago, middle of 2024, by the FDA, called Crexont. That is carbidopa-levodopa, Sinemet, extended release. This is a medicine that says, you know what, we want to try to stretch out the way the medicines work, make them last a little longer. It puts these beads of short- and long-acting carbidopa-levodopa mixed together, and then with what the company calls a mucoadhesive polymer, basically makes it stick a little bit in your intestine. You take the pill, and it sticks a little bit in your intestine, and then it slow releases the medicine over a little bit of a longer period of time.

This medicine also helps people have a smoother day, a little more on time. This figure here is showing that the immediate release, that is IR, carbidopa-levodopa, CD/LD, for people in this study were lasting about two hours per dose. They're picking people who are a little bit further along, getting a little bit of those ups and downs. They found that this extended-release version gave them an extra hour and a half or so per dose, on average, for example. Another way, an extended-release version that you can try to smooth out your day, have less ups and downs.

These are all fine and well. This is a great tool, and it can be really effective for some people. But wouldn't it be nice? One of the nice things that I wish we could do, and we now can do, spoiler alert, is give people a steady level of dopamine. That is, instead of having any up and down, even a smoother one like in this dark blue line, give people something like the green line that is just a steady dopamine level all day.

This, I think, has been a really big update for people who need it, a really significant update in our armamentarium, the tools we have to treat folks. There are two pumps that actually both came out in the last year or so, a little over a year now. One is called Vyalev, the brand name. It's a foslevodopa-foscarbidopa pump. The basic idea of these medications is instead of taking a pill, which gets absorbed in your stomach and then kicks in and wears off, and you get those up-and-down curves of the medicine kicking in and wearing off, it would be really nice if we could just drip, in some way, this medicine steadily into you so that you could have a steady day.

We have had one way to do this for about 10 years. That's called Duopa, or carbidopa-levodopa intestinal gel. This was where they would put a tube in the stomach, and you could carry around a pump that would drip the gel into the stomach, or just past the stomach, to help you have a steady day. The downside of that one was mostly that you had to have a tube put in your stomach, which is a surgery. It's essentially a feeding tube, but we're not using it for feeding. That was a barrier for a lot of people to use that therapy.

We now have two new pumps that are much easier to access, and these are both what we call subcutaneous pumps. That is, instead of putting a tube in the stomach and dripping the gel into the stomach, you put a little sticker on your skin, and it drips the medicine directly underneath your skin. Your body then absorbs it, and you can increase the rate or go up or down on the rate of the drip to give yourself a little more or a little less medicine through the day. You can see that shown in the picture on the top right, the person with the sticker on their stomach, a little bit of tubing, and then a pump that they're carrying around all day.

Dr. Pavan Vaswani 00:17:29
This can be really effective for folks. It can really smooth people's day out. I'll show that number on the next slide. But there are a couple of downsides. It's important that we talk about both the upsides and the downsides of these medicines. There are sort of two big categories of downsides. One is that you have to deal with the pump. Every morning, you have to take a syringe, which you can see shown in the left picture, and you have to put it on top of a vial and pull up the medicine in the syringe. You have to put it inside the pump and close the pump, connect some tubing, put the sticker on your belly, and then hit start on the front of the pump. Then you have to carry the pump around all day.

I will say this turns out, for most of my patients, not to be such a huge deal. I think the coordination is unfortunately something that is tricky in Parkinson's, but because folks can be on the pump all day and all night, usually folks don't feel too bad in the morning and are able to get through that part without too much trouble.

The other downside of the pump is it can cause a little bit of skin irritation. It turns out that the medicine's a little bit irritating to the skin, and so people get little bruises. You can see a picture shown here of someone with a bruise or the skin reaction. They get little what look like bruises, I should say, on the belly at the infusion site. You change your infusion site between every one and three days, and then these tend to heal up. Occasionally, though not often, people do need some antibiotics if they look a little worse than the one you can see here. I think I took out the slide with the graph, but this does work, and it gives people three to five more hours of good on time per day in the clinical trial.

There's another pump that came out that's called Onapgo, which is a different medication called apomorphine. That pump is a little bit physically smaller, but the same idea. You have to have the medicine that's connected to some tubing, you put a sticker on your belly, and it drips the medicine underneath your skin in a steady way. This one I use a little bit less because it tends to have more side effects, tends to cause a little more lightheadedness or dizziness, low blood pressure. So I tend personally to use the first one, which is Vyalev, though this one is a little bit smaller if the size of the pump is a barrier for you.

So two options to smooth out your day with medications, and then two new extended-release versions of medications that have come out in the last couple of years.

Dr. Pavan Vaswani 00:19:55
Suppose you try these and they work. They smooth out your day a little bit. They help avoid some of the ups and downs. But maybe the pump doesn't work quite as well as you'd like, it's a little bit too much of a hassle to carry around, or the skin reactions are too much. There is, and I will say not a new option, another option that is available for folks that are having a lot of ups and downs, a lot of motor fluctuations, which you can see in that figure on the top right. This is called deep brain stimulation. If I could ask Crista to click play on the video on the left, we'll see if this works for us.

This is where a wire is put in one of two pretty small structures, or one of a few possible small structures in the brain, and then that's connected, you can see a picture on the bottom right, to an extension cord and then a battery pack in the chest. We can use electricity at the tip of that wire to try to make the Parkinson's circuit act more normally. If you have tremor, to basically turn off your tremor and try to smooth people's days out. Because the electricity is on constantly throughout the day, it's also a good option if you have side effects from your medicines, if they make you nauseous or a little light-headed. You can often reduce your medicines significantly with this treatment. If the meds work but give you trouble in some other way, this, for some people, is an option. You can see the electrical contacts there at the tip of that wire in this picture.

I will mention that deep brain stimulation, or DBS, is not a new or experimental therapy. I know it certainly sounds like science fiction. It's something that is in some ways really cool in that way, but not new or experimental. It's been FDA approved for tremor since 1997 and for Parkinson's disease since 2003, so over 20 years. It can be a really, really good option for the right person at the right time. There are a lot of details here that are really, really important. If this is something you're interested in, I encourage you to talk to your doctor who knows you personally. But at a big-picture level, a few things to know about DBS: It's a good option for people who have one of two things, either a tremor that doesn't respond well to the medicine or motor fluctuations, those ups and the downs that we've been talking about. There are some extra cases if the meds work but give you side effects, things like that that I alluded to, that can also be a reason to consider DBS.

It is a surgery, and it is a brain surgery. The anesthesia, the putting the wire in, can affect people's balance and cognition a tiny bit, and so you have to have balance and cognition that are in a decent place for surgery. Your general health, in terms of your heart and lungs and all of that, also has to be in a good enough place where having a surgery is safe for you. I think the most important thing to know when you're considering DBS, the biggest predictor of success, is knowing what it helps and what it doesn't help.

DBS, unfortunately, is not a cure. I really wish it were. A lot of people may hear that, oh, it can sort of fix everybody, and that's unfortunately not true. But if you're going in it for the right reasons, that is, you want to improve your tremor or you want to improve the ups and the downs, the ons and the offs, DBS is very, very good at those things. It unfortunately doesn't treat all of the other symptoms of Parkinson's, but it helps the motor ups and downs and it helps the tremor a lot.

Dr. Pavan Vaswani 00:23:14
There have been a number of really cool, exciting updates in deep brain stimulation. In January of 2024, one of the companies, Medtronic, had a new rechargeable device. In February, just a month later, one of the other companies came out with a rechargeable device as well. Boston Scientific has had a rechargeable for some time. The three DBS companies and the batteries are shown here.

All of these companies have also been working, with these new batteries and new software updates and things like that, on making the ability to adjust the electricity at the tip of that wire work better and helping us find a good place to do it in a faster way, to get it optimized faster for you. A lot of these companies have been doing really, really cool things to make that a reality.

One of the companies, Boston Scientific, has really been exploring what we call image-guided programming, that is, making these really detailed images of where the wire is in the brain and finding electrical contacts on these really fine images. These structures here are very small. This is a millimeter in diameter, the wire there. Then using this to guide us and saying, hey, look, you might want to stimulate on this spot or that spot in an effective way, or doing really complicated shapes of electricity to try to help people get better faster.

One of the other companies, Medtronic, has been developing this really cool technology called BrainSense, where they use the wire that's in the brain to listen to your brain activity while you're going about your day, walking around, having breakfast, whatever. It listens to your brain activity. That has been available for a few years, allowing us to use the sound of the brain at different spots on the wire to try to pick a good spot quicker. Then in January of last year, they came out with a really cool technology that, if you need it, can be really powerful, called adaptive DBS, where it listens to the sound of the brain activity and it says, hey, I think your meds might be wearing off; I should click the DBS up. Oh, hey, I think the meds have kicked in pretty well; maybe I should click the DBS down. It adjusts itself up and down over the course of your day, which, if you need it, can be effective.

I will say most people don't need this. Run-of-the-mill DBS has been around for 30 years and works really, really well, like I said, but this can be a little bit of the icing on the cake if it is something that you need. Then the third company, Abbott, has since about 2020 been developing and is continuing to advance the ability to do programming, that is, the adjustments of the wire, over telemedicine. That is, we can connect to the battery with, I will admit, a lot of security. It's almost a little annoying how much security there is in the process, but it's what's important to keep everybody safe. We can connect to your battery over the internet and then make adjustments just like you would in the office over the internet connection.

I think that last one can be really important for veterans. I know a lot of veterans live in rural areas. I know accessing a movement disorder specialist is a little challenging for anyone, but the VA has really spent a lot of time and effort, from way before COVID even, developing and supporting telemedicine, that is, connecting to your doctor over the internet. That can be really powerful for folks that use that as a way to connect to their doctors.

Dr. Pavan Vaswani 00:26:31
The last advanced therapy, the last procedure that I just want to mention has had some updates, is that there is another surgical procedure for Parkinson's disease called focused ultrasound. This is where they use sound waves to burn a hole, and you can see the little white spot there inside that yellow circle is the hole that they've burned in one of the areas of the brain. This can be a treatment that is useful for some people. The main advantage of this compared to deep brain stimulation, the wire, is that it's one and done. They burn the hole in this spot in your brain, and then that's it. But that is also the main disadvantage.

With deep brain stimulation, with the wire, I can adjust the electricity, and over the years, if you need a little more stimulation because your symptoms have progressed, I can turn it up. If you get a little side effect, a little speech problem or a little balance, I can turn it down or shape it in a different way. The main disadvantage of ultrasound is it's one and done, though it's also nice that you don't have to come back for those adjustments and manage the device.

I will say I find for Parkinson's disease in particular that focused ultrasound is a little more side-effect prone, and people can be stuck with those side effects. For most patients, not everybody, but for most patients, DBS is a better choice. But that discussion is more complicated than just the three or four sentences I'm saying here. If this is something you're interested in, again, I would talk to your doctor about your individual situation.

Like I said, we were going to spend the majority of the time talking about treatments for motor symptoms, both the medications and the surgical approaches. I'm going to talk briefly about the non-motor symptoms and then non-pharmacologic approaches, and then we'll talk about VA care in just a minute. I don't have to tell this audience too much about this, but we know that we focus a lot on the motor symptoms, the tip of the iceberg here: tremors, stiffness, walking problems. But there are a lot of symptoms, what we call non-motor symptoms, that is, anxiety, blood pressure problems, mood changes, cognitive changes, bladder problems, constipation, things like that, that affect people's quality of life in many cases more than the motor symptoms.

For most of these symptoms, we treat them the same way in people with Parkinson's as we do outside of Parkinson's. I will say, big picture, I'm not going to list off the medicines that come for each of these because there's a long, long list for each of them. But the big picture is that we treat them similarly inside and outside of Parkinson's. I think the most important thing to know about non-motor symptoms is that they are or can be connected to your Parkinson's, and so it's important to tell your Parkinson's doctor or your primary care doctor about them so that they can be addressed. Just recognizing that they're there and that they're a part of this condition is, I think, the most important piece to getting the treatment that you need.

Last, but certainly not least, like I said, probably the most important thing I'm going to say today is something we've known for a long time: it's not just about medications or surgeries. Lifestyle factors, and in particular exercise, are also an incredibly important part of the care of folks with Parkinson's disease. The Parkinson's Foundation has a nice flyer about this and a lot of material online that I encourage you to look at.

The long and the short of it is that exercise is the only thing we know that slows down the course of Parkinson's. It's the only, not quite cure, but sort of in that space treatment we have. It's really, really important to exercise. Some of my colleagues will write prescriptions for exercise in the office, and we should be doing more of that. Really, really important to know that this is also a big part of your treatment approach.

Dr. Pavan Vaswani 00:30:05
It takes a team, and physical, occupational and speech therapy can also be a very big part of that team. If you don't see a Parkinson's therapist, occupational, speech or physical therapist, it's worth asking your doctor if that would be appropriate for you and getting a referral to see them.

All right, so that's the bulk of the talk, which is the updates and the advances in the care of people with Parkinson's disease in the last couple of years. I'm going to spend the last three or five minutes I have talking about veteran Parkinson's care.

I think it's important to know that there are differences in the way that we think about and, to some extent, treat veterans with Parkinson's disease. We know that veterans are at increased risk for Parkinson's disease due to exposure to certain chemicals that folks may have had while they were serving. For example, the biggest known ones are Agent Orange and other herbicides for folks that served in Vietnam. Also, being at Camp Lejeune from the 1950s to the 1980s, there are exact dates online on the VA website and I think the Parkinson's Foundation website as well, has also been associated with Parkinson's disease. The VA recognizes both of those exposures and will consider Parkinson's a service-connected condition if you have Parkinson's and have those exposures.

Another very big part about veteran care and Parkinson's is that there are benefits related to conditions related to your service. The PACT Act actually has a really nice summary of this, as does the VA website, but the Parkinson's Foundation summarizes it very nicely. It's worth checking that website out for the benefits that are relevant for you.

Beyond the specific considerations, the VA is also, I think, a unique pathway to access care and really specialty care. Treatments only really work if you can access them. This cool new list of exciting things we have, if you don't have a doctor to talk to about them, it's hard to get them. We're very fortunate to have, and both Dr. Kannarkat and I work at, what we call the PADRECCs, which are the Parkinson's Disease Research, Education and Clinical Centers, essentially centers of excellence in the VA. You can ask your primary care doctor or, if you have a general neurologist, you can ask them for a referral. We can do video visits really to anywhere in the country, which is a thing that we're fortunate to be able to do through the VA, not something you can do necessarily outside the VA, if you live far from one of our sites.

I think I lost my slide here, but there are six PADRECCs. There is one in Philadelphia, one in Richmond, one in Houston, one in San Francisco, LA, and then a pair that are considered together in Portland, Oregon, and Seattle, Washington. I encourage folks to ask their primary care doctor or their neurologist for a referral if that's something you're interested in.

Big picture to summarize, there are more treatments and options than ever for Parkinson's. We're very fortunate that we have new things coming out. We have a lot of tools in our toolbox, and really customizing therapy for you is an important part of your relationship with your treatment team. It's not just about medication. I know I didn't talk as much about exercise and working with the therapist, but that's probably the most important part of the care of people with Parkinson's. It's the only thing we know that slows down Parkinson's, and it really takes a village and a team, both you and your caregivers, support groups like the Parkinson's Foundation, as well as your physicians, your case manager, your social worker, your nurse, your neuropsychologist, your surgeon. All of those people really go into having a really good team for the care of Parkinson's disease.

We're fortunate that it takes a village and that we have a village, and we certainly have a village within the VA as well. I encourage you to reach out to us at the PADRECCs, or if you have a great neurologist in the VA already, that's wonderful. I encourage you to chat with them if any of these treatments seem like they'd be appropriate for you.

With that, thank you. I will pass it back to Crista to take it from here.

Crista Ellis 00:34:24
Thank you, Dr. Vaswani, for enlightening us about the latest advances in Parkinson's treatments and also acknowledging that managing Parkinson's disease is multi-dimensional. I'm looking forward to asking you some questions that we're getting from our community here.

Now we're going to turn toward advancing discoveries and research. We'll talk clinical trials, and looking ahead, I'd like to introduce our second speaker for today's webinar. Dr. George Kannarkat is a physician-scientist and assistant professor at the University of Pennsylvania and the Philadelphia VA Medical Center. He specializes in caring for people with movement disorders, including Parkinson's disease, with a particular focus on at-risk populations. His research explores how factors like protein misfolding, environmental exposures and inflammation contribute to neurodegenerative disease. Through this work, Dr. Kannarkat aims to better understand where and how Parkinson's begins and to identify new biomarkers that can improve diagnosis and care. Dr. Kannarkat, thank you for being with us today.

Dr. George Kannarkat 00:35:31
Thank you for the introduction, Crista, and thank you for the opportunity to speak to you all today. It's really, I think, an important topic to talk about research and clinical research, particularly as it pertains to veterans and veteran populations. I'm glad to be here.

I'm just going to show this disclosure, financial disclosure slide, just to mention that I do have research funding from various organizations, and I have a couple of consultancy roles. Like Dr. Vaswani, I may mention some off-label uses of medications, and I'll try to stick to generic names, but sometimes we'll use brand names just because they're easier to say.

All right, so we'll open with just a question, just to get a sense of where everyone is. How comfortable are you with your understanding of how PD research happens?

I don't see the results yet, but if Crista or someone else does, feel free to chime in.

Crista Ellis 00:36:52
Sure, we can end the poll, and let's see if those results get shared out. Yeah, can you see those results?

Dr. George Kannarkat 00:36:58
I can. Thank you. It looks like the plurality of you, 45%, said somewhat confident, and 36% said not very confident. Nine percent said either not sure what to ask, or nine percent said very confident. I think many of you have fallen in the not very confident or not sure what to ask categories. Hopefully this discussion will be helpful for approaching how you think about PD research and whether that's something that you want to get involved with.

We'll talk about what clinical research is, why to participate, and then think about and talk a little bit about how it happens and how we get from an idea that someone may have in a lab or treating a patient to an actual treatment that gets approved down that pipeline.

First, just to talk a little bit about what clinical research is and the ways in which it can happen. There are a few different ways to break it down. One is just by how the study is designed. In the leftmost group, we think about observational studies. This is where researchers are observing or collecting samples, biospecimens. Thinking about taking blood samples or spinal fluid samples, recording how someone walks or taking measurements on tremor, and using those observations to understand various things. You may hear words like cohort or case-control or cross-sectional studies thrown around, and those are all observational trials.

Observing someone or groups of people and making conclusions about them. These are studies that are largely done to identify risk factors and also biomarkers. What we mean is, what are the things that put a specific group of people at risk for developing Parkinson's disease? In the past year, I think there were some key studies that came out about trichloroethylene and people who were stationed at Camp Lejeune for specific years in the '80s. That is an example of a retrospective observational study that tied the risk of trichloroethylene in drinking water to the development of Parkinson's disease. That's an observational study, for example.

Then biomarker studies. You may be aware of, now clinically, we're able to use both spinal fluid testing and skin biopsies to identify a misfolded protein, alpha-synuclein, and use that as an aid to diagnose Parkinson's disease. Those biomarkers came out of these observational studies looking at large groups of individuals who have Parkinson's disease, to identify those biomarkers in the skin and the spinal fluid. That's how these observational studies can be helpful. Not necessarily to develop a specific treatment, but it helps us to better diagnose or better prognosticate, tell who's going to progress faster versus more slowly, if they have Parkinson's disease.

The next really big bucket is interventional studies. These are studies where we're trying to figure out whether a therapy actually changes the course of someone's disease. There can be different kinds of interventional studies. They can be randomized or non-randomized, and I'll talk about that in a second. But the overall goal of an interventional study is to test whether a drug, a device or some sort of behavioral change can influence an outcome. Ideally for Parkinson's disease, it's whether it improves symptoms or changes disease progression.

Dr. George Kannarkat 00:41:02
An example of that may be testing a new physical therapy protocol or testing a new exercise regimen. That's considered an interventional trial. That would be helpful if you showed, okay, we have a group of people with Parkinson's disease and their caregivers participate in a program, and then we measure, did that program actually help with the Parkinson's patient's symptoms or reduce the stress that a caregiver is experiencing? That would be an example of an interventional study that's not necessarily a clinical trial.

Clinical trials are really the backbone of how we develop therapies, and you may hear about a clinical trial that went through the Food and Drug Administration, the FDA approval process. Clinical trials are really the gold standard for how we get different therapies approved and get them into clinical use. But a clinical trial really is a subset of an interventional trial. We are taking a group of people and having them undergo some sort of intervention, and seeing whether it worked or it didn't.

These are prospective trials, meaning they're happening in real time, where we're recruiting people into a study and having them undergo the intervention or not, and seeing what happens to them moving forward. These are really controlled. There's a lot of regulation around them. There's a lot of safety checks. They're often randomized, meaning that you go into the study and you may not know, you may not really have a choice in terms of whether you're in the arm of the study that's getting the treatment versus not getting the treatment. Often, there's what we call a placebo arm, where you're in the arm where you're getting a mock treatment or a sham treatment that's mimicking the treatment but doesn't have the active compound or the active therapy, for example.

I'll have a little bit more information about the whole framework on the next slide. Dr. Vaswani talked about the infusion pumps. All of those levodopa infusion pumps went through this kind of clinical trial framework. You might have heard in the news, right, oh, phase three trial results came out for this drug and the levodopa infusion. That's an example of a clinical trial.

Specifically for Parkinson's disease, you can think about the types of clinical research that are going on in terms of being either disease-modifying, so somehow being neuroprotective, and the goal of those is to slow, halt or reverse neurodegeneration. Later on, I'll talk a little bit about big groups of therapies that are undergoing investigation for the purpose of being disease-modifying. As Dr. Vaswani already mentioned, we don't have any FDA-approved therapies that are disease-modifying, but that is really the holy grail of what we're trying to achieve with clinical research in Parkinson's disease.

Then the other category is symptomatic therapies or functional improvements. Even if it's not changing the course of your disease, it still makes you feel better on a day-to-day basis, or it's treating some sort of motor or non-motor symptom or dyskinesia as a side effect of the treatment that we're giving you for your motor symptoms. There are a whole host of those that Dr. Vaswani already talked about that are approved and actively being clinically used, but there are many that are under investigation as well. I'll mention a few of those in a few slides.

Dr. George Kannarkat 00:44:51
This is a slide that I put up here to just kind of give you a sense of how long and what it takes to really get from point A to point Z. A lot of these ideas and therapies come out of either studies in the lab, in a test tube or a dish, or observation from clinicians like Dr. Vaswani, who observe something in their patients and want to test it out.

That then has to go through testing in what we call basic science research or preclinical models before they even touch humans, to show that there is a benefit. We have to show, okay, in cells in a dish, this compound has a benefit, or maybe we're making rats exercise, for example, and showing that that has a benefit for a Parkinson's disease mouse or rat model. That can take up to a decade or longer sometimes.

Then we move into studies that are actually looking at humans and the effect on humans. Those are phase one, and those are looking at really just safety and what dose we can safely use in humans. You can see that takes a couple of years. Then they move on to phase two studies, which are looking at, in a small group, how efficacious is it? How effective is it? Are there side effects that we need to watch out for and monitor for? Again, kind of the scaling up of the safety idea. We want these therapies to be safe when we're using them and when we're testing them.

That again takes a few years, and then phase three is when really we're testing, is this therapy efficacious? Is it going to be effective on a large scale? This is where we usually use a placebo control to test, okay, it's not just because we're watching people in a trial and we're giving them something, even if it may not work. Having that comparator shows that really there is a benefit over that placebo control group. That's where we get the most excited when there's a signal in the phase three trials.

Along this process, the FDA is monitoring all of these stages for safety, for efficacy, for effectiveness. Ultimately, the FDA has to undergo a review of all of the data and say, okay, we think this drug is safe and effective enough to be used in the real world. Then the FDA will approve the drug.

I'm making it sound a lot simpler than it is for the sake of time, but this is a long, complicated process, with lots of rules and regulations around it. Even after the drug or therapy is approved, there is post-approval surveillance that goes on to make sure, okay, are there things that are happening even after we use this in the real world that are causing safety concerns? Is this therapy really as efficacious as when we were studying it in a controlled setting or in a more controlled setting? That's ongoing as well.

Dr. George Kannarkat 00:48:17
You can imagine this takes years, decades to occur. Of 10,000 compounds that are screened, only one may reach the FDA approval stage. This is a really long, intensive process, and it takes a decade or more, costing a couple of billion dollars to test. It's just a really difficult process.

For things that look more promising, the FDA, in the past decade, has developed these accelerated pathways to kind of push things that really look more promising down the pipeline because we obviously don't want people to wait 10 years for something that looks really promising to become used in the real world. There are those pathways, and then there are Parkinson's disease-specific programs that are trying to generate or help fast-track things that look really promising. The Michael J. Fox Foundation and the Parkinson's Foundation are involved in generating not only the funds, but also helping with the regulatory and approval processes for those therapies that look the most promising.

I just wanted to touch on, I think, a question is, okay, are people really looking at veterans? Are we studying things that are really veteran-specific? I just wanted to put this slide up that, yes, certainly from a government perspective, there is money that's being put up for veteran-specific funding and Parkinson's disease-specific funding. The PADRECCs are one way, but there's also Department of Defense funding that's independent of PADRECC funding that's looking at Parkinson's disease-specific therapies and diagnostic tools. That is in existence, and I think really that has come from grassroots efforts, efforts from the Parkinson's Foundation, Michael J. Fox Foundation and others to say, hey, we need to look at these things, and veterans groups, of course, to look at these issues.

I think, just to emphasize, this is how we get government funding for these important issues. Along with government funding comes funding from other private sources as well, and getting pharmaceutical companies interested and really recognizing, okay, this is an important problem and an important population to work with.

I just wanted to touch on briefly too, if you may be thinking, okay, why should I participate in Parkinson's disease research? Maybe as a veteran, why should I, or why is it more difficult, why does it get difficult to participate in research? For clinical research, it's really on the cutting edge. It's stuff that's really new and maybe, if it works, you're one of the first people to be able to access it and to use it. Often, people that are participating in these phase three trials are able to continue, for certain therapies, even after the clinical trial phase is over. It's usually called an extension, like an open-label extension phase. You still get to be on the therapy, especially if you feel like you're getting benefit from it.

Dr. George Kannarkat 00:51:36
The VA, for U.S. veterans, the PADRECC Network is really cool because we can actually do trials at multiple sites all at the same time. Even if you're not necessarily near one site, you may have access to a trial that your friend who's not a veteran doesn't have access to. I think that's also cool.

Also, as a veteran, you have unique exposures that are not necessarily exposures that your civilian friends may have. Being able to study and see, okay, are these therapies going to be relevant for me and for other veterans with Parkinson's disease or at risk for Parkinson's disease, is really important.

People that are in clinical trials, you get a lot more face time with clinicians and also people that are seeing people who have Parkinson's disease. It is nice to have that extra monitoring support, be able to ask questions, maybe understand your disease a little bit better, and maybe get some extra testing as well. Sometimes there are other additional tests that are done more frequently as part of these clinical trials, so it's nice to be able to access that.

Maybe reasons that you may be cautious or just want to ask more questions to your provider before you get involved in a clinical trial: U.S. military veterans may have a lot of other comorbidities, meaning other conditions, like traumatic brain injury, PTSD, sleep apnea, or other specific toxic exposures during your time in service. These are things to just ask about. Taking other medications to treat those other conditions may make it complicated to actually qualify for some of these studies. But again, this is where talking to your clinician and whoever is running the trial is important.

Getting to the sites often enough sometimes can be difficult, especially depending on where you live in relationship to where the site is happening. More and more clinical research is trying to move toward what are the things that we can do virtually, or not having people come in. I think that's slowly becoming less of an issue, but again, that can be a logistical barrier if you have to come in four times a year or more to participate in clinical research.

One thing that does come up, I just want to mention, not as a reason that you shouldn't participate, but a question that often comes up: with Agent Orange and with Camp Lejeune, it took a lot of effort to really get the government to sometimes recognize that these were exposures. There might sometimes be mistrust of the scientific process or the government funding some of these studies. But I just want to re-emphasize, it's not just one person that's checking the safety of these studies. There are layers upon layers of regulation that are governmental, non-governmental, scientists, clinicians. There are layers of safety networks that are there, both on the local and national levels. While I think it's reasonable to be cautious, hopefully this kind of layered safety network makes it really difficult for an unsafe medication or therapy to get through. I think, really, we tend to err on the side of being more cautious and making sure that the burden of evidence is really there before something goes out into the real world.

I'll stop there before we get to the next topic, just to gauge how comfortable you are with knowing how to participate in PD research.

Dr. George Kannarkat 00:56:24
Okay, and the majority of you, 53%, said somewhat confident, 13% were very confident, and 28% were not very confident. I'm glad a majority of you are somewhat confident. That's great to hear. I'm just going to review a few resources on how you can actually get involved in Parkinson's disease research if you're interested. A few different levels: the VA system, national databases, and then talking to your provider.

I think the simplest way to figure out, okay, within the VA system, what are the trials or clinical research that may be available to me, is actually to go to clinicaltrials.gov. It's a government website that lists all the clinical trials that are available for all conditions. As a clinical trial, you're actually mandated to be listed on this register, on this website. It's very comprehensive.

For you specifically, you can set your condition here to Parkinson's disease, or if there's a specific symptom, like a non-motor symptom you're interested in, you could list that here. Sometimes there may be trials that are irrespective of what condition you have. They may be looking just to treat a specific symptom, irrespective of whether it's Parkinson's disease or not. The other important thing here, if you're looking for veteran-specific trials, is to put the term veterans here in other terms. Then there's a whole host of other eligibility criteria that you can specify, right? Your sex, your age, are you looking for phase two, phase three trials, things like that. But I think the key thing here is the term veterans, and then Parkinson's disease or the other condition you're interested in.

What I did was, these are the two trials that are actively recruiting or not yet recruiting at the Philadelphia VA. You can also set your location, which I did for this search. This is just an example of what the results pop up as. You can see that these are sponsored out of the VA. If you were to click on the blue link under the name of the study, the study title, it will actually give you probably more information than you ever need for this trial. It'll give you who is leading the trial, what sites are involved in the trial, the inclusion and exclusion criteria. But I think most importantly, it is the contact information for how you get more information about the study. If you click on that link, it will list that out.

You can email that contact, and they should be able to get in touch with you and talk to you about whether you are eligible for the trial, when they might be recruiting if they're not yet recruiting, things like that. You could certainly do that for the trials that are in your city or in your area. Again, I know this is a veteran-specific talk, but I also encourage you to look at maybe there are trials that are in your city that are not necessarily veteran-specific that you may be eligible for.

Dr. George Kannarkat 00:59:46
I'll also point you to the PADRECC website. I think the easiest way really is, if you just search Veterans Affairs PADRECC or VA PADRECC, it'll come up in Google or another search engine. I just pulled a screenshot from our Philadelphia PADRECC website here, but all of the PADRECC websites are listed on this Philly PADRECC website, and vice versa. Some of the PADRECC websites have resources for what research studies are available and have links to other national resources as well, so it's a good resource.

There are a few national databases that are not necessarily veteran-specific but are good resources to go to. The Parkinson's Foundation website has several studies listed. The Michael J. Fox Foundation has a Trial Finder, which lists Parkinson's-specific studies, so you can search there as well. I already pointed you to clinicaltrials.gov, but it's again a great resource for trials for Parkinson's disease, irrespective of whether you're a veteran or not.

Also talk to your Parkinson's disease provider, your neurologist or even your primary care physician. How do you find out about research studies? You can ask at your local VA, or if you have a university affiliate, like University of Pennsylvania is a common one for our veterans. They really know what's best in terms of what studies you would qualify for because they know your comorbidities, what medications you're on, things like that. They can also discuss what kinds of studies you are comfortable with.

I'll talk a little bit about some of the studies that are ongoing, but some of them are very observational. They may just want to do an exam, all the way to brain surgery. It runs the gamut for what kinds of things that you might want to participate in. I think the other thing that's helpful is it can help even accelerate the enrollment or access to clinical trials if you talk to your clinician. Just like any other industry, word of mouth: hey, I have this patient who is super motivated and interested, can I get them enrolled in the study? It's an email or a phone call, and it can accelerate the process. I think that's also helpful.

I will also maybe stop here for this poll for how interested are you in participating in PD research? Yeah.

Dr. George Kannarkat 01:02:50
So 28% said very much, 43% somewhat, 22% not very much, and 7% not at all. It's exciting to see that there's a range here. I'll talk a little bit about some of the PD research that is ongoing. This is by far not comprehensive because there's just a lot going on, but I color-coded it based on whether they're tagged by whether it's disease modifying or symptomatic, and what phase they're on. I included some FDA-approved studies just to give you a sense of what are the things that are going on, and maybe some things may pique your interest, or just think about, oh, I didn't know that we're even doing that or thinking about that in Parkinson's disease.

The first big group is dopamine receptor targeting. Dr. Vaswani already talked about the idea that, and you can look at the image in the top right, in Parkinson's disease, the release of dopamine is impaired in specific brain cell populations. The idea is, can we fix that release of dopamine or replace it in some way, and does that help motor symptoms and some non-motor symptoms? We know that it does. Thinking about better strategies for doing that. As you can see, most of these are really symptomatic therapies that are listed on this slide because, again, we're just replacing the dopamine that's not there. It's not fixing the underlying process.

I think one drug to really keep your eye on is tavapadon. It is a dopamine agonist, similar to things like pramipexole or ropinirole, but it works at a different receptor. The idea there is, can we have some of the benefits of those medications without the side effects? Dopamine agonists can cause people to feel sometimes really sleepy, can make people confused, and can also cause impulse control disorders, leading to uncontrolled gambling or hypersexual behavior. People are sometimes really cautious about using it because there are really damaging and dangerous side effects. The idea that this type of medication, tavapadon, can potentially have the benefits of treating motor symptoms without having those dangerous side effects is the idea. The FDA is reviewing this data, so hopefully this year we'll find out whether there's some news about approval of the drug.

Dr. George Kannarkat 01:05:30
There are some other drugs coming out. P2B001 is a combination of an MAO-B inhibitor plus a dopamine agonist, so again, kind of a way to reduce pill burden. Viylev, or foscarbidopa/foslevodopa, is one of the infusion therapies that Dr. Vaswani mentioned. There's another related compound that's also in a phase three trial right now, so that will provide kind of a third option if that gets approved. SER-252 is really like a subcutaneous version of the apomorphine. Again, kind of a nice alternative to maybe even the infusion therapies. The idea there is to be able to inject it under the skin rather than being hooked up to an infusion pump. Those are kind of just a quick snapshot of those therapies targeting dopamine replacement.

There are also many therapies looking at misfolded proteins. When we look at someone that has Parkinson's disease, their brain under the microscope, we see these clumps of proteins. If you look at a brain cell under a microscope, I think of them as these dried cranberries, or Craisins, because they're always stained red when we look at them. You can imagine these dried cranberries gumming up all of the brain cells in Parkinson's disease. The idea there is, can we remove those clumps before they form, and maybe help slow down or reverse the Parkinson's disease process?

Similar to the anti-amyloid therapies for Alzheimer's disease, there is one antibody here, prasinezumab, that's given via an infusion. The idea there is that it's supposed to remove the precursors to the clumps that form in the brain cells. There are some trends in some of the early studies toward reduction. They're still studying this compound further to see whether there's a signal for effectiveness.

There are also active therapies looking at whether we can use vaccine-based therapy to actually have the body generate your own antibodies to clear alpha-synuclein, the misfolded protein. There's also a small molecule, minzasolmin, and that is a molecule, just like a chemical, that also inhibits the aggregation and clumping of alpha-synuclein. There's also an interesting study looking at citalopram, which is an SSRI, a drug that's often used for depression and anxiety. There's some evidence that it actually helps reduce the accumulation of amyloid beta, which is the protein that clumps together in Alzheimer's disease, in about half of people with Parkinson's disease. The idea there is, can we reduce cognitive decline in people with Parkinson's disease by reducing the amyloid that accumulates in people with Parkinson's disease?

Dr. George Kannarkat 01:08:57
Again, this is just a snapshot of some of the interesting things going on. There are several drugs that are being tested for genetic forms of Parkinson's disease. We know that these pathways are disrupted even in people who don't have genetic forms of Parkinson's disease. They're being tested in these genetic forms, but also people who don't have the genetic forms, to see if they have a benefit.

These compounds range from being things that you take as a medication by mouth to ones that are injected into the spinal fluid around the brain, to actually a therapy that's genetic therapy that's administered via a virus that's infused into the blood. Again, these therapies are targeting similar pathways but via various different mechanisms and routes of administration. Just again, an example of how you can now have the option to pick and choose maybe some therapies that you're particularly interested in if you're interested in research.

Another big category is brain-targeted gene and cell therapies. I'll start with the image on the right side. This is actually a way for us to take stem cells. A couple of decades ago, there were actually stem cells taken from embryos and used to try to treat Parkinson's disease. But now, since the early 2000s, there are ways to take cells that are from someone's skin or from someone's blood and reprogram them to become stem cells. We can actually turn those cells into brain cells that produce dopamine in a dish in the lab, and then take them and inject them into people's brains. Again, it sounds a little science fiction-y, but we're actually doing this in clinical trials.

We have the option of doing that from even someone's own cells. There are actually two different strategies that are being tested right now: taking someone's own cells, and then actually taking donor cells and injecting them into someone's brain. For the latter strategy, you have to be on immunosuppression for a year, but it looks actually safe from the data that we have right now. That is something that's being tested actively.

There are therapies that are looking at actually delivering genes via viruses and other methods to see if that can actually be neuroprotective or neurorestorative. These are genes that actually help make the brain cells more robust or more resilient. That's the other thing that we're testing.

Dr. George Kannarkat 01:12:07
Finally, the last big category I'll talk about is using different therapies that target inflammation. These are either small molecules, small chemicals, or even cell-guided therapies. So infusion, again, of a different kind of stem cell to reduce inflammation. We know that inflammation can be a key player in people with Parkinson's disease in the disease process, so targeting that is another strategy.

Then, throwing up here, adaptive DBS, which Dr. Vaswani already talked about, also went through this FDA approval process. But I think there will be several iterations of that coming down the pipeline as well, so look out for those.

I'll stop there, but just a few key takeaways I want to emphasize. As veterans, there are systems that you can access on a national level, both the VA and elsewhere, to participate in clinical research and maybe take advantage of some of these really cutting-edge opportunities that may really change the way we treat people with Parkinson's disease.

In the last few years, veteran-specific research is increasing due to grassroots efforts to get funding for it, but also realizing that the veteran system has a great network that we can access that's already integrated. Dr. Vaswani mentioned the telehealth system, and that's really great within the VA, where we're able to take care of people on a national level no matter where we, the clinicians, are. This also applies for research.

I just want to emphasize, participating in research can really allow for advancing Parkinson's disease care and being on the cutting edge. Without people participating in research, we can't develop new therapies. I will stop there and thank you for listening, and I'm happy to answer any questions you might have.

Crista Ellis 01:14:17
Thank you, Dr. Kannarkat. I'll invite Dr. Vaswani to join us back for our question-and-answer session. I want to ask Dr. Kannarkat, is there usually a cost to participate in a clinical trial?

Dr. George Kannarkat 01:14:32
I wouldn't say, in terms of talking about costs, there's no specific fee for you to participate, but there is the hidden cost, I guess, of if you need to travel to a site to participate in a clinical trial. Many clinical trials actually reimburse those costs. It's important to ask about those things and not assume, okay, I'm going to have to pay for my own gas or transportation to get somewhere. That's not necessarily true. Sometimes, depending on how involved the trial is, you're actually reimbursed for your time and trouble to a degree. It's also, I think, important to ask about that and not just assume those are costs that you're eating yourself.

Crista Ellis 01:15:20
Would you mention any red flags or things to be cautious about before joining a clinical trial?

Dr. George Kannarkat 01:15:29
It really depends how risk averse or risk friendly you are. I know there are certain people that are like, yeah, get me in on the ground. This sounds really exciting. But there are some people who are like, I want to make sure this is really, really safe before I get involved. Paying attention to what phase the research is in: is this a phase one study or is this a phase three study? By the time a drug has gotten to a phase three study, it's really undergone multiple rounds of safety testing, so we really know what to expect in terms of the adverse or side effects that you might experience.

Other things, just making sure you're comfortable as a research participant. Ask all the questions you need. Take the time to ask about anything that's not clear about what's going to happen with the study, what's involved with your time, or the procedure that you might be undergoing. There's no rush. We, as the people conducting the research, want you to feel comfortable and we want all your questions answered before you get involved, because the last thing we want is for you to be unhappy that you participated in the research, because that just breaks our heart.

Crista Ellis 01:16:47
Dr. Vaswani, I want this to be a dialogue, so if I ask a question directly to Dr. Kannarkat, feel free to ad-lib.

Dr. Pavan Vaswani 01:16:54
I will chime in one other thing there, which is that, in the concept of a clinical trial, I agree with Dr. Kannarkat, it's about your personal thoughts. I will say there are a few things you can find online that mimic these trials that are not trials that it's important to be aware of. Please don't fly to Costa Rica or Turkey and get stem cells from someone who isn't part of a trial or it's not regulated. That can, in some cases, be quite dangerous, and in the most benign case, just expensive, but the dangerous case is the one we worry about. If you stick to official clinical trials in the U.S., ClinicalTrials.gov is a great website to triple check that. I think you're in good shape. Just be careful of those occasional mimics out there.

Crista Ellis 01:17:38
What does it look like for the 28% who were somewhat interested in participating in a clinical trial? How might you describe the process of getting engaged in clinical research, from exam, conversation with your provider, to receiving treatment?

Dr. George Kannarkat 01:17:59
It can either be initiated by the clinician, by your clinician, or by you as the patient. I often ask, "Are you interested in research?" Or a patient will say, "Oh, hey, I heard about this study that's going on," or "I'm interested in research for X, Y and Z reason." At that point, if you are interested, often we'll talk about the options that are locally available. Depending on where you live, for people that live in the Philadelphia area or between New Jersey, a lot of times it's not a big deal to drive to New York. You can talk about those trials that are maybe at New York locations, for example.

Then the next step is usually putting you in touch with a research coordinator. That research coordinator will usually call you or email you, depending on your preference, to talk you through, okay, these are the studies that are available based on what you tell them you're interested in doing or not interested in doing. If you say, look, I only want to be involved in studies where I take a medication by mouth. I want nothing that is an infusion or a surgery. They will only talk to you about the things that you want to do.

Then they'll get more information about, if these are the studies you're interested in, what are the criteria? What are the things that the study is looking for? Usually that's things like how long have you had Parkinson's disease? What medications are you taking? Have you had DBS or not? Things that make you eligible for participation versus not eligible for participation.

After that, usually we'll have what's called a screening visit, where they really go through a rundown of a checklist of all the things that make you eligible or ineligible for a trial more formally. Then there'll be usually another visit where you're actually formally enrolled in the study and maybe even start taking the intervention if it's an interventional study. Dr. Vaswani, feel free to add anything if I missed anything.

Dr. Pavan Vaswani 01:20:18
No, I think that was all the steps. At some point in the screening timeline, they'll get formal consent. They'll go through and talk to you about the risks and benefits in detail. Then usually, you either take the drug or the placebo for a couple of years, a year or two, sometimes six months, sometimes a couple months, depending on the duration of the study. Some studies have a period where you take one medication and then maybe they switch you to placebo or off placebo. You usually don't know, so there can be different moments in time where you're being evaluated. Then, when the study finishes, there can often be a little bit of a gap until the data is reviewed and folks see if it was successful. Sometimes in that period, they do what's called an open-label extension, where whether you got the placebo or not, you can be offered the treatment for a little while. That can be sort of at the tail end of a study. There are a lot of different structures as you go through the process.

Crista Ellis 01:21:09
I know in my previous life of being a clinical research coordinator, our participants received a lot more benefit beyond benefit from receiving the intervention. Could you speak a little bit about some of the benefits that go with seeing your provider more often or being connected to what's driving our research forward?

Dr. George Kannarkat 01:21:32
Some of the direct benefits are being able to ask more questions and also being able to understand the disease better. You just have conversations about, okay, why are we studying this therapy? Or you hear about, okay, we're using this drug to treat this symptom in addition to your motor symptom, and it's like, oh, I didn't even know that happened in Parkinson's disease. You learn about the disease process.

I think the other benefit is being able to connect with other people that are interested in Parkinson's disease, whether that be other patients or other clinical research coordinators. You just learn. Many of us have stories for why we got into this field in the first place. For me, my grandfather had Parkinson's disease, and I hear these stories all the time. It builds that sense of community for people too.

Crista Ellis 01:22:32
Dr. Vaswani, you opened our webinar talking about current treatment options, and I just want to acknowledge those options would not be options without the research that Dr. Kannarkat alluded to. I'd like for us to turn back to the treatments that are available. We have a question from one of our participants who shares that some of the medications, like the extended-release carbidopa levodopa, aren't available where they live. Any recommendations if newer therapies aren't being offered in their area or maybe not covered by the VA?

Dr. Pavan Vaswani 01:23:06
There can be both inside and outside the VA, I think that's important to acknowledge, a little bit of a lag in terms of when the FDA approves a medication, say today. It has to be reviewed, the pharmacy has to figure out if it's going to stock it, who's a candidate and when it's appropriate to give it, work out with the company how to get it, and the company has to make enough. There can be a delay between the medications being approved by the FDA and available.

We, as a group, also evaluate if it makes sense. Some of these medicines can be expensive, not to you individually but to the system initially, and we think through who does this make sense for? Is it giving people benefit, and in what way? Where should we prescribe it, and who's the right candidate? Who is it safe for? There can be a little bit of a delay in terms of having access, both inside and outside the VA, and that delay can be months to sometimes a year. Getting things on formulary with either an insurance company outside the VA or with the pharmacy can also be a delay.

For example, the extended-release Crexont is something that we at our VA are in the process of getting access to around now. The long and the short of it is, talk to your doctor, see what the options are. I didn't compare them to the other drugs, but there's another extended release that's been around for a few years that is similarly effective, so that may not be the only choice. That's, I think, the main takeaway: talk to your doctor, because it may not be the best fit for you and there may be very similar choices. Usually, it's just a little bit of a process and you have to bear with the system a little bit as we go through the process to get access to these over time.

Dr. George Kannarkat 01:24:44
The only other thing I'll add to that is sometimes it can be site-specific. Sometimes veterans ask me, "Okay, why can I not get this medication?" or "Would it be easier if I went through my outside neurologist?" Sometimes the answer I tell them is yes, go to your outside neurologist because it's actually easier to get it, because it's not on the formulary here. But sometimes it's actually easier in the veteran system depending on what medication it is. Definitely ask the question. It's site-specific sometimes.

Dr. Pavan Vaswani 01:25:19
Absolutely.

Crista Ellis 01:25:21
A lot of what I keep hearing between listening to what you both shared was ask questions. Ask your provider questions. I really appreciate you empowering our community to ask those questions, not just during these webinars, but also in those moments with your provider at the VA and outside of the VA.

Lots of interest, Dr. Vaswani, in the extended-release options. One of our participants is asking, how does the extended-release version of medication differ from the regular version in terms of how often you take it or should take it throughout the day?

Dr. Pavan Vaswani 01:25:57
That's often very personal. Even the immediate release, some people take three times a day, some people take eight times a day. Some people take once or twice a day. There's a big spread, so it depends on your individual situation.

If you have someone, I'm going to give a hypothetical patient, if I have someone who takes the immediate release and it tends to last three-ish hours, so they take it five, six times a day, the extended release is going to last an extra hour and a half or so. Four and a half, five, maybe a little longer. They might go from medications five, six times a day to four-ish times a day is pretty typical. Now, sort of the rule in Parkinson's is typical, there's really no one who's exactly typical. It's a very personal journey, and everyone's a little different. But that's roughly how it goes, is folks go from four, five, six times a day to four-ish times a day with the extended-release versions.

Crista Ellis 01:26:46
It's deeply personal. Every Parkinson's journey is deeply personal. I appreciate you reminding us of that. Once again, ask your provider. Ask your provider.

Dr. Kannarkat and Dr. Vaswani, we continue to receive questions about government funding for Parkinson's disease clinical trials. Can you share any words or wisdom with us about whether or not government funding has impacted Parkinson's clinical trials negatively or not?

Dr. George Kannarkat 01:27:20
I haven't heard necessarily of active Parkinson's-specific clinical trials shutting down because of it. Dr. Vaswani, maybe you can correct me if I'm wrong, if you've heard of any. But I think what we are worried about is moving forward, even if it's funding. The pie is getting smaller, right? The amount of funding that's available from the government is smaller. Also, the approval process is getting more complex and more unclear. It's hard for us to predict, even if we submit an application for a clinical trial, is that going to get approved, or how do we make it successful?

I would advocate for, yes, more money for Parkinson's disease research, but also being mindful about when we're making changes to the system, how do we do it in a way that's transparent and clear and going to protect the future of research?

Dr. Pavan Vaswani 01:28:24
The only other point I will make is a lot of the researchers being affected are people earlier in their careers. As Dr. Kannarkat showed, it's a 10-plus-year process to get the data from the early mouse studies to the early human studies to the formal clinical trials. It is important. A lot of folks I know are a little concerned, and if we have a little gap in funding, are folks going to leave science, or are we going to have a little delay in the process? Given that it takes so long, we don't want to disrupt that pipeline. It really is a flow through.

If that's something you're interested in and think that we need more support for, obviously advocate with your representatives, if that's something that you think you'd like to support.

Crista Ellis 01:29:08
Thank you both so much for your wisdom. Before we close out, any final words you'd like to share with our community?

Dr. George Kannarkat 01:29:19
I was just going to say, I think just reinforcing, ask questions if you don't understand. Be your best advocate. I think we have the best intentions as clinicians and researchers, but sometimes we're busy and sometimes we just ask for your patience and forgiveness if we overlook something that's important to you. Just feel free to ask questions. Research is so important to get new therapies off the ground, so please be your advocate locally and nationally if possible.

Dr. Pavan Vaswani 01:29:52
I'll just highlight the point that everyone's journey is different. I know I talked about a few options for medications, but it's totally reasonable to ask. If your doctor says, no, I don't think that's a good choice for this reason, or I think that's a great choice for this reason, just be open and prepared for that because it really is a personal journey. It takes a team. It takes patients and their caregivers, and the whole team, and your physician or provider to think through the best choices for you. Have that conversation and learn more as you go. There are some great choices and there are some that may not be the right fit for you. Just recognize that it is a very personal journey.

Crista Ellis 01:30:28
Ask questions. Offer grace and kindness to yourself, and also to your providers who are managing so much, as we all are in our abundant lives. Dr. Vaswani, thank you so much for your wisdom, and Dr. Kannarkat, for your role in driving research forward. I acknowledge that we wouldn't be where we are without providers like you pushing this work forward. Thank you.

Today's webinar and the entire Veterans Webinar Series is presented with support from the Don and Lorraine Freeberg Foundation. I want to take this moment to thank the Freeberg Foundation for helping to make these programs possible.

The Parkinson's Foundation wants to hear from you. Through our My PD Story page, the Foundation shares stories written by anyone in the Parkinson's disease community. These stories help bring awareness to this life-changing disease and help to inspire others. As a veteran or the loved one of a veteran, your experience with PD is unique. I'd like to encourage you to submit your PD story and share your experience with others in the community. To learn more and to submit your PD story, please visit Parkinson.org/MyPDStory.

Don't forget to visit our webpage and explore the resources offered by the Parkinson's Foundation that can support your navigation of living with Parkinson's as a veteran. That website is Parkinson.org/Veterans.

If you had a question today that was not answered, please reach out to our Helpline by calling 1-800-4PD-INFO or emailing Helpline@Parkinson.org. You can use that same contact information to order our free resources, such as educational books and our Hospital Safety Kit. We thank you for joining us today. I hope I see you again soon.

Dr. James Beck 00:00:00
Hello everyone, and welcome to the Parkinson's Foundation Expert Briefing. I'm Dr. James Beck, Chief Scientific Officer of the Parkinson's Foundation, and it's a pleasure to have you here today. In today's briefing, we will explore the latest discoveries, where the science is headed, which I think is going to be really exciting today, and how these advances may guide new and more effective treatments.

Before we begin, I'd like to give a warm, generous thanks to Genentech Therapeutics for sponsoring today's Expert Briefing. Their generous support helps make programs like this possible, and we appreciate their commitment to the Parkinson's Foundation's mission.

As we go to our next slide, I want to ask everyone who's out there listening today: please tell us what your connection is to Parkinson's disease. This is something we like to do on a regular basis. A little poll should pop up. If you're on Facebook, just put into the comments what your connection is to Parkinson's disease. We like to keep track of who our audience is, and our speaker gets to see this as well and can really make certain we're recognizing our audience today even though we can't see you, ensuring that what is being delivered is something that you find really interesting, as I think we will today.

And so we'll just give that another few seconds and see where that goes.

Great. Not surprisingly, a lot of people with Parkinson's or closely related to Parkinson's, a few scientists and physicians mixed in, healthcare professionals.

Welcome, everyone. I'm really excited to move on with our Expert Briefing today. But before I do, I always like to let everyone remind everyone that our focus at the Parkinson's Foundation is to really make lives better for those living with Parkinson's disease. We enhance care and advance research.

These efforts are deeply rooted in collaboration with the Parkinson's community, ensuring that everything we do aligns with the needs and priorities of those who live with PD, you and your loved ones. Today's program is just yet another example of how we're working with you to meet those goals. One of our key initiatives at the Parkinson's Foundation is PD GENEration. Here at PD GENEration, we offer free genetic testing and counseling to people living with Parkinson's, and by participating, you can learn more about your genetic connection to PD and contribute to Parkinson's research, with the idea that one day this information will help drive treatments towards a cure. And with your commitment, I'm sure we will.

So I think this is an example of where, together, we can really make a difference in Parkinson's disease. As we do every time, we're recording this Expert Briefing and we'll make it available to everyone after this is over. If you have to step away and you miss something, or you have friends who weren't able to attend, you'll be able to download this and watch it at your leisure, over and over again if you like. I think this will be one of those oft-repeated ones.

As we talk about this Expert Briefing now, let me introduce our speaker today, Dr. Laurie Sanders. She's an associate professor of neurology at Duke University and a leader in translational neuroscience focused on Parkinson's and other neurodegenerative diseases. She serves as the faculty lead at the Duke Clinical Research Institute, where she also co-directs clinical trials and has led multiple studies as a principal investigator. Dr. Sanders is widely recognized for innovative work in biomarkers and therapeutics and with several awards and patents that are there to advance the field in Parkinson's disease.

Dr. Sanders, thank you very much for your time and for joining us today.

Dr. Laurie Sanders 00:03:30
Thank you so much, Jim. I'm going to now see if I can share my presentation. Thank you, everybody, as I navigate through here. Can you see it okay?

Dr. James Beck 00:03:50
Not yet.

Dr. Laurie Sanders 00:03:51
Oh, okay. Let's see...

Dr. James Beck 00:03:55
There. Starting now.

Dr. Laurie Sanders 00:03:57
There we go.

Dr. Laurie Sanders 00:03:58
Okay, thank you everybody for your patience as we get technology to catch up here. Thank you for this opportunity from the Parkinson's Foundation to speak with all of you today. I must admit that this is really such a privilege for me to be able to engage with all of you. I will also say that for those of you that live in the South, as I do in Durham, you know that it's pollen season. So excuse me as I'm a little congested with the allergies right now, because it's a major pollen season for us. Thank you for your patience.

I did want to mention a few of my disclosures, which again don't have any influence or any impact on what I'm going to talk about today. But I did want to mention that I do sit on a scientific advisory board for Neolaia Bio. I will be talking a little bit about how we've used our patent for a blood-based biomarker today, and I will share a little bit about some of the studies that integrate into some of the very, very exciting work that's going on around the world for a couple clinical trials and a new consortium that I'm so privileged to lead in terms of the Gut-Brain Parkinson's Disease Consortium.

So for today, the science is moving so fast. I can tell you, as a scientist in the Parkinson's field, it's such an amazing time to be in the Parkinson's field, and I'm going to have the pleasure of being able to describe to all of you today how our scientific understanding of Parkinson's has really evolved over the last several years and why researchers like me are increasingly hopeful with the new science that's emerging.

I'm going to focus on three key research areas that I think are really being transformative in the field: alpha-synuclein, mitochondrial function and inflammation, sort of separately, but really how all those key research areas are integrated and how we're thinking of them now more as a pathway with each other.

And then I'm going to be able to identify where I think the current research trends may shape future treatment strategies for Parkinson's disease. Of course, at the end, I'm very excited to take questions and engage with all of you.

Dr. Laurie Sanders 00:06:45
Unfortunately, I really don't need to mention the big picture and why this matters. We all know that Parkinson's disease is the most common movement neurodegenerative disorder. It's staggering that the latest numbers are over 11 million cases globally. That's over a million in the U.S. alone.

It's remarkable to even think about the estimates that, by 2050, we're projected to exceed over 25 million cases. And while there certainly, unfortunately, is no cure yet, the progress is accelerating at such a rapid pace that you'll see why I'm so optimistic that all this research really is leading us to better treatments and towards disease-modifying therapies.

And partly due to the Parkinson's Foundation and other Parkinson's disease-related foundations, this is just released, sort of hot off the press, that in 2024, Parkinson's disease cost the U.S. $82.2 billion. I'm sure that's even more in 2025 and 2026. It's hard to even wrap your mind around that economic impact.

While I'm sharing with you the numbers of total people with Parkinson's disease and the economic impact, I think it's really important that this is all of us, right? This is impacting all of us at such a personal level. While these numbers are staggering, these are our families, these are our friends, these are people that we really care about. I've been a scientist in the Parkinson's disease field for a long time, and I just want to share that it affects me personally as well.

My postdoc mentor, Dr. J. Timothy Greenamyre, who many of you may know, in Pittsburgh, a few years ago shared in a Science article that I encourage all of you to check out. You can find it. I'm happy to share it afterwards, where he described being a physician-scientist and being diagnosed himself. And so this has really deeply affected me as well. I will say that more recently my mom has been diagnosed with Parkinson's disease.

And so I can tell you that I have been a hundred percent committed towards moving the field forward towards better treatments and cures. And now it's even more personal for me. I can tell you that, from my perspective, I'm really optimistic and hopeful, even with all that I described, that we're really moving in such an exciting direction.

Dr. Laurie Sanders 00:10:15
So what's driving this progress? For you history buffs, there are some really interesting ancient scripts talking about Parkinson's disease and the symptomatology. Even over this last several hundred years, and this is by no means exhaustive, really showing from those initial James Parkinson essays describing the symptomatology and the movement symptoms of Parkinson's disease to the pathology, over time, this has really started to change and evolve and shape how we're thinking about Parkinson's disease.

This is sort of a nice roadmap, I think, again, not exhaustive, of where we've traveled since those initial essays from James Parkinson, where, in the mid-20th century, we really began to understand the pathology around Parkinson's disease and that it's this dopamine loss in the substantia nigra that then really led to the development of levodopa therapy in 1961 as the first symptomatic treatment against Parkinson's disease.

Even honestly from the 60s until maybe about 20 years ago, there was really that focus on motor symptoms and symptomatic treatment. But that's begun to change, even since I've started to train in the Parkinson's disease field, where certainly, of course, there are the motor symptoms of bradykinesia and increased risk of falling and others associated, but even the refinement of those motor symptoms and how it might affect one's speech or difficulty in swallowing.

But even beyond the motor symptoms is really beginning to appreciate the non-motor features of Parkinson's disease, and that this really extends and goes beyond into this multi-system involvement. Certainly, there can be cognitive effects, GI symptoms, urinary problems, sleep disorders and many others that are not mentioned here. We're really thinking of this now as a whole-body and multi-system disease, as opposed to just this motor symptomatology.

Beyond that, and this has really happened in the last 20 or so years, is that due to these molecular and genetic insights into Parkinson's disease. Here I have a map of some of the most well-known and now studied genetic risk factors for Parkinson's disease. It has really been a game changer for us in understanding what might be causing the risk and the development of Parkinson's disease, and maybe even the progression.

Dr. Laurie Sanders 00:13:33
Here on the lower-frequency end, these are rarer genetic risk factors for Parkinson's disease, like LRRK2 or SNCA, which is synuclein, or even PINK1 and Parkin. While these are rare, these have really taught us a lot about those molecular changes and insights into pathway dysfunction that is underlying Parkinson's disease. On the more high-frequency end, over 90 genes now have been associated with a risk at what we call loci, or genetic loci, in the development of Parkinson's disease.

And so this has really opened our eyes into not just the motor and now non-motor features, but those underlying cellular pathways that may be dysfunctional, which is so important because that gives us a window into understanding how we might be able to best treat Parkinson's disease.

And so I was mentioning those cellular pathways and what we call cellular pathogenesis. That's the underlying pathology that may be driving what we're seeing as those clinical manifestations of the motor and the non-motor symptoms. We're kind of focused on proteinopathy, or that synuclein, mitochondrial dysfunction and neuroinflammation. Each of these are critical components to what we call the hallmarks of neurodegenerative diseases and Parkinson's disease.

I did want to mention there are other cellular pathogenic pathways here in terms of synaptic and neuronal networks, cytoskeletal abnormalities, and DNA and RNA defects that also play important roles towards ultimately driving this neuronal cell death and pathogenesis that we see in Parkinson's disease.

Where I think our field is really evolving and changing is thinking about how not any one of these separate pathways may be influencing the biology underlying Parkinson's disease, but how they're now all interconnected, and what might come first and, on the other hand, what might be a consequence of many of these other pathways. That more holistic understanding of these hallmarks has really been breakthroughs in understanding again how to treat Parkinson's disease.

Dr. Laurie Sanders 00:16:24
But I can't even mention all of the amazing other advances that have been occurring in the field that have really been driving a lot of the progress at light speed. Certainly advances in imaging, so PET ligands, high-resolution MRI, other diffusion imaging, have given us new insights into imaging into the brain, not just in animal models of Parkinson's disease, but in humans as well, so that we can really begin to understand some of the inflammation that's occurring in the brain, but also some of those protein aggregates such as synuclein.

I'm excited to talk about the discoveries of the biomarkers in the field, certainly the alpha-synuclein seeding assays, also known as RT-QuIC, other fluid biomarkers such as neurofilament light, or NFL, and other inflammatory markers that really began to, at a molecular level, be able to define that cellular pathway in people with Parkinson's disease.

Molecular tools, so single RNA-seq, CRISPR screens, cryo-EM structures of these synuclein fibrils and other conformations. Improved models: these are all, again, not perfect models, but being able to have induced pluripotent stem cells derived from either people with Parkinson's disease or people without Parkinson's disease, neurons, microglia, even organoids, little brains in dishes and refined animal models, gives us better tools to be able to test some of our hypotheses for that cellular dysfunction.

It's just sort of a 10,000-foot view, too, I think, and this is certainly hats off to the Parkinson's Foundation in terms of really encouraging and fostering global collaboration, not just within the U.S., but all around the world, certainly PD GENEration and other efforts that are going on internationally so that we as a community can get a better understanding in all different cultures of how Parkinson's disease manifests and what might be the genetic drivers.

And certainly, thanks to probably many on the call here, I would certainly encourage you that we can't make some of these discoveries without patient populations and research, and it's fundamental for our progress forward. That's really, and many, many others that I haven't mentioned here, in terms of driving progress in the field.

Dr. Laurie Sanders 00:18:54
This has really led to the translational momentum and the clinical trial landscape. I have here the citation of this great summary of all of the clinical trials that are in the pipeline currently. The last one here was 2024. Hopefully what you can appreciate here is that there is a ton in the clinical trial pipeline, certainly in that early phase trials and even the later phase trials of phase two or three.

What's exciting to me is, I just did it right before I logged on here, to see how many clinical trials are, if you go into clinicaltrials.gov and just type in Parkinson's disease, there are over 200 clinical trials currently either actively recruiting or about to recruit. I think this really speaks towards this momentum of being able to test not just symptomatic therapies, which are obviously critical and key, but also this shift towards testing the disease-modifying therapies and being able to hopefully halt or stop the progression of Parkinson's disease.

And so there's a lot here to be optimistic about. This has really, I think, shifted our evolution of our understanding of where in the field we historically had been thinking about focusing on that dopamine loss, more motor symptoms and really thinking it through that primary lens.

But now we have a much better understanding of how Parkinson's disease is really this whole-body, multi-system disease, and that this includes not, which is obviously very important, the motor, but also these very key non-motor symptoms that really matter to people, and that we now have tools for earlier detection and intervention than we have ever had before. Hopefully you can tell that there is a lot of hope, which I share genuinely.

I think this is really due to what happens when people with Parkinson's disease, researchers and clinicians work together, because we really have the same goal. Hopefully, from what I've explained so far and what I'm going to share now with you, you all will share the hope that I have with me every day, that we are working closer and closer towards disease-modifying therapies for people with Parkinson's disease.

Dr. Laurie Sanders 00:22:12
Alright. So what's happening in the brain?

Certainly, we know that loss of dopamine-producing neurons in the substantia nigra in people with Parkinson's disease, but also this protein buildup of synuclein and other proteinopathies in the substantia nigra and also throughout the brain, and we'll talk a little bit also about the gut, and how this leads to cellular stress and dysfunction through the mitochondria and immune system, and how these are all interrelated.

So I'm going to first start with focusing on alpha-synuclein.

Dr. Laurie Sanders 00:22:54
So we think what's really important to understand about alpha-synuclein is that, while it certainly is causing havoc in Parkinson's disease, alpha-synuclein has a physiological and normal role in the brain. This is a protein that's found normally in all our cells and our brain, myself included, and has specific roles in our brains that help us. It's a protein that's known to be in the presynaptic part of our neurons that helps us with neurotransmitter release, such as dopamine, as well as what's called vesicular trafficking, so moving things around in our cells or neurons normally, and other pathways that are really important in terms of learning and other pathways in our brain.

This really, synuclein helps us communicate between neurons and between different parts of our brain. However, what we know happens in Parkinson's disease is that synuclein begins to misfold and clump together, and this starts to cause pathway dysfunction. Its role is not really fully understood in how it does this, but we know certainly that it's a good target for disease.

There's been a lot of work focused on the pathological role of synuclein in Parkinson's disease. But I think it's really important to mention that because it has this normal and physiological role in our brains, this makes it tricky in order to target it, right? Because you don't want to affect the normal and physiological role of synuclein.

And so there's been a lot of work in trying to figure out how to specifically, selectively target the pathological or the misfolded types of synuclein, so we can protect the monomeric or physiological role of synuclein. In our dopamine neurons, which have really interesting biology around them, there are incredibly long neurons in terms of their terminals.

Dr. Laurie Sanders 00:25:36
From the substantia nigra, all the axons and dendrites that go all the way into the striatum are really, really, really long and travel really far in our brain. The synuclein is not just in the cell body of neurons but also along that track and those axons and dendrites. Understanding whether to target within the cell body and along sort of that, you can think of it like train tracks, into different parts of the brain has led to some barriers in trying to figure out how to target synuclein.

From that monomer, this is sort of what we think of as synuclein going wrong, that misfolding and what we then call oligomers and fibrils. These are these higher-order structures, and I have a picture of that represented here, that then form these Lewy bodies, which is sort of the hallmark of Parkinson's disease in the brain.

I would say that there's still some controversy and context dependency about whether we think those Lewy bodies are protective or are actually causing part of the problem in Parkinson's disease. But what's really come to light over, I'd say, the last decade or so is this idea that synuclein actually can propagate between cells, almost like this prion-like seeding. It's this interaction with lipids, and those are fats, and membranes of different organelles that will then lead to this cellular dysfunction, including mitochondrial effects and inflammation. That's what we're really trying to target in Parkinson's disease.

There's very strong genetic and pathological evidence linking synuclein to Parkinson's disease. We know that point mutations and multiplications in the synuclein gene cause familial Parkinson's disease, and there's a dose-dependent severity here in terms of clinical severity.

There are genetic modifiers, such as GBA and LRRK2, that actually influence the biology and risk with regards to synuclein. We know it's a central pathological hallmark of Parkinson's disease, although I will mention that even beta-amyloid and tau have become really significant and important, too, in terms of these protein aggregates that are co-occurring in the brain.

Dr. Laurie Sanders 00:28:32
And we know that synuclein pathology is correlated with cognition and linked to disease progression. All of this taken together has really formed the foundation, or rationale, for many different approaches for targeting synuclein and the development of some groundbreaking biomarkers around synuclein pathology that we can then use in clinical trials and clinical practice.

Okay. So there are many key questions and challenges that are still ongoing in the synuclein field. You perhaps might have seen that there's been this proposed biological definition of neuronal alpha-synuclein disease as defined by the seed amplification assay. I think there's a lot of controversy around this and what this means clinically, and around using a biological definition instead of a clinical one.

We'll see if some of the questions come up around this, and I'm happy to talk about that. It wouldn't have been possible to have that biological definition without the seed amplification assay. I will say one of the barriers and challenges there of the seed amplification assay is that right now, it works really well in the CSF, or from a lumbar puncture, but obviously that's very invasive.

Currently, there's no blood iteration of the seed amplification assay, but there are a lot of people working on that to be able to get it to work in the blood. I think we're going to see some really exciting developments in the next couple of years about that.

One of the most exciting things that's come out in the last couple of years is that, in addition to these oligomers and fibrils that I talked about, these different higher-order conformations of synuclein, there are so many different conformations and forms of synuclein, close to a hundred, and there's probably even more. I think the real question is which are the most toxic, and that's important because which are the best to target?

And so that's where I really see part of this synuclein field putting their efforts towards better understanding that.

So, I kind of focused on the brain, talking about synuclein, but now we know that synuclein is not just found in the brain. Synuclein is also found in our olfactory system as well as the gut. There are these really interesting hypotheses around sort of gut-first and then into brain, in terms of development of Parkinson's disease, or brain-first and sort of going the other way to the gut. This is exploding research in the field, which is really exciting.

I'm really pleased to share with you that our website just went live for our Gut-Brain Parkinson's Disease Consortium. We think it's really important to be able to define those GI symptoms in a snapshot and then longitudinally over time. You can find out more information about our human study so that we can really begin to answer some of those questions of the peripheral versus more central nervous system, or brain, origin.

The heterogeneity, in that not all Parkinson's disease, I think, is equally driven by alpha-synuclein biology. There's emerging evidence for tau, especially in LRRK2 Parkinson's disease. How do we think about targeting that? I think this is one example of working on a drug, buntanetap, which targets synuclein, tau, amyloid and many of these other types of co-pathologies.

And so, I think this is a really interesting perspective in thinking about how we can tackle the disease from multiple angles.

Again, toward that optimism, there are many therapeutics that are targeting right now, or in development for, synuclein in terms of reducing production, reducing aggregation, clearing these aggregates from an immunotherapy perspective, blocking the propagation, enhancing the clearance, boosting glucocerebrosidase activity, which is that GBA protein and enzyme that are intimately involved with synuclein clearance, and proteostasis enhancers.

Those are just the general categories of all the exciting developments that are happening just in focusing on synuclein and trying to be able to reduce that pathology burden. So, so much to be excited about.

Okay.

Dr. Laurie Sanders 00:34:14
And I could talk all day about synuclein, but we're going to pivot to mitochondria, again, another love of mine. Certainly, that's close to my heart in terms of thinking about mitochondrial function. So, what are mitochondria? I think they're probably well known for being the powerhouses of the cell and producing energy for important brain function. However, what I'm hoping that you all walk away with today is that the mitochondria are so much more than just producing energy for the brain.

They are these double membrane-bound organelles that are found in almost every cell type in your body. They contain their own DNA, so as opposed to the nucleus, where it has chromosomes, the mitochondria actually have their own set of DNA called mitochondrial DNA that encodes many proteins and RNA and all these things, just like the nucleus. And there's a lot of cross-talk between mitochondria and nucleus to maintain homeostatic function for the cell.

So, in addition to obviously the respiration or energy functions of mitochondria, they do so much more. This is just a pictorial example that there's protein import and processing that happens at that double membrane of the mitochondria. So, sort of shuttling these important proteins. Sometimes, actually, synuclein and tau get inside aberrantly into the mitochondria.

There's the biosynthesis of really important iron-sulfur clusters and other cofactors that are used not just for function within the mitochondria but also outside of the cell and are critical. The mitochondria not only have the cross-talk with the nucleus that I spoke about, but have all these other organelle contacts, such as the ER and others, that really help with maintaining that function and homeostatic function. As opposed to the nucleus, mitochondria can be selectively targeted and purged from the cell when they become dysfunctional or sort of wear out during a normal aging process, during a process called mitophagy.

We think that this is actually dysfunctional in Parkinson's disease. And so it's this accumulation of dysfunctional mitochondria that build up. But beyond that, there's sort of signaling and all these redox processes and the metabolism of amino acids, lipids and nucleotides, and the transport of these metabolites, in addition to energy metabolism. Think of the mitochondria managing all these processes and really important functions of the cell that, when things start to go wrong, actually will send a signal to the rest of the cell, or neuron in this case, for cell death.

Mitochondria are key in terms of that signaling of whether or not that neuron will survive. There are many consequences to mitochondrial dysfunction, in addition to obviously this energetic failure, but an increase of this oxidative stress or reactive oxygen species, impaired mitophagy as a consequence or cause of dysfunctional mitochondria.

Where we focus a lot of our efforts is in terms of damage to that DNA, that can either lead to mitochondrial DNA damage or mutations that we know definitely happen in Parkinson's disease and ultimately can drive cell death. We know that neurons are especially vulnerable to this mitochondrial dysfunction, and so this is a really exciting area of research, not just in my lab but many, many others around the world.

There is a strong rationale, from many, many decades of research that's been done, both in the preclinical space as well as in humans living with Parkinson's disease, that really substantiates this idea that mitochondrial dysfunction is playing a key role in the pathogenesis of Parkinson's disease.

We know from toxins such as paraquat, rotenone and MPTP that, when administered to animals, they reproduce, not perfectly, but reproduce many of the features that we know happen in human Parkinson's disease. We know that this is due to complex I deficits. So it's that first initial part of the respiratory chain that helps us produce our energy in the mitochondria, that there's this specific complex I defect that we can reproduce with many of these toxins. But also, we know from human Parkinson's disease and tissues that there's this complex I defect not just in the brain, but also systemically, in muscle and blood and other tissues.

We know that mutations of select genes cause Parkinson's disease. Some examples of that are DJ-1, PINK1, Parkin and LRRK2. More recently, we know that even POLG, that mutations in POLG will lead to nigrostriatal degeneration in carriers of mutations with POLG and sort of look parkinsonian.

Many, many data that I can't even describe here show that we certainly know that mitochondrial pathology has been observed both in the brain and the periphery in many of these monogenic forms of Parkinson's disease, as well as idiopathic forms of Parkinson's disease. Why this really matters is that our brain cells really need this high energy. Our brain cells are one of the highest consumers of this high-energy demand, and as that dysfunction starts to occur, this contributes to risk and maybe even disease progression for Parkinson's disease.

Dr. Laurie Sanders 00:40:52
So, I just want to briefly comment that while we've certainly known that mitochondrial dysfunction is such a key part of the pathogenic cascade in Parkinson's disease, what's been a challenge in the field is the development of a biomarker to be able to use this for clinical trials and clinical practice. We've spent a lot of efforts towards developing a biomarker around mitochondrial dysfunction.

There are many different types of biomarkers, and the one that we've really concentrated on is one to be able to patient stratify. What that means is to be able to identify people with Parkinson's disease with that particular cellular dysfunction so that we can then match that person with Parkinson's disease to the right therapeutic with that biomarker.

And so, of course, I'm always happy to talk about this in great detail, but we've been able to really develop our mitochondrial DNA damage as a blood-based biomarker of early Parkinson's disease. This was enabled through technology called MitoDNADX. This is published, and I'm happy to geek out in the technology here. It's in the question-and-answer session, or later you can email me. I'm always happy to geek out about this.

We're essentially able to measure whether mitochondrial DNA damage is out of homeostasis. What that means is if there's an increased DNA damage or a decrease that might be due to DNA repair or mitophagy or others. Why we've been able to move this along the translational pathway is that this is a PCR-based assay. We can do this in a high-throughput manner, and we can go from sample to answer in a day from a blood sample. And so we're really excited about moving this.

This has been published. You can find some commentaries about our work, about our blood test. I'm really excited to share that we are moving this along so that we can be able to use this in clinical trials and hopefully, ultimately, into clinical practice, so that we really can start to use this as a way towards precision medicine.

I think I didn't mention this in the beginning part of how we're evolving and how we're thinking about Parkinson's disease, but part of that is really this precision, or what you might know as this personalized medicine, approach. This is really coming, I think, to Parkinson's disease clinical trials. Our assay, or thinking about mitochondrial dysfunction, is just one example of that. But this can be applied to any pathways of lysosomes, immune systems, synuclein, right?

We're really being able, at a molecular level, to identify that underlying pathology so that we can identify, or as they say, patient stratify, and find that person with Parkinson's disease with, let's say, that mitochondrial dysfunction so that we can then best match them to a mitochondrial therapeutic, for example, and, equally as important, stratify out those that would not benefit from these drugs. I can't tell you how exciting it is that we are really moving in this direction in Parkinson's disease.

This sort of precision neurology approach has been taken in cancer, right, for decades and decades, but it's really coming to neurology and Parkinson's disease in terms of the biomarkers as well as therapeutics. It's really evolving our way in which we can design clinical trials and hopefully be able to get approvals and an FDA win.

So, I think one of the really open questions in the mitochondrial function space is: is mitochondrial dysfunction really the driver? Is it the cause of many of those downstream cellular dysfunctions? Or is it secondary? Is it a consequence from synuclein and immune disturbances? And so, really distinguishing that causality versus consequence.

That might be really different for different people, which makes it a challenge, but certainly one that I think we really need to tackle. An interesting development in general in the mitochondrial field is this idea of mitochondrial donations, where you can take a healthy mitochondria and actually donate and transfer them from cell to cell. I really have my eye on those developments and, if they should prove successful, how we might be able to apply those in Parkinson's disease.

But there's a challenge in these beautiful neurons that we have in our brain, especially these dopamine neurons. As I said, those are really long axons, right? How do we deliver some of these therapeutics to certainly mitochondria in the cell body versus these long axons or the dendrites that are really far from the cell body? Because the mitochondria, in terms of their dysfunction, differ whether they're really far away from that cell body or not.

Now, hopefully, what you're taking away is that mitochondria are much, much more than these sources of energetic function. How do we modulate mitochondrial function safely, where we can rescue maybe some of those defects without harming some of the other functions of mitochondria? As I mentioned, that patient-level heterogeneity, you're going to see that in all of these key challenges. Not everybody is manifesting the same pathology, even though the clinical manifestations may be the same.

How do we account for that? I think part of that is through biomarkers. Certainly, I'm excited about all of the developments in terms of mitochondrial therapies for Parkinson's disease, and these include mitophagy enhancers, metabolic enhancers, some of these through the NAD pathways that some of you may be familiar about, and gene therapy approaches to rescue mitochondrial function.

Dr. Laurie Sanders 00:48:11
Okay, so inflammation. So, now we've walked through the mitochondria and synuclein, but equally as important is the inflammatory cascades. Just like you might think about inflammation throughout the rest of your body, it's your body's response to harm. This is where your brain cells, such as microglia or astrocytes, become active, and then they release these chemicals in trying to protect or sort of clean up that damage that might be occurring in your brain.

For the most part, the response is short and very well controlled, and it's helpful. However, when the inflammation response becomes chronic or too strong, this can actually damage a healthy brain and make some problems worse. We think that some of that might be happening in Parkinson's disease. One of the brain cells, microglia, you can view as sort of the cleanup crew. They sense the trouble, and most of the time they're helping with that cleanup.

But when they become really activated, which, again, we have evidence in Parkinson's disease that they do this, it starts to harm those connections and signaling. Now, what's interesting is that synuclein aggregates, as well as dying neurons, can actually trigger microglia to switch on. This releases those cytokines and inflammatory and other toxic substances, which will then increase further that inflammation, right?

So, really thinking about that, there's this vicious cycle between the inflammation trying to help, but then it gets activated and it can't turn off. During normal healthy aging, what happens is that there's this decline in immune cell function, with also this immunosenescence and actually loss of some of these functions of the immune system. We think that's enhanced in Parkinson's disease.

So there's that normal aging that's happening, in addition to certain gene risk factors and environmental exposures, that are all conferring this risk and maybe contributing to that vicious cycle with our immune system, but also synuclein and mitochondrial dysfunction.

As part of this, our blood-brain barrier can become leaky. What that means is that the immune system that normally is in the periphery can now get into our brain. This is really important because now there's this two-way highway that doesn't exist physiologically and is contributing to that immune activation. This is really significant, as now we know that immune activation is not just happening in the brain, but it's also happening in our gut. That also may be happening through our vagus nerve, sort of in two-way traffic.

Why this really matters is that now this is connecting multiple disease pathways. As I said, this is really integrating now. None of these pathways are happening sort of in silos or in isolation. This actually may accelerate disease progression, but also gives us opportunity, with our better understanding of this, as a potential for new treatment targets that we can actually target all of these simultaneously.

So there's a lot of research momentum certainly in inflammation, with many strategies to reduce those immune responses, to dampen them, so that hopefully we can develop some of these neuroprotective strategies and really also take advantage of that better understanding of that role of the gut-brain connection. This has been a development of drug development focus from many different angles.

Some of the key research questions that stand out, at least to me, are: Is inflammation friend, foe or both? I think the answer is probably all of them, but it's really going to matter in terms of stage of disease. It's going to be really context- and cell-dependent, really understanding when we want to harness the immune system and what its job is normally doing, but then also to be able to dampen it when we need to, if it might be causing that activation that we want to turn off.

What I find particularly exciting that's happening in the last few years in the inflammation space in Parkinson's disease is that we can actually measure some of that immune activation in the brain with PET imaging, what's called TSPO. In addition to some of the other very exciting imaging in the brain that we can use, we can now do this and understand better who has this activation and inflammation and who may not.

Where it starts to really tie together is this idea of immune exhaustion and how this may be caused by metabolism and mitochondrial dysfunction. Hopefully, what you're gathering by this point is how these are all interconnected. Synuclein can be driving also that immune exhaustion and mitochondrial dysfunction, and vice versa, and how these are all intertwined together.

Dr. Laurie Sanders 00:54:13
Again, that heterogeneity, where we're thinking about these immune signatures that really vary across people with Parkinson's disease and different stages, gives us a real opportunity to target in terms of dampening or supporting the immune responses.

We are not at a loss. There's a plethora of different therapies that are in the pipeline targeting inflammation. Obviously, that anti-inflammatory perspective, but also specifically microglia and innate immune modulators, the adaptive immune strategies specifically, and how that might be different from the innate strategies.

What if we just target the peripheral immune systems and take advantage of what we now know in terms of dysbiosis of the microbiome, also gut-targeted therapies, and how that might actually help in the brain without even directly targeting the brain? Even vagus nerve stimulation and how that might improve brain function.

So, bringing it all together, with all these exciting developments that are happening across synuclein, mitochondrial function and the immune system, there's so much cross-talk between synuclein, mitochondria and the immune system. It's not just in the brain. This is a whole-system and multi-system disorder that we now have such a better understanding of.

There's this cross-talk between what may be happening at the immune cell system as a result of that mitochondrial dysfunction and synuclein triggers, or vice versa. You'll see that these arrows are going in both directions, right? Really understanding what might be initially the trigger versus what might be perpetuating that vicious cycle between all of these different pathways.

This is not just happening in neurons. It's happening in the immune system, in our brain and peripherally, as well as in our guts and other tissue types throughout our bodies, and really understanding how that is now contributing to not just the motor dysfunction but many of the non-motor features of Parkinson's disease, which are so important.

So, we're not really thinking about these laterally anymore, right? It's more of how synuclein, inflammation and mitochondrial function are all intertwined, and that these are interconnected and no longer thinking of these as isolated issues.

Dr. Laurie Sanders 00:57:09
So, I will continue to maintain why I am so hopeful and that we're really moving beyond these dopamine-only therapies. This has only been possible with a really stronger understanding of disease biology. This is due to earlier detection possibilities with a seeding assay, better tools and technology for imaging, and all the other things that I mentioned, where we're able to now really be able to target disease progression.

I feel really optimistic about these disease-modifying therapies that are in the pipeline and the many, many growing pipelines for the clinical trials. We can move not just away from dopamine-only therapies and really disease-modifying, but toward that personalized precision medicine approach to be able to identify the right target and therapy for the right patient in Parkinson's disease.

So, what this means for all of you that are here today is that, while symptom-only therapy is key and is still in development for better treatments for symptoms, we're really light years going against development for slowing progression. It's this shift towards disease-modifying therapies in our clinical trial pipeline. The research is ongoing, evolving and so fast.

It's only because of the participation, as well, from all of you in the research that's helping us move at such a fast pace. It's important because then we can all make informed decisions about our health, and that really empowers us moving forward. So, what's ahead?

Certainly, biomarker development in Alzheimer's disease and Parkinson's disease is allowing for better and earlier diagnosis, which is really feeding this ongoing clinical trial space. But also, an area that we're starting to get into as well is really thinking about these combination therapies. We know now all of these pathways are intertwined and feeding each other. Can we use combination therapies to really tackle these multiple pathways so that we can have a better outcome for these disease-modifying therapies? I'm really excited about the development of those.

So, the key takeaways for today are that understanding Parkinson's is evolving rapidly, and I'm sure it's going to be very different even 10 years from now. There are three major drivers: alpha-synuclein pathology, mitochondrial dysfunction and inflammatory cascades. We're really moving towards not just treating the disease, but really being able to tackle the underlying pathology to develop these disease-modifying therapies.

Thank you so much for listening and your attention. I'm excited to engage with all of you during this question-and-answer period of time. I thought it was also important to show some of the faces that are doing the research. Such an amazing crew of dedicated researchers are really dedicated and committed towards making a difference for people with Parkinson's disease.

I want to thank them and certainly all of our funders and collaborators that really help us move and make this research move forward. So, I'll stop there. Thank you.

Dr. James Beck 01:01:09
Thank you very much, Dr. Sanders, for that excellent presentation. Before we jump into questions, I'll just remind our audience that our team is organizing questions as they come in, but understand that we can really only address, because we've got an overwhelming number of questions, the ones that are really specific to today's subject. Those will be addressed first. If we have time, we can get to some of the others, but know that we look to answer just about every question that comes in, either here or through my colleagues who are eminently capable on the Helpline as part of that process.

That was a really interesting presentation. I think it's really great to hear as we begin to think about the trials that are coming to the fore, what three areas are. I like the idea of your focus on biomarkers and gut-brain, and we've got questions ranging the whole course of what you covered. It's amazing, these questions that come in as part of the process.

I think one of the interesting questions I'd like to start off with is from one of our listeners, Ronny, who just talks about how no two people with Parkinson's have the same symptoms. How does that impact your research? You've mentioned time and time again the heterogeneity of this disease.

How do you account for that when you begin to take a look at this? I think also, again, you kind of touched on it maybe a little bit with your biomarker approach, maybe mitochondria. Do you think there might be a biological basis to this heterogeneity?

Dr. Laurie Sanders 01:02:48
Yeah, thank you. Thank you for that question, Ronny. I will say that this idea of heterogeneity, and that a person with Parkinson's disease, their journey, looks so different from one another, right? That experience is just so different. That really struck me as a postdoc, actually, where I thought it was really important to meet and talk with people with Parkinson's disease to really understand from their perspective what's happening.

What really struck me, and I think that's really changed the course of how I studied this in the lab, is that I think you can't model a lot of that. This is a real heterogeneity that people are experiencing from a biological perspective as well as a symptom perspective.

One approach that we've taken is that we start with the patient first and then we go back to the lab to model it. We do human studies, and sometimes that's taking patient material from a wide range of people to best understand what might be happening across that patient experience, but we can see that molecularly, and then take that understanding and model that particular aspect in the lab, because our models are just not doing that justice.

Then, from what we get from those modeling in cells or neurons or animals, we go back and see if it actually works in our human cells. To get at your question, I think that's been a lot of the barrier to the progress in being able to really nail down and understand that heterogeneity that we know is happening in human Parkinson's disease.

Dr. James Beck 01:05:06
Yeah. So, that's a really interesting answer. It just makes me think, one of our listeners also had the foresight to ask this question as well, Charles. I appreciate the effort to try to model what you're seeing in people in animal models. As a researcher, maybe this is an unfair question to ask of you because I kind of know the bind you're in, but do you think our clinical trials have failed to date because of our lack of ability to model adequately?

Or is it something else that you're working on too, which is trying to find a way with which to measure PD, the biomarker approach? What do you think is maybe behind some of the struggles the community has faced to really put a stop to this disease?

Dr. Laurie Sanders 01:05:58
Yeah, no, that's such an insightful question, and one that we think a lot about. Unfortunately, right, we all want wins, being able to get these approvals. Why are these clinical trials failing? Why are they not reaching endpoints?

I think part of it is our inability to model the complexity of the pathways and cellular dysfunction that we know is happening in human Parkinson's disease. Our models have just been inadequate in that way. So, that's one piece of it. That's why I think of it as, we distill a little bit. We know we're just studying that one angle.

But also, I think, as sort of alluding to, now that we have a better understanding of the complexity and how these pathways are interrelated, we've been doing one at a time.

Dr. James Beck 01:07:00
Yeah.

Dr. Laurie Sanders 01:07:01
What if we took more of a multi-pronged approach and targeted multiple of these pathways at once? I think that's also part of why we've not seen successes, and that we really need to tackle the immune system, cytokine, mitochondrial systems and others in order to really move the needle. I think there are a lot of reasons, but those are two really key reasons as to why I think those have been such barriers in clinical trials.

Dr. James Beck 01:07:34
Yeah. Okay, yeah, I very much appreciate that answer because it's one we clearly don't know the answer to, right? Because if we did, then we could have solved for it and then we'd be that much closer to a cure for Parkinson's.

A lot of questions come in about aggregation of alpha-synuclein. It's interesting how you also started at the very beginning, and I do think it's controversial, this idea of neuronal synuclein disorder. Not in the sense that it's bad to try to define Parkinson's disease as a biological disease. Right now, it's a clinical presentation.

I think everyone in the audience knows firsthand the implications of that, which means it's hard to diagnose, your diagnosis is uncertain, and it can be a long time to do it. If there was a biological basis of the disease, like with diabetes, oh, your A1C level is above the norm, you need to really target your insulin level to this, it would be entirely different for us as a community to be able to tackle this disease.

So, getting to the point about aggregation with alpha-synuclein, what are your thoughts then? Are we looking at the bystander of what's contributing to Parkinson's? Because you've talked about mitochondria, you've talked about inflammation, and these things could lead to the proteostatic dyshomeostasis where you have problems with proteins inside cells. Sorry, I'll use the right words for my audience.

Is that leading to this? And then we now see this cyclic effect where, in essence, you've got something like a stain in the normal. Something pushes it out of whack, and now it just becomes a spiraling cycle. So, lots for you to go on, Dr. Sanders. Maybe just narrow it down. Let's talk a little bit about aggregation and alpha-synuclein maybe as a start.

Dr. Laurie Sanders 01:09:24
I certainly acknowledge that that is a very tough question, right? Very controversial. So, I will try to answer that.

I think it's useful to have definitions that we can then use and build upon, much like the Alzheimer's disease field, in terms of these biomarkers and staging and biological definition. I will say where I struggle is that there are, for example, in the LRRK2 field, we know that patients with the LRRK2 mutation don't have synuclein aggregation, but they have Parkinson's disease. And they're negative, right, for this.

In one answer to your question, I will say that we know you can get to Parkinson's disease without maybe that trigger of the synuclein aggregation. Now, there might be Lewy neurite pathology. There have been a couple papers to suggest that maybe you don't have the Lewy bodies, but maybe you have these Lewy neurites, right? That's also controversial. So, there might be, but it's not this full-blown Lewy body disease that we know that defines it. I think there are multiple ways in which you could get there, and it's not always through synuclein.

That being said, we know that synuclein pathology happens really early. It can be in the gut decades before somebody might manifest clinical symptoms. Certainly, over time, that's going to drive many of the clinical symptoms that we might see and certainly can drive disease, right? I'm not sure that that's an answer, because there are just these examples of different ways. I think that's understanding that maybe you get to the same point eventually. It may not matter from that perspective of symptoms, but it's going to matter for disease-modifying therapies, what those initial triggers are.

I think that's where we need to define it, and it's really critical for some people that synuclein pathology is driving the mitochondrial dysfunction, is driving the immune system dysfunction, and that's when we need to intervene and how. But it's not going to be the same for each patient.

Dr. James Beck 01:11:52
Yeah, for sure. Pesticides are a topic du jour. Lots of questions come in about that. I think about that as we run a large genetic study with PD GENEration, people come back negative, yet they have a family history of Parkinson's. I think one of the biggest things that we haven't really talked about and are beginning to explore as an organization at the Foundation is: what is the environmental influence for Parkinson's disease?

In your work, what role, I mean your thoughts just broadly about what pesticides might be doing here, what kind of toxins might be playing a role within Parkinson's?

Dr. Laurie Sanders 01:12:32
Yeah, absolutely. Of course, I will say, from doing my postdoc at Tim Greenamyre's lab, I certainly have thought about, since his rotenone discovery and with Caroline Tanner showing risk, obviously, for developing Parkinson's disease. At least the way I think about it is that what we've been able to identify in the field is increasing one's risk for developing Parkinson's disease. They have a common denominator in the way that they're working in the cell, and that's been through mitochondria.

I think, at least where I would see putting the efforts, is understanding that pathway dysfunction and then how that's generating disease, as opposed to the specific exposures. That's at least where I would put my efforts because there are a lot of even just plant derivatives that mimic these complex I disruptors. I think that's what it's really telling us that they're working through.

Maybe there are some other types of exposures that might be working through different mechanisms that would be of interest because then we know at least where it is that we could start to block or be able to understand that dysfunction, as opposed to the specific exposure per se, if that makes sense.

Dr. James Beck 01:14:00
It does, and I think what you're alluding to is really the pathway, and we have different drivers of perhaps the same pathway. Here you're talking about mitochondrial dysfunction. If one can figure out how to solve that problem, you might be able to then prevent PD from toxin exposure, because if it's driving that same pathway, then a medication in theory could be of benefit for everyone, whether it's a genetically driven form or not, which I think is really exciting.

This is where I think fields like your work are helping to advance, to find these commonalities from different aspects that could be driving the disease.

I know we're at time right now. So, Dr. Sanders, I want to thank you very much again for your time today and really presenting what I thought was a really interesting topic. It led to a lot of questions. I apologize again that we haven't been able to get to them all as part of that process, but I think this is something that will be food for thought for us as we go on. I know we have a discussion around pesticides later this year in November, and coming up in May, we have some really interesting things about AI involved in Parkinson's. I love to think about how that can happen today.

I want to thank everyone for their time, and just a reminder to continue on with our program and to follow on with what we have coming up. We've got one more episode in May. As I said before, we take a pause during the summer and continue again in the fall. If you have questions, sorry, I'm a little out of order with our slides. If you have questions, feel free to reach our Helpline, 1-800-4PD-INFO.

My colleagues there are phenomenal and can really answer a wide variety of questions, either from today or just around Parkinson's disease in general. So, I really encourage you to do that.

I would like to just at the end thank again Genentech for their support for this particular expert briefing. It was fantastic. I'd also like to thank the Light of Day Foundation for supporting the PD Health @ Home series. They are a great supporter of education and outreach for people with Parkinson's disease. So thank you very much for their generosity for doing this.

As we end the webinar, this is a Zoom world, and so what will happen is the screen will go black, but what should happen is a questionnaire pops up in your browser. Please feel free to fill that out. We use that feedback. It's really important to us to understand how we can always improve our presentations, share that with our speaker and be able to ensure that we're there and meeting your needs as a Parkinson's community. So, until we speak again in May, take care.