Dr. James Beck 00:00:00
Hello everyone, and welcome to our Expert Briefings. I'm Dr. James Beck, Chief Scientific Officer of the Parkinson's Foundation. Our expert briefing today will be centered around Parkinson's disease and how the gut is connected to the brain. While stomach or intestinal distress can lead to anxiety or depression, gut-brain connections go much further. New research strongly suggests a link between the gastrointestinal system and Parkinson's disease. Today, we will learn a lot more about the gut's potential impact on symptoms and progression.

Before we begin with the formal briefing, let me share a little bit about the Parkinson's Foundation. The Parkinson's Foundation is a nonprofit focused on bettering the lives of those living with Parkinson's through improving care and advancing research.

Importantly, everything we do is done in close concert with our community to ensure that our actions are aligned with the needs and priorities of those living with Parkinson's disease. We're focused on improving care for those living with PD, advancing research toward a cure, and empowering our global community. Today's briefing is an example of just how we reach our goals.

Before we do that, I want to highlight what's going to happen next Wednesday, on October 18. We're hosting a special program designed for people living with Parkinson's who have not shared their diagnosis publicly. As we all know, this is an issue, and we'll highlight the challenges many people face when deciding how and when to share their diagnosis. You can learn more about this webinar at our website, www.Parkinson.org/PDHealth.

As our next step, what I would like to do is get a chance to know who's on the call today. We've got a lot of people today, and there's a poll that just appeared. Go ahead and select whether you're a person with Parkinson's, a scientist or researcher, someone else who's joined, or you have a friend or family member with Parkinson's disease. This is really helpful for us to get a sense of who our audience is today and also for our speaker, so they can have a sense of who's on the call and make adjustments to their presentation. Let's give a few more seconds, and then we'll see what the poll comes back as. Great.

Not surprisingly, a lot of people here have Parkinson's, and a lot are partners of those living with PD. A fair number of healthcare professionals too, which is great, and scientists and researchers. I think we're going to have a great talk today that will cover a lot of ground and have something for everybody.

For your convenience, I want to highlight that we are recording this episode. If you've missed this or you need to step away, or you have friends and family members you think could really benefit from watching this episode of Expert Briefings, know that it will be made available at our website, and we'll also be emailing a link of the recording and other resources related to today's topic to all those who registered for today's briefing.

Dr. James Beck 00:02:52
Now I'd like to go on and introduce our expert presenter, Dr. Carley Rusch. Dr. Rusch recently became a medical science liaison in medical affairs research at Abbott Nutrition and specialized in adult therapeutics. Before that transition, she was an instructor in nutritional sciences and a neurology dietitian at UF, University of Florida Health, Norman Fixel Institute for Neurologic Diseases, for many years. Dr. Rusch completed her master's degree in food science and human nutrition and completed her dietetic internship at the University of Florida. During her training, she was involved in research studies on a number of topics, including gastrointestinal dysfunction, inflammation, pre- and probiotics, and the gut microbiome.

Dr. Rusch earned her PhD in Nutritional Sciences, also at the University of Florida, where her research investigated the effect of the Mediterranean diet on improving constipation and intestinal inflammation in Parkinson's disease. Dr. Rusch's work appears in numerous peer-reviewed journals, and she has been invited to present her research on nutrition-related topics at both state and national conferences. Her clinical experience spans a variety of disease states, such as cancer, gastrointestinal and neurologic disorders, malnutrition, and critical care. Dr. Rusch, it's a real pleasure to have you, and thank you for sharing your time and knowledge with us today.

Dr. Carley Rusch 00:03:59
Perfect. Thank you, Doctor.

I am really honored to be invited as a guest speaker for the Parkinson's Foundation for these Expert Briefings. I've had a long relationship now, I think, with the Parkinson's Foundation doing some more local work and speaking, so again, I'm really honored to be invited to chat with everyone here today. Just taking a look at the number of people that we have so far, we're up to 850 people and growing. This is amazing. Welcome.

Before beginning, I just have a couple disclosures that I do want to share. As you heard, I am now an employee within Medical Affairs and Research at Abbott Nutrition. While the program today is not intended for any individual medical advice or continuing education for healthcare professionals, I hope that you will find that it is an evidence-based review of the literature on this topic.

Here are my objectives for today. We're going to talk a little bit more about how the gut microbiome is altered in someone with Parkinson's disease and discuss the role of the gut-brain axis and how diet may impact Parkinson's symptoms and gut health too.

Before beginning, I just wanted to share very briefly with you a little bit of my background in Parkinson's. It was approximately almost five years ago now that I was invited to join the Norman Fixel Institute for Neurological Diseases at the University of Florida. I've done a number of work with them, partnering with their Parkinson's Foundation Symposium that was locally held in Gainesville, Florida. I saw numerous patients in our outpatient clinic that you see there with my photo in the middle. Maybe some of my former patients and caregivers are here on the line, and maybe some clinicians that I've worked with in the past too.

Then, of course, like I mentioned earlier, I have given multiple talks for the Parkinson's Foundation on diet and Parkinson's disease.

Dr. Carley Rusch 00:06:02
Let's talk a little bit about the gut microbiome and the gut-brain axis. I will preface my talk today: I know there are a lot of people with Parkinson's and care partners on the line, and we also have a really great number of healthcare professionals and researchers too. What I do want to say is that the content of the program today is probably going to be a little more on the technical side, but with my experience with people with Parkinson's and their care partners, you guys are all very smart individuals and a very smart group of people. I hope my job today really takes a complex topic with a lot of nuance and simplifies it down together.

All right. Now, before diving into the meat and potatoes of my talk today, I want to start off by sharing this image. This is a cross-sectional image of the colon in a humanized mouse model. The blue fluorescent color is a stain that shows both food and tissue. The yellow represents the mucus in the colon, and purple is going to be the bacteria. This paper was published in 2017 in the Proceedings of the National Academy of Sciences, and it was an important paper because it captured the structure and relationships between bacterial microbes and their host.

These relationships are significant because we know our resident bacteria are more abundant than even our human cells too. The genetic capability of our resident bacteria is enormous. Even though I'm showing you an image highlighting bacterial microbiota, we're beginning to learn even more about other members that reside in the microbial community, such as fungi, which we call the mycobiome, and viruses too.

What I really enjoy about this image is, when you magnify it a little bit further, you can really appreciate the ability of our bacteria to break down food from the diet that I have on the photo here on the right.

What is the microbiome? I always love to start this conversation off by just giving some definitions because we use a lot of these terms interchangeably, so I think it's really important to set some groundwork too. The microbiome, when we hear that, is referring to the totality of microorganisms and their collective genetic material present in the intestinal tract. We know that the microbiome can really span from the mouth all the way down to the colon. The gut microbiota are microorganisms of the intestinal tract, and these could be bacteria, viruses, fungi, and even protists too.

Dr. Carley Rusch 00:08:50
When we think about the gut microbiome, we often think about the colon, right? That's because we have the greatest density and diversity of bacteria in particular located in the colon. For the purposes of today's presentation, I'm going to primarily focus on the microbiota composition and metabolism that's located within the colon, but certainly, especially within Parkinson's disease, there are some papers out there that do refer to the microbiome in the oral cavity too.

What is a healthy microbiome? We might want to first consider that too when we're talking about this type of topic. It's really something that researchers have debated and really struggled to specifically define, even someone like myself. However, it's generally accepted that a healthy microbiome is a diverse one. We see lower diversity associated with different disease populations. We can measure diversity within individuals called alpha diversity by measuring the number of species present, called richness.

This figure that I have here on the left shows richness of samples from people with IBD, including ulcerative colitis and Crohn's disease, compared to healthy controls. You can see that blue line, that as we sequence more bacteria, people without irritable bowel disease have a higher number of species present than those with ulcerative colitis or Crohn's. When we quantify this, you can see that there is a trend toward lower diversity in people with Crohn's compared to healthy controls, which I have in that little shadow box here at the top left. We can also show diversity in a 3D space too and compare diversity between different populations. This is known as beta diversity.

Each dot that you see here on the right is an individual, and the closer those dots converge, the more similar they are to each other. You can see in this figure how similarities between healthy controls without irritable bowel disease group together in that red shaded area, and how diversity changes or becomes less similar from one another with active or inactive irritable bowel disease. Diversity isn't only affected by specific disease states like Parkinson's disease; it's also influenced by other factors like diet and lifestyle too.

Dr. Carley Rusch 00:11:18
When it comes to our gut microbiota, we know that there are several different inputs or factors that shape our microbiome. These factors are stress, whether intentional like physical activity or unintentional such as metabolic or psychological stressors. Pharmaceuticals such as antibiotics, we classically know, will shape or even remove some of our microbes. We understand that diet is important, which we will discuss a little bit more later. Some other additional factors to consider are geography of the host or the person and potential pollutants in the environment. I know that's still talked about very frequently within the Parkinson's community. Even other lifestyle stages can contribute to individual variability. As we age over time, our microbiome may also change too.

We know that the gut microbiota can produce signaling metabolites such as short-chain fatty acids. These short-chain fatty acids can be broken down by bacteria to produce acetate, propionate, and butyrate. We'll talk a little bit more about those short-chain fatty acids later.

These bacteria can also produce inflammatory molecules such as lipopolysaccharide, or endotoxin. They can even deconjugate some of those bile acids and influence cholesterol metabolism, and even produce other nitrogenous metabolites like TMAO, which you may hear a lot about within the cardiovascular disease realm. All of these signaling metabolites can communicate and influence not only the GI tract and immune system, but also the liver, the adipose tissue, the brain, of course, which we're going to highlight a lot today, the cardiovascular system, lungs, and even the skeletal muscle too, we're learning more about.

There is so much interest that has developed in specifically human nutrition and the microbiome. You can see on this graph here, I have a number of published studies that's growing exponentially each year.

Documented studies have really been described as early as actually the 1400s on the benefits of bacteria in yogurt, for example, for treating diarrhea. But we had this inflection point that occurred in the early 2000s with the development of high-throughput sequencing, in which we could take someone's stool sample and identify thousands of bacterial DNA present. What was exciting for me personally is that I actually began my research career in the microbiome during this bloom of current studies that were coming out. It's really exciting to see how far we've come in even the last decade too.

Dr. Carley Rusch 00:14:00
What I thought was really fascinating, and what I can kind of compare on this graph, is when we actually look at the number of published studies on Parkinson's and the microbiome, we're truly only in the infancy of our understanding. But what have we learned, right?

How this came about was we started to notice that there was pathology occurring along the GI tract in people with Parkinson's disease. We know people with Parkinson's have a progressive loss of dopamine neurons in that substantia nigra of the midbrain. It's estimated that between 60 to 70% of those neurons are lost when those motor symptoms appear. That's what they refer to as that motor stage.

The pathology that's found in the brain is an accumulation of Lewy bodies, so an aggregated alpha-synuclein, that are found in the neurons of people with Parkinson's. Now, there's a lot of debate when it comes to proteins in the neuroscience community like alpha-synuclein, but it has been postulated that this accumulation of alpha-synuclein may trigger loss of those dopaminergic neurons. We can also find these proteins in other neurodegenerative diseases, so they're not very specific.

What has got us thinking more about the gut as it relates to Parkinson's is that we have actually been able to find alpha-synuclein pathology all along the GI tract of someone with Parkinson's, whether that's the submandibular gland, the oropharyngeal region, the stomach even, the appendix, and of course, the colon too.

When we think about those non-motor symptoms of Parkinson's disease, I know probably one of the most common ones that I'm sure plenty of people with Parkinson's and those care partners who are here on the line experience daily is some type of gastrointestinal dysfunction. That's because it is fairly common in someone with Parkinson's. Whether that be dysphagia, it's estimated that up to 77% of people with Parkinson's have some type of dysphagia. Current treatments available, of course, would be speech therapy, surgical treatments if necessary, and then potentially even some dopaminergic medications too if it's indicated.

Dr. Carley Rusch 00:16:22
Gastroparesis, or delayed stomach emptying, is another one that's highly prevalent in about 70 to 90% of people with Parkinson's. Right now, most of the treatments that we have for gastroparesis involve dietary interventions, whether that's modifying fiber sources or fat, potentially using certain types of prokinetic agents if it's indicated, and other types of therapeutics too. Then, of course, which was the focus of my research, was constipation. Constipation may affect up to 70% of people with Parkinson's. Of course, we have current therapies like increasing fiber, fluids, and physical activity, as well as other therapeutics that are over the counter or prescribed, like laxatives, stool softeners, et cetera, too.

Shifting back to the microbiome, knowing that we have this gastrointestinal dysfunction that is highly common in people with Parkinson's, and knowing that alpha-synuclein pathology also can be found along the GI tract, a lot more researchers over the years have started actually sequencing the microbiome of different people with Parkinson's. This image that I have here is actually a systematic review that really looked at the number of studies and tried to find any trends of specific bacteria that were altered in people with Parkinson's.

What I will highlight is that beneficial or commensal bacteria, such as Prevotella, Faecalibacterium, and Roseburia too, are found to be reduced in people with Parkinson's when compared to someone without Parkinson's. These bacteria are important because they produce beneficial signaling metabolites like those short-chain fatty acids I mentioned earlier. We'll talk a little bit more about that later too. They've also found Parkinson's is associated with increases in other specific bacteria, like Bifidobacterium and Lactobacillus too, and these are actually known commensal microbes. It's suspected that these might be increased due to the high prevalence of constipation.

Dr. Carley Rusch 00:18:27
We also have increases in pathobionts like Bilophila and even Akkermansia too, which is an interesting one that I won't touch on too much right now that might be beneficial or not, depending on how abundant it is in the GI tract.

We've also had some studies published over the years looking at different markers for intestinal permeability and inflammation in someone with Parkinson's. On the left here, I have an image showing you measures of fecal zonulin. What zonulin is, is essentially a protein or a marker of intestinal permeability. We know that this marker is increased in GI inflammatory conditions like celiac disease, IBD, type 1, and even other autoimmune diseases.

You can see when we compare fecal zonulin in people with Parkinson's to controls, that is significantly elevated, indicating increased intestinal permeability. On the right here, I have calprotectin. This is another marker of intestinal inflammation. It's actually very highly sensitive but low specificity as a fecal marker for other irritable bowel diseases. But again, you can see in people with Parkinson's, calprotectin, and this is just one study, but there have been a couple others that have been published too, is significantly increased compared to those without Parkinson's, signaling some type of intestinal inflammation going on.

With our knowledge of these changes in the GI tract occurring in someone with Parkinson's, it's led to this early hypothesis about 20 years ago by Braak et al. that we call the Braak hypothesis. What Braak and his colleagues postulated was that the alpha-synuclein pathology may actually spread from the GI tract via the vagus nerve to the brain. This is just an image here showing that hypothesis too. There's still a number of researchers trying to investigate this hypothesis, but this is the origination of this gut-to-brain spread in someone with Parkinson's disease.

Dr. Carley Rusch 00:20:46
We do have some recent preclinical models that do suggest this type of gut-to-brain spread via the vagus nerve. This was a study that was published in Neuron, and it was a fabulous study. It's a very technical paper, so I'll do my best to simplify it down for you all. What they did was they injected mice with these exogenous preformed fibrils, or PFF, is how I'll refer to it, and the alpha-synuclein within the GI tract of mice.

What they aimed to do was measure the amount of that pathologic or aggregated alpha-synuclein accumulation in the brain. They saw that mice with intact vagus nerves accumulated that aggregated protein, that alpha-synuclein, in the brain, specifically in that substantia nigra region, and they did develop PD-like symptoms.

However, when these mice, when they actually performed a vagotomy to cut the actual vagal nerve and they injected with those preformed fibrils, the mice did not develop that pathologic alpha-synuclein or PD-like symptoms.

To prove that you actually need to have this endogenous alpha-synuclein to develop these PD-like symptoms, they actually did perform the same experiment in mice that didn't have a gene, which is the SNCA gene, to code for that endogenous alpha-synuclein. Ultimately, this study demonstrated that you do need aggregated Lewy bodies or that alpha-synuclein to develop PD-like symptoms, but it also established again that connection between that gut-brain axis and its development of Parkinson's disease.

This is just kind of a summary slide to put together this Braak hypothesis and the gut-brain axis. You can see here, it's postulated that we have maybe some environmental, genetic inputs that cause maybe some immune dysregulation and inflammation, leading to a reduction in beneficial microbes, those beneficial short-chain fatty acids, and an increase in those pro-inflammatory cytokines or signaling molecules, an increase in that LPS, zonulin, and calprotectin, as well as that increase in intestinal permeability.

Dr. Carley Rusch 00:23:07
This leads to potentially what we refer to as leaky gut, right, that you see here down at the bottom. That communication may spread from that enteric glia within the GI tract through the vagus nerve to that central nervous system in the brain for PD-like symptoms. This is just a theory, but this is to summarize this gut-to-brain axis spread in someone with Parkinson's. Particularly for me, as a dietitian by training, I've always been interested in how diet may modulate this mechanism. Can we utilize dietary interventions to increase those beneficial microbes, short-chain fatty acids, and decrease that inflammatory response?

We know that the influence of diet on low-grade inflammation and intestinal barrier function is becoming more relevant to our understanding of metabolic diseases. The gut barrier consists of beneficial microbes, the mucus layer, the intestinal epithelium, immune cells, and dendritic cells, which are those purple cells that you see here on the picture, are continually sampling the lumen of the GI tract to promote immune tolerance through proliferation of regulatory T cells and mediate pathogen evasion via secretory IgA.

We also have Paneth cells, which are that red cell that you see there, that can actually secrete antimicrobial peptides, or AMPs, in response to immune signaling induced by the gut microbiota. When we consume fibers and prebiotics that are added to the diet, we actually have conversion of those fibers to those short-chain fatty acids by the microbiota, which supports mucus production by the goblet cells, expression of tight junction proteins to hold those epithelial cells tightly together, and reduce inflammation.

We know that low-fiber diets are associated with a decrease in the mucus layer and reduced expression of tight junction proteins that promote intestinal permeability, leading to inflammation and further contributing to the development of metabolic diseases and potentially Parkinson's disease too.

Dr. Carley Rusch 00:25:27
Just to give you a little bit more information on short-chain fatty acids, like I mentioned, short-chain fatty acids are produced by the microbiota through fermentation of fibers or non-digestible carbohydrates. One of the short-chain fatty acids that I love to talk about and a lot of microbiome researchers are very interested in is butyrate. That's because butyrate is a major energy source for colonocytes. But despite this, it's actually the least abundant short-chain fatty acid produced by those intestinal microbes through fiber fermentation. We know that butyrate-producing microbes frequently rely on the cross-feeding of others, which I'll show a slide on a little bit later. Butyrate has the ability to influence immune function and even gene transcription too, so primarily this anti-inflammatory effect.

Recently, just last year actually, researchers have looked at the relationship of fecal butyrate and how it correlates in someone with Parkinson's. This study was a case-control study where they compared someone with Parkinson's and those without. They found that people with Parkinson's had significantly less fecal butyrate in their stool samples that you can see on the figure on the left. When they compared that butyrate to those MDS-UPDRS Part III scores, for those that aren't a movement disorder neurologist, these are going to be those motor symptom severity scores that our movement disorder neurologists are testing on visits.

You can see this inverse relationship. As butyrate decreases, motor symptom severity potentially increases too. But again, this is a correlation study, so our interpretation of this evidence is pretty limited and preliminary at this point right now.

Now we're going to shift gears in the presentation and really dive a little bit deeper on dietary interventions that can modulate the gut microbiome.

Dr. Carley Rusch 00:27:29
Bringing it back to this figure that I showed you earlier that describes those different inputs, as a dietitian, you can probably expect I've always been fascinated by how dietary interventions can modulate the microbiome to improve our overall health and quality of life. Initially, this interest definitely began with fiber, prebiotics, and probiotics, but it's now even expanding into others like synbiotics and postbiotics. We'll discuss a little bit more on that later. Again, with these inputs of diet like fiber, for example, that microbiota can ferment to produce those short-chain fatty acids like acetate, propionate, and butyrate.

When we look at how specific diet factors influence diversity, which I mentioned earlier is important for the microbiome, this was a recent study that actually further attempted to explain these factors that influence diversity using both stool and blood samples across thousands of people. This was over 3,400 people in this study. What I want to do, because I know this is a very nuanced and small slide, is when we blow this image up to show some of the beneficial factors on diversity of the microbiome, you can see in these green boxes here that higher consumption of plant foods such as fruits and vegetables are associated with higher microbial diversity. This is likely due to the high content of dietary fibers found within these foods.

When we look at our intake of fiber just as a population here in the U.S., you can see dietary fiber is actually frequently under-consumed here in the U.S. We compare intake of dietary fiber using this adequate intake that comes from the DRIs, and it's recommended that we should be consuming 14 grams of fiber per 1,000 calories. For example, if you are someone that consumes a 2,000-calorie diet, it would be recommended to get in about 28 grams of fiber in your diet. Where this information comes from is actually its benefits on cardiovascular health and outcomes too.

Dr. Carley Rusch 00:29:40
When we actually look at how fiber intake changes over different age groups, you can see overall most people are only consuming probably about 14 to 18 grams of fiber per day, or about eight to nine grams of fiber per 1,000 calories.

When we look at older adults, especially because a lot of our people with Parkinson's are over the ages of 60 and above, but even my young-onset Parkinson's too, you guys can see both of these intakes still not meeting those fiber recommendations. Again, we know that dietary fiber can aid in both GI health, but also providing that energy source for beneficial bacteria in the microbiome.

Dietary fibers, just to give a brief overview of that, are very known for their ability to promote laxation, right? We hear about it a lot when we think of constipation management. They can even decrease the rate of absorption of cholesterol and glucose from the diet too. Dietary fibers promote microbial diversity through fermentation.

Prebiotics such as fructooligosaccharides, galactooligosaccharides, and inulin are actually another class of fibers that are selectively utilized by host microorganisms to confer a health benefit. This benefit is usually due to increased abundance of beneficial bacteria, like Bifidobacterium, for example, that can lead to increases in those short-chain fatty acids, like acetate, propionate, and butyrate. These short-chain fatty acids can actually be used as an energy source for other microbes and colonocytes, and even modulate that immune function and colonic pH too.

Short-chain fatty acids can increase secretion of gut hormones like GLP-1 and PYY. These are peptides that are related to gastric emptying, appetite, satiety, and even glycemic control. Increased secretion of these peptides via short-chain fatty acids are also implicated as targets for treating other metabolic disorders too, like type 2 diabetes. I know there's a lot of work in this area as it relates to the gut-brain axis on how increases in these peptides may also impact appetite and satiety too.

Dr. Carley Rusch 00:31:58
Just to give you a brief, quick summary of how that fermentation occurs by the bacteria. We have this dietary fiber, which is that non-digestible carbohydrate that's seen in that green chain there. I have an example of different types of fiber that may be used. When that fermentation occurs, we have normally a primary fiber degrader, maybe it's Ruminococcus bromii, that can break down that fiber into smaller fiber units and even those short-chain fatty acids like acetate, propionate, and butyrate.

And then we also have cross-feeding by secondary fiber degraders. That could be, for example, Eubacterium hallii, which can further break down those smaller fiber fragments into short-chain fatty acids like butyrate that can work as a signaling molecule on the GI tract, the immune system and potentially the gut-brain axis too.

Moving on to talk a little bit more about prebiotic fibers, these are substrates, again, that are selectively utilized by host microorganisms to confer a health benefit. What I really want to point out is that not all fibers actually meet this definition. We have some foods that naturally contain prebiotics, like bananas, onions, garlic, chicory root, which is a source of inulin, artichokes and even beans too.

We know that prebiotics can also be added to food products in the form of GOS, FOS, oligofructose, chicory root or inulin. You might see this, for example, in different food products like fiber bars, or lately I've been seeing this a little bit more with protein shakes and other types of drinks too.

When we look at the recommendation for how much prebiotics we should be getting in our diet, we actually can look to the International Scientific Association for Probiotics and Prebiotics. This is an expert consensus working group of researchers in this area that came together to establish these definitions of what is considered a prebiotic, a probiotic, a synbiotic, et cetera. I have this figure here just to use as a reference to show you how prebiotics are different than dietary fibers and other fibers that aren't prebiotics too.

Shifting gears, I've spent some time discussing the prebiotic effect of fermentable fibers. However, we know that other compounds, like polyphenolic compounds and, for example, proanthocyanidins found in grapes or cranberries, can also be considered a prebiotic, and they're important for that intestinal barrier function of the GI tract. We have bacteria like Akkermansia muciniphila that resides in the mucus layer of the GI tract and is a potential biomarker for barrier integrity.

I will say that, especially within the neurological and Parkinson's disease world, Akkermansia can be a little bit more nuanced and complicated. We see people, for example, with obesity and diabetes actually have low counts of this microorganism, and it's associated with intestinal permeability. But it's interesting: we actually see the opposite in someone with Parkinson's, where they have this overabundance of Akkermansia in the GI tract. There's really more work to be done in this area, and maybe it's just a signal that there's this balance occurring.

We know that Akkermansia can metabolize those polyphenolic compounds down to other phenolic metabolites as well, and that can be reabsorbed back into the liver and enter systemic circulation too.

In the GI tract, they can also signal production of mucin by the goblet cells, which is used as that energy source for Akkermansia to bloom. An abundance of Akkermansia can have this bidirectional effect on stimulation of mucin secretion. To show what it looks like when Akkermansia is at work in the colon, this is just a cross-sectional image here of an obesogenic mouse model that was fed a standard chow diet, a high-fat, high-sugar diet or a high-fat, high-sugar diet with polyphenols.

You can see, at the same magnification, the mucosal thickness was drastically reduced with the high-fructose, high-sugar diet compared to controls. The thickness was normalized when supplemented with polyphenols, and it was associated with a bloom of Akkermansia. Again, these investigations really need to be further confirmed in humans, and their relevance to improving clinical outcomes, especially as it relates to someone with Parkinson's who actually might have some overabundance of Akkermansia, but that can also have some variability there too.

I definitely predict we're going to see a little bit more of Akkermansia and polyphenols even as therapeutic targets for different disease states, like people with Parkinson's.

Dr. Carley Rusch 00:37:10
Moving on to probiotics. You probably hear about probiotics very frequently. These are going to be those live microorganisms that, when administered in adequate amounts, can confer a health benefit to the host. But one of the things I always want to keep in mind, especially within the Parkinson's community, is that benefits of probiotics are going to be species- and even strain-specific. Not all probiotics are going to function the same way. They're not going to function the same way in everyone with Parkinson's, and they're definitely not going to function the same way between different individuals too.

When we think about the differences between probiotics and fermented foods, there's evidence for a health benefit, but that's not required for fermented foods. Examples of that would be yogurt, kefir, kimchi, even cheese and some breads too could be a fermented food, but not a probiotic. You might have also heard the term synbiotic, which is a combination of a probiotic and a prebiotic. One of the things to keep in mind is that there really isn't a general recommendation that exists for consumption of probiotics.

I do have this clinical guide that I'll reference here for you all. It's a website for probiotics in the U.S. I find it really helpful. I have the link here at the bottom where you can actually search the different types of probiotics that are available on the market in the U.S. and take a look at the strain and its potential application that's been found in research too.

When we think about diet for someone with Parkinson's, what I always am communicating right now is that we're not there yet as it relates to what's the best diet for someone with Parkinson's, but we are getting closer. The majority of research has focused on identifying risk factors for Parkinson's, and trials haven't actually shown strong results in humans unless you have a clinical deficiency. So a lot of the research, especially in Parkinson's, and for my scientists on the line, I'm going to challenge you all to think about this too: we've done a lot of research looking at single food components, but we know that we don't just individually eat one specific vitamin or protein, et cetera, each day. We eat a whole pattern of foods. You really want to consider this as we move the research forward too.

Just to briefly share with you some of the evidence that we do have right now in the literature as it relates to probiotics and someone with Parkinson's, this was a synbiotic drink that a research group out in Italy did back in 2016, showing that a synbiotic drink increased the number of complete bowel movements in someone with Parkinson's after six weeks.

These results were also similar in a multistrain probiotic that increased spontaneous bowel movements after four weeks in people with Parkinson's. This was, I believe, an Asian, maybe Japanese group that was published back in 2021.

One of the things about these studies that you really want to keep in mind is: what does the diet look like when you're adding the supplement? When we actually take a further look at this study, we find that average fiber intake at baseline, before intervening, was about 30 grams per day. When you think about someone in the U.S., we're consuming half of that too. So it's interesting to think how these results might actually differ here in the U.S.

We also have a new area of dietary interventions that can modulate our gut microbiota, which are called postbiotics. This is a new definition by ISAPP. It's basically a preparation of inanimate microorganisms that can confer a health benefit to the host. I know I'm getting short on time, so I'll just briefly review this. If you look at the figure here, at the top, it's the live and active form of a common probiotic, Lactobacillus rhamnosus GG. At the bottom, you can see it's an inactivated form.

There's been some evidence for efficacy of even postbiotics in treating conditions like infections and other disease states, like IBS and even COPD too. However, we do have some limited safety studies published in this area and really no regulatory guidance from the FDA in this category. But I anticipate you may see some new research down the line as it relates to postbiotics in the gut-brain axis even too.

Dr. Carley Rusch 00:41:41
Finally, we're going to end by talking about the Mediterranean diet. We know that the Mediterranean diet, and the health benefits it provides, includes antioxidants from plant foods that act as scavengers to help prevent or slow damage to our body cells. It also provides a high level of omega-3s from the fish and seafood in the diet that can influence brain health and function, and even dietary fiber from plant foods too.

There have been a number of different studies that have looked at the Mediterranean diet and how that changes microbial composition in healthy populations and some other disease states too. It's also been associated with higher levels of those beneficial short-chain fatty acids like butyrate, which I mentioned earlier.

When we think about how the Mediterranean diet might actually influence brain health, the PREDIMED trial is really that classic trial that demonstrates this. This was done in Spain and published in 2015. They took older adults, over 65 years, who were at high risk of heart disease and assigned them to either a Mediterranean diet with extra virgin olive oil, a Mediterranean diet with nuts or a healthy control diet, a low-fat diet. They actually intervened for four years, which is a very difficult thing to do in research. What they found was that a Mediterranean diet may slow age-related cognitive decline. This didn't matter whether you were supplementing with olive oil or nuts, but these tended to do better than that healthy low-fat diet group.

When we look at the Mediterranean diet's association with Parkinson's disease, we've had a couple studies showing that it's associated with lower risk of developing Parkinson's. For those in your family, this might be something to think about in terms of diet quality and risk of developing Parkinson's. Even prodromal symptoms too. That prodromal stage is going to be before that motor stage, where a Mediterranean diet is associated with fewer non-motor symptoms in that early phase.

Those flavonoids and flavonoid-rich foods that are found within the Mediterranean diet have also been associated with decreased mortality, or risk of death, in someone with Parkinson's as well.

Even a small study that we did here at the University of Florida found that a five-week Mediterranean diet altered some of those bacteria that we find are altered in someone with Parkinson's. For example, Roseburia and Bilophila here too.

When we put this all together, that brief take-home point is how this works: we really want to consume a diet rich in those plant foods, like a Mediterranean diet, or other prebiotics, fibers, et cetera, and really ensure that dietary fiber intake is between that 25 to 30 grams per day range to increase production of beneficial microbes and their byproducts, which are those short-chain fatty acids that can potentially modulate the gut-brain axis and brain health too.

In the future, we're definitely going to see this leverage of machine learning and AI, and precision nutrition for treatment of Parkinson's disease. In this old framework, we took a target population, gave them a dietary intervention, sequenced their stool samples, and we had lots of different heterogeneous outcomes. Where we're actually moving in the literature now is to a new framework of inputting the microbiome, metagenomics, diet, genetics and other clinical parameters into these machine learning models, in which we can use AI to predict and create precision nutrition strategies that will modify an individual's microbiome and further improve the response to a specific diet. This is definitely still in its infancy, but a decade ago, this model definitely seemed like a dream, and now it's actually becoming more of our reality. I'm really excited to see where this next decade of research in the gut-brain axis takes us.

In summary, we talked about how the gut microbiome and gut-brain axis are implicated in people with Parkinson's. Diet, like fiber, prebiotics, probiotics and even the Mediterranean diet, can shape the microbial diversity and metabolic capabilities of the microbiome. That response to the gut-brain axis is going to be host-specific. So we really need, and this is a callout to all the researchers who are listening in, those precision nutrition strategies to potentially differentiate responders to these dietary interventions as well.

With that, I am happy to take any questions that you all may have. Thank you again for your time.

Dr. James Beck 00:46:40
Thanks, Doctor. Gosh, I really appreciate that. That was an incredibly detailed presentation, and clearly the research in this area is evolving tremendously. Thanks for that tremendous overview. It seems like, given the technical nature of where we stand, how do we turn that into something that becomes really pragmatic for our listeners? I think one of the slides you showed began to get there. Part of it, and if I can summarize, it seems like a bottom line here is fiber. It's really something that people should be focusing on. We don't take enough of it. It greatly impacts our microbiome, and our microbiome, by giving off various chemicals, some good, some bad, certainly plays a role in gut health and then impacts brain health as a result of that. Is that a fair assessment?

Dr. Carley Rusch 00:47:34
Yes, it's definitely a fair assessment, Dr. Beck. When I was practicing as a dietitian in the clinic, I was always educating people to start with the basics. We're seeing the forest for the trees. I might have butchered that analogy a little bit. We really just want to go back to the basics of diet quality, which includes increasing fruits and vegetables, getting more dietary fiber in the diet and making some modifications from there. That's how we can really begin to customize and provide that individual nutrition strategy, because if we don't have the basics and that foundation set up, then it's really hard to supplement or determine what's going to be the right fit for someone with Parkinson's as it relates to the microbiome and the gut-brain axis.

Dr. James Beck 00:48:24
Fantastic. Let me just pause real quick and let our audience know to continue to submit questions using the Q&A icon below. If you're on Facebook, share your questions in the comments. My colleagues are organizing the questions as they come in, but a lot of them are coming in, so we're not able to respond to all of them as much as we would. Our Helpline is also a resource to answer questions that may not be answered and are still persistent as part of that.

Let me just kick off with some additional questions. I think we've established this brain-gut connection. It's both the physical one through the vagus nerve that may contribute to the development of Parkinson's disease, but it's also this less clear one, let's say through the circulatory system, where the impact of gut health, whether it be constipation or the microbiome itself, can have an impact.

A lot of people with Parkinson's are here on the line, and they're asking some questions. Let's just tackle a practical one as we think about gut health. People with Sinemet a lot of times experience nausea as a side effect of it. But is it all because of nausea? Can constipation lead to some of these issues? This gets to the idea again of when we talk about gut health and the microbiome, what can we do as part of that?

Dr. Carley Rusch 00:49:47
That's a wonderful question, definitely probably the number one question I always got when I was in clinic too, as it relates to taking Sinemet or that levodopa medication and how the influences of GI dysfunction impact it. I was first author on a review paper that was published earlier this year in npj Parkinson's Disease, which is a partner journal with the Parkinson's Foundation, that actually describes this interaction between GI dysfunction and levodopa. There are a few studies that have looked at the pharmacokinetics of when we take oral levodopa, and how GI dysfunction impacts those pharmacokinetics. Constipation certainly may impact the pharmacokinetics, reducing the efficacy of levodopa. Gastroparesis, or that slow gastric emptying, as well too.

For my providers who are listening in, and even my people with Parkinson's, when we think about when our levodopa isn't correctly working the way it should be, and we're not getting that good on-and-off time, oftentimes when we think about diet, we always think about the protein aspect because there are potential protein interactions with levodopa. One of the things I might want to challenge my healthcare providers and even people with Parkinson's and their caregivers is to think about the GI dysfunction and how that might also impact the pharmacokinetics of the medication too.

Dr. James Beck 00:51:11
Fantastic. Let me just say I'm going to post a link to your paper to my colleagues, and they can push it out. The great thing about npj Parkinson's Disease is it's an open access journal, so anyone listening can download it without a paywall as part of that process. Great stuff.

Thank you for that answer. Taking into account some of the things you were talking about today, butyrate and some of these short-chain fatty acids that are playing an important role, is the research suggesting that you take it exogenously, or is it better to spur one's microbiome to make more of it directly? Where are we headed with that?

Dr. Carley Rusch 00:51:47
That's a really great question. We definitely need more research on butyrate as it relates to how it can modulate, especially, the gut-brain axis. There are actual oral exogenous forms of butyrate on the market. I know, for example, I think tributyrin is one. The challenge with taking exogenous butyrate is that the taste is very terrible because it is a short-chain fatty acid. If anyone's tried exogenous ketones, for example, you might experience a similar flavor profile as well. It's just terrible.

That's been one challenge with oral butyrate. The other challenge is how to study it too. When we take exogenous butyrate, I mentioned that colonocytes are epithelial cells. They're constantly rapidly turning over and producing new ones. When we take something exogenously, whether that's by mouth or, actually, there are butyrate enemas that some studies have looked at, particularly in a critical care population, those enterocytes in the GI tract metabolize, I think the number is around 70% of that butyrate just for those enterocytes, and the remaining amount might get back into circulation.

It's really difficult to study how much of the butyrate that I gave you actually does end up in circulation. Usually you need a more sophisticated method, like radioactive labeling, to really investigate that type of mechanism too. That's why you've seen the literature really focus on these other interventions to increase butyrate production. So this indirect effect on the gut-brain axis, like fiber, prebiotics and probiotics too.

Dr. James Beck 00:53:34
Yeah, because it seems like you mentioned it as a food source for other bacteria in your gut, and they rely on it. It seems like it could be beneficial for that to help restore the microbiome. It leads to my next question. We talk about the microbiome. How stable is it? Using dietary fiber as an example, we're clearly not taking enough of it. If you take more of it, how long would it take to see a change? Then I guess the other point you bring home in your talk is that not all dietary fiber is the same. How do you do that? One of the things you mentioned is bananas, which, for a person with Parkinson's, is not exactly the fruit they reach for first because of the constipation factor.

Dr. Carley Rusch 00:54:20
Yeah, it's a really great question too. How to manage this? Actually, Dr. Beck, can you repeat the first part of the question because I think I'm blanking on it a little bit?

Dr. James Beck 00:54:33
I threw a lot in there, so no problem at all. How stable is the microbiome at all? It seems like, especially when we take probiotics, you're hoping to change, but I think, and this is my terrible analogy, if you have an unhealthy microbiome, it's like your yard covered with weeds. If you're taking probiotics, it's like throwing grass seed down. I still have weeds. What do I need to do? Clear house? Do you have to do that in order to really get probiotics to work? Do you need to take antibiotics in order to purge your gut and then start fresh? What are people thinking these days?

Dr. Carley Rusch 00:55:12
I really like that question. In terms of stability of the microbiome, our microbiome is very stable when we look at it over time. It can change in the short-term period. For example, if we give someone a short-term antibiotic or if we give someone a probiotic, we can see some short-term changes in that resident microbiota. But over time, especially as we come off the medication and there's some type of a washout period, now you're back in your normal environment, you're eating similar foods again, you tend to see that people tend to move back to their resident microbes.

When it comes to changing the microbiome, that's been one of the most difficult challenges that researchers have had. That's why particularly fiber can be a great strategy, because you're getting those broad-spectrum changes. Those fibers aren't specifically targeting one bacteria. They can be broken down by multiple types of bacteria that other bacteria that are resident to your microbiome can use for cross-feeding, et cetera.

When we give a probiotic, we're only increasing abundance of one bacteria in the community in the hopes that it creates a new niche and it takes residence in that microbiome. But often what we see is that when you take a probiotic, if you miss a couple of days, your microbiome kind of goes back to normal too. There have been some researchers who have been looking at whether we need to do maybe some short-term antibiotic treatment and then do a dietary intervention as well, whether that's a probiotic or another type of therapeutic too, and see how that changes the microbiome and whether that can create stability.

We're definitely in our infancy there. Even fecal transplants too. I know, in a lot of people with Parkinson's, there's been more interest in the community there, because again, you're changing someone's microbiome. But even with fecal transplants, you still may get some changes back to your original resident microbiota over time. The question becomes, do you need to do multiple fecal transplants? Again, definitely in its infancy. But I love the analogy that you made as it relates to the seed starter over the weeds, because you're right. That's a really good analogy for it too.

Dr. James Beck 00:57:45
Thanks. I think also about the fact that I could understand why it's hard to establish the change, because you really need to change the conditions for the bacteria to grow. You can take the probiotics, that's great, and unless something else fundamentally changes, then it may not help. Perhaps that could be fiber, because that really seems like a good food source for a lot of this stuff.

We talk about fiber, then, and I know we have just a few minutes left. How do you measure that on a practical level? You go out to eat, hopefully, and you're trying to have this, and not everything has labeling on it. How do you make these choices? Are there resources available, perhaps, that you could recommend as part of the process?

Dr. Carley Rusch 00:58:32
Yes. In general, your high-fiber foods are going to be plant foods: your fruits, your vegetables, beans, whole grains even too, and sometimes other types. Then you could also have additives as well.

If you don't have a label, those are going to be the things that I'm looking for to get more fiber in my diet. I'm going to be looking for plant foods. It's recommended by the USDA, MyPlate. You can actually go on to ChooseMyPlate.gov, where you can see more very simple nutrition education resources. What they recommend is actually using the plate method, filling half your plate with fruits and vegetables. That's one way, as a visual strategy, to get more fiber in the diet. Of course, if you do have labels available to you, you can take a look at labels as well.

It will actually have a daily value percentage next to that fiber. One of the questions is, well, how do I know if this is a high-fiber food? You can look to that daily value, and if it's over, I believe, 10%, it's considered a good source of fiber in the diet.

Dr. James Beck 00:59:47
Okay, awesome. Well, I think we've reached the end of our time. I appreciate all the questions that have come in as part of that. Again, thank you, Dr. Rusch, for offering your knowledge and time today and talking about the gut-brain connection. Big thanks to everyone who's joined us today. We again had a lot of questions and were not able to answer them all. If a question was not answered, please call our Helpline, 1-800-4PD-INFO.

I also want to highlight that we've completed a good chunk of our Expert Briefings today. We've got one left, and it's going to be one that's not to be missed on Wednesday, November 8. It's about hallucinations. This is something that people are concerned about, and some people have at various levels. I think it'll be a great one to register for and to learn about as part of that.

We are here for you as always. Our website, our Helpline via telephone or email, those are good ways to get in contact with us beyond questions regarding this gut-brain axis and other issues that you may be facing. But before you go, we're in the Zoom world, and it's just going to go to black when we end this webinar, but a survey will appear afterward, and we really want your input on this.

We use that survey to provide feedback to our speakers. We use those survey results to provide feedback on our program as a whole. So please just take a few minutes and complete that survey when it appears. Otherwise, we will look forward to speaking with you again come November. Take care.

Arthur Roach 00:00:10
It's really a patient-led initiative to work like a seed venture fund to find projects that are aiming to create new treatments for Parkinson's. It's very much focused on new treatments driven by the priorities of the Parkinson's community and funded by the Parkinson's community. Because all the funding and the motivation and priorities come from the Parkinson's community, we'll fund projects that perhaps other people won't, might fund them in a way other people won't, but ultimately, we think this will lead to more and better treatments for Parkinson's.

John L. Lehr 00:00:39
We're still working with levodopa, which is a therapy that does very well for people with Parkinson's, but it's not a cure, and it has a lot of side effects. It's been the frontline therapy for 50-plus years. Although there have been adjustments to it to make it even better, it's still only really the one therapy that we have for dopamine replacement that we can give to people. I think talking about hope, giving people hope that there are new and better therapies coming, is critical.

Arthur Roach 00:01:11
And we hear a pretty consistent message that people do want disease course-modifying treatment. They want the cure, they want something to stop their Parkinson's in its tracks at the early stages for sure. Maybe that's a dream, but they also have these symptomatic needs, especially as people living with Parkinson's today have gone a little bit beyond the early stage.

The problem of creating new treatments for Parkinson's is a big problem. It's an international problem. It's a problem that will take many years and many millions to solve. The answer to that, we all know, is collaboration, is cooperation. Our collaboration on the Virtual Biotech is a great example of that. Even throughout the Virtual Biotech, beyond that, we have collaboration with other funders, sometimes private funds. Part of what we're doing here is forming those collaborations to allow us, of course, to have more impact and bring forward bigger projects.

John L. Lehr 00:02:02
Parkinson's, as we always say, is just too big of a disease for any one organization or any one entity to do it alone. We have to come together, we have to collaborate, we have to trust in each other and rely on each other, and bring our greatest minds forward for these programs that we think are really going to change the course of this disease.

Arthur Roach 00:02:25
Part of our rationale in approaching the Virtual Biotech and the way we're doing it is that it's difficult to find investment for early-stage Parkinson's projects. But there is interest, there is a market, if you like, there. The pharma companies do want Parkinson's projects. We can see that. There are lots of pharma companies that are investing tens, hundreds of millions in new Parkinson's drugs. They just are a little bit shy of those early projects, the higher-risk projects. There's always something they're in competition with, whether it's Alzheimer's or cancer or something else. The early stages often don't get funding, even though there is interest there.

John L. Lehr 00:03:00
We're fortunate because we have people who are willing to support drug discovery and development philanthropically at a very high level. But when we do have progress and something turns out to be positive, being able to reinvest those funds in second- and third-generation therapies is just really critical. It's what makes it such an exciting endeavor for us. Cystic fibrosis and leukemia and lymphoma, there are lots of other examples in diseases, not Parkinson's, where there's been success in using this model.

Arthur Roach 00:03:36
The projects we have funded over the last five years or six years of the program — in fact, we've gotten up to 13 projects we've committed to — many of these projects are quite large, and we often can't fund the whole project. But the fact that we're in there, we understand Parkinson's, you're in there, you understand Parkinson's, gives other investors some confidence to go forward and co-invest, raising the amount of money available. The clinical trial in Parkinson's dyskinesia showed a clear positive result.

We found a good project, we found the funding, they did the study, and the result was positive. The next stage for that might be a partnership where many more millions of dollars could be available for that project to move it forward for Parkinson's and possibly bring a new dyskinesia treatment to the market.

John L. Lehr 00:04:26
I think we'll get to a point where we're able to raise tens of millions of dollars from donors to support this initiative. And the more we raise, the faster we can go, the more therapies we can get into development.

Arthur Roach 00:04:38
As years go on, in the future we'll see even more and more success, and hopefully there'll be new treatments in the clinic in a number of years that have the Parkinson's Virtual Biotech stamp on them. We supported them, the Parkinson's community, your supporters in the U.S., ours in the UK, made these happen. They should be proud of that. One thing that we tell our supporters, and I truly mean it, is that this is a way to create new treatments in years, not decades. People have heard too many times, it's 10 more years, 10 more years, everything's 10 more years. Well, we have some projects in our pipeline that actually in two or three more years, if they go well, could lead to a drug approved, certainly in the UK, and that will open the door to approval in other countries.

John L. Lehr 00:05:15
Years, not decades. That's going to provide a lot of hope to people living with Parkinson's.

Heather is the founding therapist of the Dan Aaron Parkinson’s Rehabilitation Center (Penn Therapy & Fitness) at Pennsylvania Hospital in Philadelphia, PA – a partner with the University of Pennsylvania’s Parkinson’s Disease and Movement Disorders Center (PDMDC). Heather received her Bachelor’s in Physical Therapy from the University of Scranton in Scranton, PA and her Master’s in Gerontology from Saint Joseph’s University in Philadelphia. She has been a physical therapist since 1994 and received her board certification in geriatrics in 1999 from the American Board of Physical Therapy Specialties. She is a LSVT® BIG certified clinician, PWR! certified clinician, graduate of the Rock Steady Boxing for Parkinson’s, certified in Music and Memory®, and is an ACTIVATOR® Trainer. She serves as an LSVT® BIG Faculty Instructor for LSVT Global, Inc., and Co-coordinator and PT Faculty for the Parkinson’s Foundation’s (PF) Team Training Program. Heather has authored book chapters on rehabilitative strategies for PD and Frontotemporal Degeneration. She also is the author of the PF educational manual “Fitness Counts.” 

Heather has taught for several CEU organizations including Medbridge and Elite Learning. Her research includes movement strategies for bed mobility, falls, freezing of gait, and functional movement disorders. She teaches about rehabilitation and PD at Thomas Jefferson University (Philadelphia, PA) and Neumann University (Aston, PA). Heather is a former board member of CurePSP and team member of both the COPE Clinic (Comprehensive Outpatient Atypical Parkinsonism Evaluation) and Huntington’s Disease Clinic at the PDMDC.

Julia Wood, MOT, OTR/L graduated with her master’s degree in occupational therapy (OT) from the University of Minnesota after completion of her clinical fieldwork in neurological rehabilitation from the Mayo Clinic, St. Mary’s Hospital campus in Rochester, Minnesota. Julia has an extensive clinical background in rehabilitation, interdisciplinary and palliative care in Parkinson’s disease and related dementias. She served as the lead OT at the University of Pennsylvania’s Parkinson’s disease and movement disorders Center of Excellence for ten years where she continues to develop and facilitate community engagement programs for people with PD and related dementias and care partners.  Julia is currently the Director of Professional and Community Education for the Lewy Body Dementia Association and serves as certification and training faculty for the LSVT BIG® program.  Julia has served as faculty for the Parkinson’s Foundation’s Team Training for Parkinson program since 2016 and served on the Parkinson’s Foundation Rehabilitation Task Force in 2021. She co-authored the first American Occupational Therapy Association Practice Guideline for Adults with Parkinson’s Disease in 2022. Julia served on the steering committee for the 2022 International Lewy Body Dementia Conference and on the Comprehensive Care Subcommittee for the 2023 World Parkinson’s Congress (WPC).

Dr. James Beck 00:00:01
Hello everyone, and welcome to our expert briefings. I'm Dr. James Beck, Chief Scientific Officer of the Parkinson's Foundation. Our expert briefing today will be centered around Parkinson's disease and the bladder. This is our fourth expert briefing in about our 14th season, so this is kicking off our fall session.

As you know, many people with Parkinson's experience urinary difficulties. Being aware that urinary problems, such as urinary tract infections, can be a symptom of Parkinson's is really the first step toward management. Today, we will learn more about common bladder problems in Parkinson's disease, why they occur, and what some treatment options are.

Before we begin, I want to share a little bit about the Parkinson's Foundation. The Parkinson's Foundation is a nonprofit focused on bettering the lives of those living with Parkinson's through improving care and advancing research. Importantly, everything we do is in close concert with our community to ensure that our actions are aligned with the needs and priorities of those living with Parkinson's disease. To do that, we focus on three particular goals. They are advancing research toward the cure, empowering our global community, and improving care for everyone living with Parkinson's disease.

Before we begin, I'd like to get a chance to know who is here listening in on our conversation. We're going to launch a poll. If you're joining us on Facebook Live, please respond using the comment section, but tell us who you are. Are you a person with Parkinson's, or are you a friend of a person with PD, healthcare professional, scientist, nurse, spouse or partner? Let us know, and then in just a minute we'll post the results to see who you are and who's listening today.

All right, great. The results are in, and not surprisingly, most of the people, 80% of the people who are online so far, are people with Parkinson's. We have a lot of those who are spouses and a couple of healthcare professionals. Welcome. Glad to have everyone here as part of that. Thanks for sharing your connection to Parkinson's.

Just to let you know, for your convenience, we are recording today's expert briefing. If you weren't able to catch everything or you want to take notes on what's available, we certainly have a download of the slides that we'll make available, but this is something that we'll be storing online and something you can come back to again. We'll be emailing a link of the recording and other resources for today's topic to those who've already registered as part of that process.

Dr. James Beck 00:02:39
Now, I'd like to introduce our experts. We're fortunate to have two today. The first one is Dr. Abhimanyu Mahajan, who is a movement disorder neurologist and assistant professor of neurology at the University of Cincinnati. Dr. Mahajan attended medical school in India and graduated from the Johns Hopkins School of Public Health with a master's in epidemiology. He completed his neurology residency at Henry Ford Hospital in Detroit and his movement disorder fellowship at the University of Cincinnati. Prior to coming to his current position, he spent three years as a faculty member at Rush University Medical Center in Chicago.

Dr. Mahajan's primary interests lie in the non-motor aspects of Parkinson's disease, which includes the bladder.

Also joining us is Dr. Ankita Gupta, who is a urogynecologist, particularly focused on female pelvic medicine and reconstructive surgery at the University of Louisville Health in Louisville, Kentucky. She serves as the associate fellowship director for the urogynecology fellowship and is from Kasturba Medical School in Mumbai, India, where she also obtained a master's in public health at the Harvard School of Public Health in Cambridge, specializing in maternal child health and public health leadership. She completed her obstetrics and gynecology residency at Crozer-Chester Medical Center in Pennsylvania and her fellowship in urogynecology at the University of Louisville.

Dr. Mahajan and Dr. Gupta, welcome. Thank you for sharing your time and your knowledge with us today. I'm going to pass the mic to Dr. Mahajan.

Dr. Abhimanyu Mahajan 00:03:56
Thank you. Thank you, Dr. Beck. Thank you for that kind introduction, and thank you for this invitation. Before I say anything further, let me just make sure that my slides work. Can anybody tell me if they can see the slide?

Dr. James Beck 00:04:11
We can see them.

Dr. Abhimanyu Mahajan 00:04:12
All right. There we go.

First of all, thank you to the Parkinson's Foundation for, a, picking this topic, and b, inviting us to speak about this topic. I think this is one of those topics that I see a number of people with Parkinson's disease in my clinic. This is one of those topics that never comes up in the first visit. If you're a shy person like I am, it will probably never come up unless my spouse brings it up or a family member brings it up.

It is imperative we talk about this topic. Over the next few slides, I hope to impress upon you the importance of talking about this because, a, it has direct implications, b, it has implications on other aspects of Parkinson's disease, and c, there are plenty of treatments available that can actually improve your quality of life and prevent harm. Let's get started.

First of all, I've been fortunate to be funded by the Parkinson's Foundation, the Sunflower Parkinson's Disease Foundation and the Dystonia Medical Research Foundation. Nothing that I'm going to be talking about today is a conflict, of course.

As all of these things begin, this conversation must start by discussing that it all started with An Essay on the Shaking Palsy by James Parkinson in 1817. As you may know, the diagnosis of Parkinson's requires bradykinesia, or slowness, with or without rigidity, or stiffness, with tremor. People with Parkinson's walk a certain way, and of course there are certain other aspects that we look at and we say, well, we know you have Parkinson's disease.

Even Charcot, one of the most celebrated neurologists of all time, mentioned that he had seen such patients everywhere, in Rome, Amsterdam, Spain. They reflect always the same picture, can be identified from afar, you do not need a medical history. In other words, what Charcot meant to say was, you see one person with Parkinson's and you know that person has Parkinson's disease. Well, that's not really true though, is it? What we know now is that when you see one person with Parkinson's, you see one person with Parkinson's.

Dr. Abhimanyu Mahajan 00:06:35
What I mean by that is, as you can see, this image has been now made popular by Dr. Okun and Dr. Armstrong at University of Florida Gainesville, where they correctly identify that people with Parkinson's look different, they may feel different. In a given day, they may be their best selves or not be their best selves. In addition to motor features, which are used to describe or define or diagnose Parkinson's disease, there are a number of non-motor features that can actually be even more important to the person living with Parkinson's disease and their care partners. You all know this.

In fact, James Parkinson also made a comment about gastroenterological issues, GI issues with Parkinson's, which we almost always forget. The bottom line is, as you all know, everybody's presentation, progression, response to medications, things that bother you, all of these things may vary from person to person. Everybody with Parkinson's has something different that bothers them, and it's imperative that we not forget non-motor features.

When we talk about Parkinson's disease, most people, or at least their care partners, particularly spouses, are able to identify when things began. It may be that people walk a certain way. Well, you know, Mr. So-and-so has always been a runner, but I noticed in the fall of 2020 that he wasn't able to keep up or he walked a little differently. Or you may notice a tremor in your thumb or your pinky. The truth is, the underlying pathology behind Parkinson's disease may start years before, even decades.

You can have constipation that may begin as early as 20 years ago. You can have sleep-related issues about 10 or more years ago. The part that we're going to be focusing on today is essentially something that is mostly noted about 10 years into the disease. Of course, as you can see, there's a large amount of variability here. You can start having these symptoms along with your motor symptoms, or a slide before, which is what we're going to be talking about: urinary symptoms. It's important to recognize that they constitute an important part of the constellation of symptoms.

What is pelvic floor dysfunction? This is a term I learned about from our colleagues in urology and urogynecology. Well, pelvic floor dysfunction, in simple terms to me as somebody who does not understand urology or urogynecology, encompasses three main areas: the GI symptoms, notably constipation in Parkinson's disease; you can have urinary issues; or you can have sexual dysfunction. Therefore, this is a broad constellation of symptoms and anatomical changes related to abnormal function of your pelvic floor musculature.

Dr. Abhimanyu Mahajan 00:09:42
Today we are going to be, of course, these are interrelated, impairment of one influences impairment of others. Today, we are going to be focusing on urological issues or urogenital issues, namely difficulty with urination, hesitancy, delay in the urinary stream and urinary incontinence, involuntary leakage of urine. But of course, all of this is interrelated.

Now you may think, why is a neurologist interested in something like urinary issues? Well, you may be surprised to know that your nervous system is entrenched in each and every aspect of your body, and urinary issues are no different. Within the brain, the frontal cortex, your basal ganglia - basal ganglia are the aspects that are associated with all movement disorders, including Parkinson's disease - the thalamus and the anterior cingulate gyrus, these are different parts, and I hope you can see this image right here. Different aspects, different parts of your brain that are pivotal to all kinds of movement and therefore important in movement disorders such as Parkinson's, may play a role also in muscles controlling the bladder.

Therefore, a part of your brain such as the caudate nucleus, you can see the caudate head and body right here, your severity of bladder dysfunction leading to issues with urine or urination may be associated with caudate degeneration. Now, micturition, or the act of urination, requires input from both the brain and the lumbosacral spinal cord. Your spinal cord is involved, and it can dictate how distended your bladder is going to be. Your bladder, of course, is the part of your body that stores urine.

Finally, something that directly leads us to Parkinson's disease, and of course dopamine. As you know, in Parkinson's disease, the primary thing that we think about is that the brain does not produce as much dopamine as it's supposed to. A reduction in dopamine can lead to a direct reduction in your control of bladder, leading to bladder contractions, which of course can affect urination.

All in all to say, your brain and your spinal cord are as much a part of the pathophysiology, or things that can cause your bladder to function perfectly well or not function well, as any other part of the body. Therefore, they are important aspects to study in people who have neurological issues.

Dr. Abhimanyu Mahajan 00:12:30
This is perhaps the most common symptom. We are going to jump straight to the symptom. This is perhaps the most common urinary symptom that I hear in people with Parkinson's disease. It's called an overactive bladder.

I put an image of a 24-hour overactive bladder diary. I think it's a good idea to have a diary like this to keep a sense of the timing and frequency of such complaints. For anybody on this call who's taking levodopa for their Parkinson's disease or has family who takes levodopa for Parkinson's disease, you know the importance of timing, the relative importance of timing and clinical symptoms that you may experience. Same way, timing of urination or incontinence episode. Why did you urinate at this time, whether it was, well, I couldn't help myself, or I just had water right before, or I had a cough and I couldn't help myself and I urinated, the amount of urination, incontinence, so on and so forth.

What is overactive bladder? It is the sudden compelling desire to pass urine, which may be difficult to defer. You can't help it. You have this compelling desire to pass urine. It is a clinical diagnosis. The official definition, and I'm sure Dr. Gupta will correct me, but to my understanding, the official definition is that it is a diagnosis of urinary urgency accompanied by frequency, so you pee more frequently than you're supposed to or than you're used to; nocturia, which is a big one, which is you wake up in the middle of the night to use the restroom; with or without urgency urinary incontinence. You have the sensation that you need to pee more, or even after you're done, you leak.

That is how I understand urinary incontinence. Of course, we are not talking about a situation where you have Parkinson's and you have a urinary tract infection. I'll get to that in a second. Or you have Parkinson's and you have something going on in your prostate or bladder in addition to Parkinson's disease. If you have just Parkinson's disease without infection or another pathology happening, and you can't help yourself and you have this urgency, usually accompanied by frequency, nocturia, with or without incontinence, that is representative of overactive bladder.

Dr. Abhimanyu Mahajan 00:14:57
Why should we care about this? Well, urinary dysfunction is highly common in Parkinson's disease. We see urgency and frequency very frequently. Here's the part where it's more than just your bladder and ability to urinate. Your inability to delay urination, of course, increases the morbidity in Parkinson's disease because, guess what, you have to go from your bed or from the chair where you're sitting all the way to the bathroom. You know this. This absolute urgency with which you have to get up and walk increases your risk of falls.

Therefore, overactive bladder is associated with worse quality of life, that one's easy, dysautonomia - the autonomic nervous system is also associated with bladder control, it's associated with blood pressure - cognitive impairment, and finally falls. Especially in the middle of the night. If you wake up in the middle of the night to use your restroom and you're in an off state, so your dopaminergic medication is not as effective now as it was a few hours ago, you're more likely to fall. Therefore, it's important that we identify this and treat this.

I put this slide up there because it's important to note this as well. The age at which we commonly see Parkinson's disease, as you know, Parkinson's disease can present in any age, but it's more common in the 60s and 70s, at least in the United States. It's also the age around which you see urgency incontinence, which is you have to go, you can't help yourself; stress incontinence, which is you cough or you sneeze and you're not able to control your bladder and you have involuntary micturition or urination; and then a mixture of these two. You see these in the age groups where you commonly see Parkinson's disease.

How widespread is it? Well, turns out quite widespread. But because we are also hesitant to ask these questions or volunteer this information, it's anywhere between 24% to 96%, based on the study you see. Regardless to say, it's highly prevalent. It's more commonly associated with increasing age, worsening cognitive function, which makes sense in Parkinson's disease.

Dr. Abhimanyu Mahajan 00:16:49
Now, both men and women can have incontinence, of course, and Dr. Gupta will talk about that, but almost 50% of all women in the U.S. more than 80 years old report at least one relevant symptom if you ask them. While lower urinary tract disease is more bothersome in women, men are more likely to seek treatment with increasing age and severity of symptoms. In women, treatment-seeking behavior is only driven by increasing bother. It doesn't matter how old you are, regardless of how old you are or how severe the symptoms are, unless you're bothered by those symptoms, women are far less likely to report these symptoms compared to men.

That's why we wanted to focus the study that we did at University of Cincinnati and Louisville a couple of years ago now, where we involved our colleagues in urogynecology, geriatric medicine and neurology, and together we surveyed women with Parkinson's disease and women without Parkinson's disease about pelvic floor health using questionnaires. We looked at, for people with Parkinson's, their motor symptoms and cognition, with the idea to find out if and how much Parkinson's disease contributed to issues with incontinence.

Well, this is what we found. Women with Parkinson's disease have worse pelvic health than women without Parkinson's disease. Despite having worse pelvic health - and pelvic health, of course, we talked about this earlier, constipation, urinary incontinence, sexual health - despite having worse pelvic health than women without Parkinson's, there was absolutely no difference in how frequently and how comprehensively they reported their symptoms and how frequently and how comprehensively they went to a physician and asked for it to be taken care of. Clearly, pelvic floor disorders are undertreated in both men and women, but especially in women.

Dr. Abhimanyu Mahajan 00:19:29
I want to briefly touch on this topic. This is a study we did a while back now, but we looked at all admissions of persons with Parkinson's disease within the United States. We had over 3 million admissions representatively. We had 3 million admissions of patients with PD documented over 10 years across the country. What we found was that while other causes of admission to the hospital were slowly trending down, urinary tract infection and sepsis were trending up.

I always tell my patients, Parkinson's disease, for the most part, is a progressive disease. It is not an unpredictable disease. What I mean by that is, if you wake up tomorrow morning and everything seems to be suddenly much worse, so you're freezing more, you're walking slowly, you're confused, chances are that there's some infection, some metabolic change, some new medication. That's the first thing I look at. If you're my patient and you're coming to me and there's sudden worsening, the first thing I would do is check for some kind of infection, and urinary tract infections are notoriously common in men and women with Parkinson's disease.

Now, of course, I've been talking all this while about the bladder and urination as if I know exactly what I'm talking about. The truth is, it is an extremely complicated field, at least for somebody like me. On the screen you can see it says women, but of course in men as well, it is an extremely complicated field. There are plenty of different reasons why you can have urgency of urination and what have you.

Without further ado, I'm going to let Dr. Gupta take over the stage and explain to you what an expert, and actually sound like an expert, talking about this extremely important topic. Dr. Gupta, it's up to you.

Dr. Ankita Gupta 00:21:32
Thank you so much. I'm going to share. There we go. I'm going to actually share my screen so that I can control the PowerPoint as we go along. Okay. Thank you again for the opportunity to talk about something that's near and dear to my heart. Even though I'm a urogynecologist, a lot of the pathophysiology, the workup and the treatments are very similar regardless of gender. Even though I am a urogynecologist who predominantly takes care of women, a lot of these interventions are available to both men and women. I have no conflicts of interest.

This is a very busy slide, but it goes over a brief kind of algorithm or pathway of how we manage patients with incontinence. Like Dr. Mahajan mentioned, there are a few different types of incontinence, and we'll talk about those in this and subsequent slides. Typically, when we get patients who come in to see us with incontinence, the first thing that we do is we start out by looking for reversible causes. What that means is we're looking for patients with infections, if they're on any diuretics or water pills, things like that that might be limiting their ability to get to the bathroom or making them void more frequently. We start out by treating any reversible causes.

We also get some more information about the type of incontinence. Like Dr. Mahajan mentioned, there are three primary types of incontinence that we break patients into. There is stress incontinence, which is the incontinence with cough, laugh, sneezing, jumping, kind of like patients would say, 'I can't get on a trampoline, I can't go running. I leak if I do those things.'

Urgency incontinence, and the overactive bladder portion doesn't necessarily have to be incontinence. We can have patients who have urgency and frequency, which means going more often or not being able to hold their urine or waking up at night to go to the bathroom, even without leaking. A lot of these treatment options apply to those patients even if they don't actively leak. But definitely urgency urinary incontinence is the type of incontinence where you can't hold your urine and you have to go to the bathroom more frequently, or you will leak. Mixed incontinence is typically a combination of both of those. Often when I see patients, based on kind of where they are, a lot of them will come in with mixed incontinence, where they have symptoms of both stress incontinence and urgency.

Dr. Ankita Gupta 00:23:59
Typically, we start out by doing a thorough history and physical examination. This is very similar to whether patients have Parkinson's disease or not. Definitely Parkinson's disease does exacerbate a lot of these symptoms and cause something called neurogenic bladder, but we start out by just getting a sense of the symptom severity. Often patients will have these symptoms that have predated or preceded their diagnosis of Parkinson's disease.

We always make sure that we get a good understanding of what patients' goals are. Everyone has different goals. Some patients might just want enough relief so that they can sleep through the night. Other patients might want enough relief so that they can get through the day or get through their work without going to the bathroom more often or leaking. We try to get a good sense of what patients' goals for treatments are.

We always screen for urinary tract infections, or UTIs. We're always checking to make sure that your symptoms are not more acute from a UTI, and we always check for a post-void residual. That means we're interested to know whether patients are emptying their bladder all the way. We're looking to make sure, either with an ultrasound or with a catheter, to make sure that patients, when they go to the bathroom, they are actually emptying their bladder, because that could be one reason why patients are voiding more frequently if they're not emptying their bladder.

Typically, if patients are complaining of stress incontinence, something like a simple cough stress test - so that means just having a patient stand or sit and cough and just kind of assessing whether they leak - can be really helpful to see if patients have stress incontinence symptoms.

Typically, when patients have Parkinson's and they come in for evaluation, we also do something called urodynamics. Patients who are in this audience who have had that done might recognize them as this, but really what we're doing is we're looking to see whether the bladder is filling and emptying at normal pressures. This is a test that we do in the office. We typically will put a tiny catheter into the urethra and use that to fill the bladder up, and then look on a monitor to see at what pressures or what volumes patients leak.

Dr. Ankita Gupta 00:26:14
That gives us some idea of how your bladder is behaving, both when you're trying to hold your urine, but also when you're trying to void or when you're trying to pee. We're looking to see: is your bladder having an extra amount of spasm that's causing you to leak urine, or are you leaking when you cough, laugh and sneeze because there's too much pressure in your bladder and not enough in your urethra? That's what this test does, and it gives us some more information about your bladder.

There are a few different treatment options, and we're going to go over a lot of these, but the most important thing is to figure out what kind of incontinence the patient has and what their treatment goals are. The treatments really vary by the type of incontinence. Typically, once we've done our initial evaluation, we get a pretty good sense of whether patients have stress, urge or both kinds of incontinence, and we tend to tailor our treatments based on a patient's symptoms.

Typically, conservative options, so that would be non-surgical options, would be things like pelvic floor muscle exercises. I know people hear a lot about Kegels; we're going to talk about that. But there are specific folks called pelvic floor physical therapists who are trained to work with patients in pelvic floor physical therapy. There are also behavioral and lifestyle modifications patients can do, things like bladder training, avoiding drugs, urge suppression techniques, things like that can be non-medical ways to fix or at least help patients deal with or control incontinence.

There are also different things like pessaries, which are continence pessaries. These are usually specifically for women because they go in the vagina, but that is definitely an option for patients with stress incontinence. Then things like medications or onabotulinumtoxin, or Botox, which has been approved for use for urgency incontinence. There are other surgical options as well. Surgery typically is done more for patients with stress incontinence. We'll talk a little bit about slings and urethral bulking options, but there is another great option called sacral neuromodulation, or a bladder pacemaker, that can help patients with urgency incontinence or overactive bladder.

Dr. Ankita Gupta 00:28:33
When we start out talking about stress incontinence, there is always the option to do nothing. Again, a lot of times when patients get referred to me, that's because they've had these symptoms for many years, they've tried doing nothing, and symptoms are getting worse. But I always like to tell people urinary incontinence is a quality of life issue. A lot of the treatments are tailored to patient goals and what their goals for their quality of life are. There is the option to do behavioral management, incontinence pessaries and then surgery for stress incontinence.

When we talk about behavioral management, typically that would be strengthening your pelvic floor. The goal of that is really to make your pelvic floor stronger so that when you jump or cough or laugh, you're able to recruit or squeeze the appropriate muscles so that you can control that leak. You can either do something as simple as Kegels, which you can do at home on your own. There are also options, like I mentioned, for physical therapists, and they can do things like biofeedback, where they can work with you on squeezing the right muscles to get better control and help you get better control of your incontinence.

Really, the goal of all of this is to strengthen the pelvic floor and really just to learn how to squeeze those muscles when you are at a time of stress or activity to help you get better control.

There are unfortunately not any medications that have been approved for stress incontinence specifically, but as I mentioned, incontinence pessaries are an option for women. Really, incontinence pessaries act, as you can see in the image, as kind of like a pressure point, and they help compress the urethra against the pubic symphysis so that when patients cough or jump or laugh, they don't leak urine because there's that compression. As you can see on the image on the right, pessaries come in a whole bunch of different shapes and sizes. Typically, we personalize or customize the pessary.

Dr. Ankita Gupta 00:30:37
We have patients come in and we try a few different pessaries until we find one that is comfortable for the patient. Typically, patients either will keep these in all of the time, so they have the option to wear them all the time and come in every three to six months for us to take them out, or they have the option to learn how to take them out and put them back in themselves. I have some patients who put them in when they are exercising or if they're at the gym, and they'll take them out other times. Self-managing pessaries can be difficult sometimes for patients with Parkinson's disease. It depends a little bit on their baseline level of function or their tremor, but definitely something to consider for patients who are in earlier stages.

As far as surgical management, the most common or the gold standard management option for stress incontinence is something called the mid-urethral sling. This is a piece of mesh, or a bladder sling, that sits underneath the urethra and helps with control with leaking with cough, laugh and sneeze. It is much more commonly used in women. There are male slings available as well, and these are more commonly used in patients who have incontinence after something like a prostatectomy. But the most common type of these things are used for women.

Urethral bulking is when we use a hydrogel. It's a gel kind of made of, like, it's 98% water and something called polyacrylamide. What it does is it acts within the urethra, and it acts as a plug or a stop point so that when patients cough or jump or run, the urine doesn't leak out or gush out quite in the same way. Both of these surgeries are outpatient surgeries. They take about 20 to 30 minutes. They typically are covered by insurance companies, and they usually have very low downtime, so don't require a lot as far as recovery, and are really great options for patients with stress incontinence.

Urethropexies are done more commonly in patients who either have had a reaction to mesh or don't want to have mesh. They're usually done through either a laparoscopic or a robotic approach and are a little bit more invasive than the mid-urethral slings and the urethral bulking, and therefore they're typically not first-line management, but are options for patients who failed the first two treatments.

Dr. Ankita Gupta 00:33:07
Talking a little bit about urgency incontinence now. And like I said, a lot of these treatments apply for patients with or without incontinence. If patients have urinary urgency or frequency, or they're waking up at night to void, they might qualify for all of these treatments even if they're not leaking. There's always the option to do nothing, and then we'll talk a little bit about behavioral management, medications, and sacral neuromodulation as well.

Behavioral management is again very similar to what we talked about with stress incontinence, but with a slightly different goal. The goal here is to stop your detrusor muscle from contracting. So to stop a spasm of your bladder, stop that contraction to help you get better control. One of the ways that we do that is we recommend something called urge suppression, which is when the urgency occurs, for patients to take deep breaths, squeeze their pelvic floor to try to prevent that leaking so that they have more time to make it to the bathroom. Bladder training drills can be really helpful as well. This is where patients, I like to describe it similar to potty training.

It's similar to training a baby or training a puppy. You're putting your bladder on a schedule. You typically would start out by going to the bathroom every hour or so while you're awake, and then if you get the urge to go to the bathroom again before that hour is up, you make yourself wait. You kind of say, no, I know I'm not drinking a whole lot, there's nothing in my bladder, I'm going to wait until my next hour comes around. And then you slowly increase that to about three to four hours between every void. What you're doing with that is you're suppressing sensory stimuli. I get a lot of patients who tell me, like, when I get home, when I put my keys in the door, I feel like I have to run to the bathroom.

Or if I go to the mall, I need to know where all the bathrooms are. If I'm doing dishes, I tend to need to go to the bathroom. The goal of bladder retraining is to suppress those stimuli so you can buy more time. The goal is again to gradually increase how much your bladder can hold. These are things that patients can do on their own that don't require any medications and therefore don't have any side effects.

There are a lot of medications that can be really helpful as well. Anticholinergics tend to be the first-line management for overactive bladder or urinary urgency frequency syndrome. The most common ones that patients will talk about are oxybutynin, tolterodine, or solifenacin. A lot of patients have tried these already. A lot of patients get these from their PCPs. Common brand names would be Ditropan, Detrol, Vesicare. These might sound familiar. They're not usually my favorite first-line treatment options for my patients with Parkinson's. They do increase your fall risk, and they also have some long-term data about cognitive decline.

So I tend not to use anticholinergics as my first line, but that is something that is an option, and certainly insurance companies tend to favor anticholinergics as the medication that they cover for OAB.

Dr. Ankita Gupta 00:36:12
There are actually two beta-3 agonists on the market now: mirabegron and vibegron. They are really great medications to help with bladder control. Mirabegron has a slight side effect of raising your blood pressure. Vibegron does not have that side effect, but those can both be really great medications, and they're once-a-day pills without any other side effects that can be used to control bladder urgency and frequency, and even waking up at night to go to the bathroom. There is not as much data about alpha agonists, TCAs, and duloxetine, so I'm not going to touch on those very much.

Definitely, things like Flomax can be helpful for patients who've got prostate issues. We're not going to fully cover those, but those might be things that you are eligible for if you've got those kinds of issues. Onabotulinumtoxin, or Botox, is a really great treatment option for patients, and I tend to use this very often in my patients with Parkinson's. This is a medication that's injected cystoscopically. Typically, we put a camera inside your bladder. We do this in the office. We have the option to do this either in the office or in the operating room, but I tend to do these in my office. Typically what we do is we use local numbing medication, just lidocaine, to numb your bladder, and then we inject Botox in that pattern that you can see on the left side, all around your bladder.

What this does is it paralyzes your bladder for about a year at a time, and so it prevents those bladder spasms that patients would complain about. The advantage of doing Botox is it's a once-a-year treatment. You typically don't have to get this done over and over again. I have some patients where it's lasted about 18 months at a time. Sometimes it wears off a little bit early, so I tell patients anywhere between six to 18 months, we can do a repeat injection.

The biggest risk or downside with doing Botox is sometimes it works too well, and it paralyzes your bladder so that you cannot pee or you get urinary retention. That happens in about 4% to 6% of the time. So four to six out of 100 patients will get retention. The good thing about Botox is it does wear off. So if you do have retention, that's a side effect that wears off over time, but we don't have any way of predicting who that side effect is going to happen to. So it's definitely a risk-benefit that I weigh with my patients when we talk about Botox.

There's also a slightly increased risk of bladder infections or UTIs after doing Botox. We typically will give patients antibiotics around when we do the Botox injection, but if they're not emptying their bladder all the way or if they develop urinary retention, they're more likely to get infections after Botox.

And then the other third-line treatment option for patients is something called sacral neuromodulation. A common term I've heard patients use is bladder pacemaker. This is an outpatient surgery, and what we do with this is we place a wire into the S3 foramen, and we're kind of implanting this pacemaker that helps you get better control of your bladder. It is covered by insurance, but it is a little bit more on the expensive side, and it is therefore not a first-line treatment. We don't fully understand why it's effective. We think it has something to do with reprogramming the afferent nerves that come from the S3.

For a long time, actually, sacral neuromodulation was contraindicated in people who had nerve-related bladder issues, but over time we found that that's not true. And it works really well even for patients with Parkinson's disease. They make a battery that's both rechargeable and non-rechargeable, and it's very patient-dependent. But the batteries themselves are good for anywhere between 10 to 15 years. So once we get a patient that, you know, we try this, they like it, we put a permanent battery in, typically they don't have to do anything with the device for about 10 to 15 years. The other nice thing about sacral neuromodulation is there's a trial phase.

There is a test series that you can do in the office where we try the device out, we let you try it out at home, and then that way we can see whether the device is working or not.

This is essentially what it looks like. As you can see from the images, there's a little lead that goes into that S3 foramen, and we're putting a wire in to help you get better control of your bladder through stimulation in that area. And then we make a little pocket site just above your gluteal area and we implant that battery. It's all inside, it all stays inside, and it's effective for about 10 to 15 years at a time.

I think that was all I had, but I'm very, very happy to answer any questions that anyone might have about this or any other conditions related to this.

Dr. James Beck 00:41:14
Dr. Gupta, that was fantastic. Thank you, Dr. Mahajan, too, for setting the stage. We've got a lot of questions coming in as part of this, as you can imagine. I just want to get started on that. But before I do that, just a reminder, as we continue with our live Q&A, feel free to continue to submit questions. My colleagues are doing their best organizing them and have them ready for us. We get a lot of questions. We may not be able to answer them all, but we'll do our best to respond and certainly have my colleagues on our Helpline who can follow up with other questions that may be too specific for us to really answer right here.

Maybe for both of you, this is a question that's come through. Just thinking about when we talk about bladder and urinary issues, I mean, Dr. Mahajan, you said this could be an age part, maybe it's Parkinson's disease. Once these symptoms arise, is this a constant battle? Is there a point where you can reach a détente, if you will, where things are under control, or is this a lot of effort? Because people with Parkinson's, especially if they've had it for a while, they've got a lot on their plates with the medications and things, and then adding this can complicate things. Is there a way to get this where symptoms are under control and they can, for lack of better words, just focus on their Parkinson's?

Dr. Abhimanyu Mahajan 00:42:28
Yeah. I think there are a couple of different questions in there. The first thing is, yes, these issues seem to happen around the same age group where Parkinson's seems to be most common. And once they develop, there are ways, there are two ways to handle this. First of all, of course you have to screen it. Not talking about it really doesn't help. But once you've screened the issue, then there are two ways to approach it.

The first thing is we all need to understand that there are issues with treating them and not treating them. If we do not treat some of these issues, of course they can lead to, as I mentioned before, worse quality of life, dysautonomia, falls, cognitive impairment, so on and so forth. The other aspect of this is, if you do treat them, it depends on what modality you're using to treat.

For example, as for botulinum toxin, if you have the right kind of incontinence and you find a urologist, a urogynecologist who's experienced in injecting botulinum toxin, and you find the right muscles and the right dose, which is not that hard, but once you identify that and you get treated with that, ideally you don't get bothered by these issues anytime because you get treated every three months or so and life goes on for everything else. Now, with medications, as Dr. Gupta mentioned, if you're using anticholinergic medications, then you have to be careful about different aspects, other non-motor aspects of Parkinson's.

Now, if you're using alpha agonists, then you need to worry about blood pressure, but for the most part, the rest of it is reasonably well managed. To answer your question in a very complicated way, these issues, once they develop, because some of them are partly issues of aging as well, they're not going away by themselves. So we screen them, and we find the best way to treat them so they don't get in the way of you doing things that you like to do on a day-to-day basis. Just ignoring them doesn't make them go away.

Dr. James Beck 00:44:40
Yeah, I think that Dr. Gupta's nice little slide, you know, ignoring them clearly is the first step, and that doesn't always seem to help. Dr. Gupta, when we talk about these different treatments, it seems like exercise is probably something we as an organization talk about all along, and here we're talking about very specific types of exercises. When we talk about Kegels, they work for men as well as women, I presume, yes? Correct. Just want to make certain everyone's aware of that. And then how successful is it with exercise? Is that, as a first line, do you see a lot of success with that?

Dr. Ankita Gupta 00:45:14
I think it depends a lot on what baseline symptoms you're starting with. The earlier you start, the more effective they're going to be. If you have someone who has urgency frequency but doesn't really have incontinence, those are great candidates for pelvic floor exercises because you can stop that or reduce that even before it gets worse. Typically, when I have patients who have incontinence episodes six, eight, 10 times a day, who are wearing pull-ups or diapers, they're less likely to be improved with just exercises alone. But certainly it's a helpful adjunct if you're doing other things and can add the exercises in as well.

Dr. James Beck 00:45:56
Yeah, it's likely, too, it's not something you have to go to the gym to do. It's part of the process. One of our viewers, Laura, mentions this to physicians and they shrug and say it's part of Parkinson's. How do you counsel people with Parkinson's to be better advocates for themselves? Should they go see a specialist? I mean, if maybe their neurologist or their primary care physician is not—

Dr. Ankita Gupta 00:46:21
I can add something to that. Honestly, I get patients all the time that have been complaining about incontinence for decades before they got to see me. So it's not just in Parkinson's. I think it's a more general issue. At least my patients, a lot of them have been told that this is part of aging, this just happens, you learn to deal with it. And I have been doing a lot of education efforts within my community to train primary cares to send patients in earlier. But definitely advocating for yourself and saying that there are urologists who are specifically trained to help people with bladder issues, and I would like a referral, I think that's one of the best ways that you can get in to see someone sooner, because I know I love to help people who complain of this.

Dr. James Beck 00:47:13
Yeah, I didn't appreciate how extensive this is, really undertreated and perhaps underrecognized as a problem. I mean, Dr. Mahajan, you've kind of really hinted to that. So what is the—people come in at different times. You mentioned, Dr. Mahajan, men seem to just wait longer for age before they come in. Women seem to, for lack of a better word, just bear it for a longer time until I guess they can't anymore. When should people start coming in? Perhaps at the first leakage, or what's the tipping point for someone to start coming in? Is it they're getting up three or four times a night, or twice a night? How do you advise people when to start making that connection to start seeking specific help?

Dr. Abhimanyu Mahajan 00:48:07
I started my talk talking about how these are issues that don't come up in the first visit and may never come up. What I specifically do is there are a number of quality measures that I have built internally. Falls is one of them, freezing of gait, these are motor features, but then of course cognitive issues and urinary incontinence is another one. I make it a point to go over them ideally at every visit, or there are certain issues that may come up in terms of just your conversation. When I'm talking to my patients and I say, how's your sleep at night? Any difficulty falling asleep or staying asleep?

Most people would volunteer, well, falling asleep may be okay, but when I wake up in the middle of the night because I have to use the restroom, I feel like I have to help my spouse, help my care partner, because people say, well, I feel like that's when I'm going to fall. That's a segue for me to start talking about incontinence and other symptoms of incontinence, including stress and urge incontinence.

I would encourage all patients and care partners who are listening to this talk or will listen to this talk in a recorded format to think about these things for yourselves and your family and your friends. I also think that it's imperative that we talk about this amongst urologists, because these are not symptoms that we typically encounter or we typically discuss. So in a very crude, crass way, it's somebody else's problem because we're dealing with so much in terms of Parkinson's disease. But it turns out it's not. Your patient is coming to you because not only does this affect other aspects of Parkinson's disease, but your patient is your patient, your responsibility. So if there's something that's affecting quality of life, you do that.

To answer your question again in a very complicated way, I would say the first time anything like this bothers you, you need to bring it up. If you start experiencing some symptoms and you don't know what the implications of those symptoms are, it does not hurt to ask.

Dr. James Beck 00:50:20
Okay, fantastic. So a question that's come in a lot, and kudos to Wally for being the first one to ask this: how does levodopa influence the frequency of urination? How do the medications that people are taking play a role in some of the issues we're talking about?

Dr. Abhimanyu Mahajan 00:50:38
That's a very complicated question, I think, because what affects incontinence or even regular urination varies. It varies not only per person, but also by stage of disease. Early on, bladder muscles, I think I had a slide on that, the dopaminergic control of bladder muscles early on in Parkinson's is definitely affected. So once there's dopaminergic replacement, you would expect that those muscles would behave themselves a little bit better.

At least early on, I do expect that these things would improve, but there's a huge amount of cholinergic involvement with these cases as well. As the disease progresses and we see some of that cholinergic aspects creep in, even with constipation, for example, remember we talked about constipation as an aspect of pelvic floor health. Most of my patients anecdotally say, well, I have terrible constipation. Once they start taking levodopa, constipation improves. As time goes on, it becomes more of a cholinergic issue. So it depends on the degree or the stage of Parkinson's. Initially, I would expect levodopa to improve not only constipation but also bladder function. Later on, it gets more unclear.

Dr. James Beck 00:52:00
And just for the benefit of our audience, when we talk about cholinergic, what are we talking about?

Dr. Abhimanyu Mahajan 00:52:08
I mean the entire system, right? The recent papers that have tried to do this even better, but we try to group all symptoms in Parkinson's as dopaminergic, or predominantly symptoms that are predominantly affected by the lack of dopamine in Parkinson's. And then we're talking about the cholinergic system. Cholinergic systems can involve all kinds of secretions and excretions.

It can involve daytime sleepiness, it can involve your cognition, etcetera, and all those are more likely to be affected by acetylcholine and not dopamine. Although, of course, as with everything, there's some interplay between them. Early on, a number of these symptoms seem to be more affected by the dopaminergic system. So levodopa should improve your bladder function to some extent, at least early on.

Dr. James Beck 00:53:01
Thank you. That was a great response. As I think about some strategies to help manage these, I think we laid out some nice approaches for exercises, potential medication. And quickly, I assume the Botox approach works for men as well. Is that an in-office approach? Yes, a little longer urethra in order to traverse, but presumably works great. Excellent.

What about hydration? I think that's something that's an issue that cuts both ways. Sometimes elderly don't drink enough as it is and they're dehydrated, and we don't want them to not drink at all to avoid these bladder issues. But what's the approach? How do you counsel people with Parkinson's?

Dr. Ankita Gupta 00:53:46
I think that's a tricky piece of it because often I'll get patients who, in order to hydrate, are drinking 100, 120, 140 ccs of water per day. I think that's where the bladder diary is really helpful because tracking to see what you're drinking and where you're voiding in association to that can be really helpful. It's not just about how much you're drinking, but also what you're drinking. Definitely water is really helpful, but if you're drinking a ton of soda or carbonated beverages or caffeine, all of those are known diuretics, and all of those make you void more. It's also a matter of when you're drinking it.

If you're drinking a lot of fluids right before you go to bed, you're going to wake up to void. One of the first-line things that we talk to patients about is trying to restrict fluids to 60 to 80 ounces per day and consuming that mostly about two hours before bed. Again, not drinking a lot of fluids before bedtime to prevent that nighttime waking up to void.

Dr. James Beck 00:54:48
Yeah, it sounds like it's also maybe part of the training the bladder approach. Oh, go ahead. Yes, please.

Dr. Abhimanyu Mahajan 00:54:54
Yeah, I think this is where the focus of the neurologist may slightly differ from the urogynecologist. I have a huge bias, and this is an evidence-based bias, so I guess it's not biased, against dehydration or not drinking enough water. I think it's one of the lowest-hanging fruits for our patients to do much better in pretty much any aspect of Parkinson's disease, be it cognition, be it constipation, what have you, general quality of life, all of it. Falls.

What I typically do, the way I approach it is, I spoke to a number of my colleagues in nephrology, and if you talk to nephrologists, they will tell you that you need to be drinking two liters of water a day. I mean, that's their standard response to pretty much anything. Two liters of water a day. They're not wrong. So what I typically say, of course it depends on your body mass index and things like that, but what I typically say is that aiming for about a liter and a half, which is about 48 ounces, is not a bad idea - of water.

Now, the question is, if you're drinking 120, 200 ccs a day and you have to go to a liter and a half, the first few days, the things I counsel patients on is, one, for the first few days, your kidney is going to be working overtime to recalibrate itself. So you will pee more. Don't be alarmed by that. This is expected. The second thing I tell them is the approach that seems to work the best is you wake up in the morning, you have a half-liter, 500 cc glass of water next to you, you drink the entire thing. That takes away a third of your requirement for the day.

And the third thing I tell them is, if you depend on your brain's ability to tell you when you're thirsty, you're going to be dehydrated. So get a bottle of water which is 750 mL or a liter, fill it up, and sip on it throughout the day, ideally most of it before 4 p.m. If you do that, chances are you won't wake up in the middle of the night and you still drink enough water. And of course, if they still have neurological, urogynecological issues, I do refer them to my colleagues as well. This way, you get the best of both worlds.

Dr. James Beck 00:57:09
That's fantastic. We're coming towards the end of our time. Dr. Mahajan, Dr. Gupta, thank you very much for sharing your knowledge today on our expert briefing about Parkinson's disease and the bladder. I also want to thank every one of you who joined us today. We had a significant response during our Q&A, and, last week, we were not able to address all the questions. But please, if your question was not answered, call our Helpline, 1-800-4PD-INFO.

I'd also like to note again, this is our fourth episode of our 14th season. We've got two more left for this year. They're listed here on the side on the 11th and the 8th. Parkinson's and the gut-brain connection; here we can maybe address some of the interesting aspects of the microbiome. And then, what about hallucinations and delusions in Parkinson's disease? You can learn more and register at Parkinson.org/ExpertBriefings, and that link will be posted in the chat.

Also, I just want to remind everyone, we have lots of resources at our organization that are available. We have our Aware in Care kit about hospital safety. We have a library of extensive materials about issues around bladder health, as well as eating and other things along those lines, as well as our regular series of our PD Health at Home series, which has a number of virtual events.

We also have podcasts every Tuesday, Substantial Matters, professional education. And last but not least, I'd like to just mention again PD GENEration, which is our free opportunity to get genetic testing and counseling to understand if you may have a genetic link to Parkinson's disease. You can learn more about that at our website again, Parkinson.org/PDGENEration.

I wish we had time to answer all your questions, but again, reminder, 1-800-4PD-INFO or our Helpline at Parkinson.org as part of that. Our Helpline is staffed by Parkinson's professionals. These are really dedicated colleagues who can really help answer almost all types of questions. I really encourage you to reach out to them.

But before you go, this is the Zoom world and the screen's just going to turn black, but a webinar like this is important. It requires a community to put it together. So a survey will come up at the end of this, and I want you to please take some time, let us know your thoughts of this, give us feedback. This is how we improve our webinar series and are able to provide the feedback to our speakers as well. I encourage everyone to do that when this ends. So this is it for today. We'll see you again in October. Please take care, and I'll talk again at our next expert briefing again very soon.

Dr. James Beck 00:00:00
Hello everyone and welcome to Expert Briefing. I'm Dr. James Beck, your moderator and Chief Scientific Officer of the Parkinson's Foundation. With this, our third Expert Briefing, we are halfway through our 14th season and we're geared to have a great discussion today. Our topic for today will be centered around understanding gene and cell-based therapies in Parkinson's. So while still in the developmental stage, genetic and cell-based therapies are or soon will be entering clinical trials. These therapies are moving forward because they may hold promise for people with Parkinson's disease. The goal of clinical trials is to understand if that is indeed the case.

We will be reviewing what we hope to expect from these therapies, both in terms of symptom management and disease progression. Before we begin, I'd like to share a little bit about the Parkinson's Foundation. The Parkinson's Foundation is a nonprofit focused on bettering the lives of those living with Parkinson's through improving care and advancing research. Importantly, everything we do is in close concert with our community to ensure that our actions are aligned with the needs and priorities of those living with Parkinson's disease. We're focused on improving care for those living with PD, advancing research towards a cure, and empowering our global community much like we're doing today with our expert briefing.

We have listeners from 22 countries across the globe today, and I want to take a moment to acknowledge this connection and celebrate that our community is coming together in education and engagement. Thank you all for continuing to show up for yourselves and for our community. Feel free to share where you're joining from in the Q&A below, and we'll keep track of that. Before we begin, I'd like to get a sense of where people are, and who they are. So, you'll see a poll just launched and tell us whether you're a person with Parkinson's, a spouse, partner, physician. And if you're joining us from Facebook Live, please respond using the comment section as part of that.

This will tell us what best describes your connection to Parkinson's disease. And we'll be closing this poll in just a few seconds to understand where you are as part of that process.

Okay. Results are in, and not surprisingly, many people here are living with Parkinson's, and many care partners are here as well. We have other family members and a fair number of health professionals are joining us today too. That's fantastic. So thanks to everyone for sharing your connection to Parkinson's. Today's expert briefing is supported by Prevail Therapeutics and the Light of Day Foundation. We want to take a moment to thank our sponsors for supporting the mission of the Parkinson's Foundation through unrestricted educational grants. And then next, I'd like to say for your convenience, we're recording today's Expert Briefing and the recording will be made available on our website, Parkinson.org/ExpertBriefings. 

Dr. James Beck 00:02:46
We'll also be emailing a link of the recording and other resources related to today's topic to all who've registered for today's briefing. So no need to worry about that. But feel free to let your friends know if they missed it today that they will be able to watch a recording of it soon. So now, I'd like to introduce Roger Barker. Dr. Roger Barker is a professor of clinical neuroscience at the University of Cambridge and consultant neurologist at Addenbrooke's Hospital. There, he runs the regional NHS Huntington's Disease and Parkinson's Disease clinics. Dr. Barker is also the lead academic scientist of the Drug Discovery Institute in Cambridge, as well as a principal investigator at the John van Geest Centre for Brain Repair. Dr. Barker's research investigates the heterogeneity and its basis in both Huntington's and Parkinson's disease. This has informed his work on studies of new experimental therapeutics for these conditions including cell and gene therapies as well as drug repurposing. So in addition to numerous professional achievements and activities, Dr. Barker is currently running two gene therapy trials for Parkinson's, a fetal dopamine cell transplant trial called TRANSEURO, and he's now just started a new trial with a team in Sweden using stem cell derived dopamine cells called STEM-PD. Clearly, he's well positioned to talk with us today about cell and gene therapies. So Dr. Barker, welcome, and thank you for sharing your time and knowledge with us today.

Dr. Roger Barker 00:04:04
Well, thank you very much. I'm now going to share my screen and I hope that everyone can see my slides in the right format. Thank you very much, Jim, and thank you very much for inviting me to talk. What I thought I would do is I thought I would start off by just introducing a little bit about where cell and gene therapies fit among the new therapies relating to Parkinson's disease. Then I'm going to walk through gene therapies and what they're designed to do and how they're working and where we've got to with trials before going into cell therapies and then concluding a little bit about how we might combine these and thinking about how to use them, in the future.

Just to begin with, my disclosures, I advise a number of companies mainly around cell and gene-based therapy as well as patient-related outcomes, which have become quite an important area for us to investigate not only established therapies but novel therapeutics.

To begin with, I wanted to talk about how do we think of Parkinson's? This is a very simplistic view, but essentially if we think that in Parkinson's, there's a genetic predisposition to the condition that in some way leads to a change in this protein called alpha-synuclein, which then either spreads, causes inflammation, the aggregation of this protein alpha-synuclein, which is a normal protein in everyone's brain, one percent of our brain is alpha-synuclein, but when it starts to aggregate, it causes problems within the cells. Those cells then die, and when a significant number of those cells have died, people start to present with features of Parkinson's.

This is a very simple cascade in which to sort of simplistically think how Parkinson's might come about. But it does help inform us about how people have thought about it therapeutically in terms of novel therapies. So, I don't seem to be advancing my slide. There we go. So, one way is obviously to improve the sort of symptomatic treatments and some of the complications we see in terms of levodopa induced dyskinesias. There are developments of new therapies around that.

There are better ways in which we can deliver deep brain stimulation now, so-called closed loop, where it can learn what's happening in the brain and control the stimulation that's given to the brain and regulate some of the problems and treat better some of the complications we see.

There's also, as you will know, attempts to try and reduce the production of alpha-synuclein. If you produce less of it, less of it will aggregate, will that slow down the disease? This is done by either targeting the production of alpha-synuclein through interfering with its pathway, a so-called antisense oligonucleotide binds to the connection between the gene and the protein, and beta agonists, the salbutamol and other things which are used in asthma. There's some association between that and alpha-synuclein production which people are looking at. There are ways of trying to stop the spread of alpha-synuclein as it moves from one cell to another. This is a very popular hypothesis at the moment.

Dr. Roger Barker 00:06:59
So could we develop vaccines either active immunization or passive immunization to stop that. There is a lot of drug repurposing, so agents which are in current clinical practice for one indication; could we use them for another? In this case to slow down Parkinson's disease around different pathways. That includes stopping inflammation. I'm going to talk about gene therapies around mainly replacing lost dopamine, either in terms of replacing dopamine or regrowing the pathway, but there's also new gene therapies which are coming to clinic around trying to slow down the disease.

I'll talk about growth factors and then finally talk about replacing the lost cells, which is really what I'm going to talk about with cell replacement therapy, the strategy here being to replace the missing dopamine cells that lie at the heart of the condition. Now it's important, I think, to get this global view because you have to position cell and gene therapies in the landscape of what else is out there and as I will come to at the end, they are not mutually exclusive. So all of these therapies in the future could be combined to treat people with Parkinson's. But if we now sort of think about gene therapies for Parkinson's disease, what has been the strategy that people have taken? Well, one approach is to regrow and rescue the dopamine system.

The idea here is that we give a growth factor or fertilizer to the dopamine system. We inject it into the brain and the idea is that the gene which is put into the brain will infect cells in the brain. Those cells will secrete a factor which basically is a fertilizer to regrow the dopamine system, which exists in the brain. So it's not it's not replacing it, it's simply trying to regrow and preserve what's already there. The second strategy which works on a slightly different principle is to say, well, actually, I'm not going to worry about that system that's there. I'm going to assume that that's dying and going.

Can I just put in a gene which will infect cells and those cells will now become little dopamine factories. So I will simply, instead of giving people tablets, I will convert a bunch of cells in their brain to be little dopamine factories to produce dopamine in the brain at the site where I need it. So these are gene therapies which are designed to transfect cells and turn them into dopamine producing cells. And then the final approach, which is as I say, a relatively new approach, is actually put in a gene therapy which is designed to affect the disease pathway, interfere with it, and by so doing,

They can actually slow down the disease process. So truly disease modifying, whereas the others in some ways are more around symptomatic therapy. So those are the three main strategies that have been taken forward with gene therapies for Parkinson's. And this has been going on for about 20 years. So although it's still experimental, it has been around for a while. And the first place where I'm going to start is with the idea of rescuing or regrowing the system. This really became very much a topic in the last end of the last century.

Dr. Roger Barker 00:10:02
And in 1993, a sort of seminal discovery was made that there was a factor called GDNF, glial cell line-derived neurotrophic factor, which was discovered to actually be extremely powerful at regrowing dopamine nerve cells, at least in the lab. And this led to a whole series of trials where people had GDNF, which I'm sure you're familiar with, where GDNF was actually infused into people's brains to try and regrow that system. And that had a sort of checkered history and ultimately it's still unclear whether it works. But linked to this was a gene therapy program which worked on the same principle.

And that was with a gene therapy called neurturin. So neurturin is related to GDNF, it's similar, but it's not perhaps quite as powerful. And the idea here was to take a GDNF-like substance, i.e. Neurturin, connect it to a gene, which is what the AAV2 stands for in that title of that slide, which is an adeno-associated virus, it's a type of virus which is commonly used to infect cells. And then the idea was to inject it into the brain at the site where dopamine is normally released, which is in the bit of the brain called the putamen. And if we inject the gene with the growth factor there, the cells will take up the gene, they'll secrete the growth factor.

That will then promote the growth of the dopamine fibers which are innervating that part of the brain. And so this went to a double-blind placebo-controlled trial, by which I mean that patients were randomized to either have the active treatment or imitation surgery. So they went to theater, they had a hole drilled in their skull, they had the entire procedure done, except nothing was actually injected into their brain. The only person who knew whether anything had been given would be the surgeon. The patient would not know, neither would the physician who was assessing them.

And essentially what this trial showed was that at 12 months, there was absolutely no difference between those that had had neurturin gene therapy injected into their brain versus those who had not. All of the patients seemed to improve to some extent, but being given the gene therapy didn't seem to give you any added benefit. In other words, there didn't seem to be any significant therapeutic benefit for this therapy. At 12 months, everyone was told what they had and then they were followed up for another six months and at the end of that time, 18 months after they'd had the original intervention, interestingly, people who had actually had the active treatment seemed to be doing slightly better.

So that then led people to think, well, perhaps this trial didn't work because we didn't give enough of it at the right sites, and we didn't wait long enough. So a second trial was done, which worked on the same principle, except now that the growth factor attached to the gene was injected into the area where dopamine is released, the striatum, and where the dopamine nerve cells live in the substantia nigra. So they had injections at two sites and they waited for two years. And the outcome of that study, which was published a number of years ago, unfortunately showed there was no difference between the two groups.

Dr. Roger Barker 00:13:05
So using this particular gene therapy approach with a growth factor, it appeared in two trials that actually regrowing the dopamine system whilst in principle a good idea didn't produce any therapeutic benefit. So that then sort of suggests, well, actually this is probably not a useful way forward and that might be a very sensible conclusion to come to. It also sort of resonated a bit with the GDNF infusion studies which tended to show similar results.

We a number of years ago actually, I think it was about, it was pre-COVID, so it's 2019, I think or '18, we held a meeting in Grand Rapids where we brought together all the groups who worked on, GDNF and neurturin to revisit this area to see if we could learn anything from the trials we'd done. And we summarized this in a paper that published in the Journal of Parkinson's Disease. And what we actually came to the conclusion was that whilst these trials didn't give us any convincing evidence that this strategy worked, there were also reasons to believe that it could be improved upon. And one of the areas which we felt that was particularly attractive was the idea to go earlier in the disease course.

And the reason for that is if you look at the number of dopamine fibers in the Parkinson brain as a function of disease duration, within the first one to three years, one still has quite a lot of dopamine fibers existing in the site where the growth factor has been given. After three years, it declines quite rapidly and by five to fifteen years, which is when most patients were entered into this trial, there's almost no dopamine fibers there.

The consequence of that is, if you're putting in a growth factor into an area that has nothing to grow, it's not going to work. And so the analogy I have is you could have the best fertilizer in the world, if you put it on a flower bed with no bulbs in it, nothing will grow. And there's nothing wrong with the fertilizer, there's just nothing there for it to rescue and grow. We feel that if this therapy is to be taken forward, it needs to be moved to an earlier stage of disease. And there are other operational aspects of it which I think also need to be considered. This having now been taken on board, there are gene therapy trials that are now moving forward with GDNF. So uniQure are doing one.

In the UK Parkinson's UK are looking to do a protein infusion, not gene therapy. But Bayer have started a new trial, not using neurturin now but going back to the original GDNF to inject that into the brain with a gene therapy. So gene therapy and growth factors for Parkinson's so far have been a little disappointing, but nevertheless they're back in the clinic and people are rethinking how to administer them. The second strategy around gene therapy is not to try and regrow the intrinsic network but simply to put in a gene therapy that will infect the cells in the brain.

Such as the astrocytes or the glial cells, the non-nerve cells, and give them the capacity to make dopamine. And there are a number of different ways in which they've done this. One is to give the cells the synthetic pathway for dopamine in its entirety. Others did this to give enzymes which only mediate aspects of that pathway and then give people medication which can then be used to convert it into the active agent. This has been the subject of a number of clinical trials and I have been directly involved with two of these.

Dr. Roger Barker 00:16:29
The first was this gene therapy trial that began by Stéphane Palfi in Paris in France and we were then involved towards the end of it in Cambridge in the UK called ProSavin, which led to a second gene therapy trial that we're involved with which only took place in the UK, which was the SUNRISE therapy or OXB-102. The ProSavin gene therapy, which is where I'm going to begin, which was run with my colleague Phil Buttery in Cambridge, involved injecting a different virus, a lentivirus as it's called.

It infects cells, and within that gene therapy are the pathways for making dopamine. They contain the enzymes for making dopamine. And essentially what we did is we looked at different doses, different ways of delivering it, and had this sort of iterative process by which it was delivered. And it was delivered in one single operation on both sides of the brain into the area where dopamine is normally released. The idea being, as I say, to infect that area so it could now produce dopamine from the cells within it. And what we found using three different doses of this agent delivered in slightly different ways was that it did produce a benefit.

So it definitely had some benefit and was relatively safe. The major side effect we saw were actually dyskinesias which could be a sign of efficacy. But ultimately, whilst we saw a signal of effect, it wasn't of a magnitude that made it competitive. So compared to things like DBS and other treatments, it was not as effective. So Oxford Biomedica went back to the drawing board and came up with a new gene therapy called OXB-102, which was then taken on by Axovant who then sold it to Sio Gene Therapies.

And this was a study which was to have three cohorts, of increasing doses. And we treated four patients in Cambridge and two in London, and then unfortunately the company Sio Gene Therapies decided that for financial reasons they would not pursue this therapy further. So they, aborted the trial at this point, stopped the trial at this point, and basically gave the license back to Oxford Biomedica who are currently, not developing this therapy. So unfortunately, we're in a position where we're halfway through or two-thirds of the way through a trial.

And we don't really know, what to make of the data except that the patients we've seen, at least in Cambridge, one of them has stabilized. In London, some of them have gone on to get deep brain stimulation. So, what we can only conclude from this is that there appears to be some stabilization, but it's hard to draw any firm conclusions.

In parallel to these studies which were done by Oxford Biomedica, Voyager Therapeutics in the US were running a trial where they only used one enzyme associated with making dopamine. They did this again in a sort of iterative way, much the same way as we did in the ProSavin study where they gave different doses to different groups of patients, the idea being, can we give more gene therapy, bigger volumes, fill up the area where we're trying to affect the cells and get a bigger response. And that's what they found is that the more they gave, the more they infected the area they were interested in, and the bigger the response they saw.

Dr. Roger Barker 00:19:51
Unfortunately with this study, they also saw some signal changes on the scanning which they weren't quite sure what it meant. They reported that to the FDA and that trial as far as I know has also been stopped. And again, there's no indication that that's been taken on, except in rare cases of children who have very specific genetic forms of Parkinson's with specific enzyme deficiencies where obviously this therapy would, you would predict, have a major benefit. And that indeed has been what was shown in this paper that appeared a couple of years ago.

So overall, I would say that dopamine gene therapies have yet to be shown to really work, but part of the problem is that the investment in this area has slightly nosedived for reasons that's not clear to me anyway. So I don't think we can come to any firm conclusions because in theory this approach should be a sensible and good way to go forward. Now more recently, and including our sponsor for tonight, Prevail, there are two new sort of gene therapies which are coming forward. One is in the clinic and the other is hoping to come to clinic, I think next year or the year after. There may be others, but I don't know.

These are the two that I do know about. So Prevail is working on the assumption that the commonest genetic form of Parkinson's disease or the commonest gene associated with Parkinson's disease is this mutation in one of these genes associated with Gaucher's disease. So I'm sure many of you are very familiar with this. It's called the GBA gene. People with Gaucher's disease have two mutations in each of their genes which gives them Gaucher's disease. About 10% of people with Parkinson's disease have a mutation in one of those genes and that seems to predispose them to getting Parkinson's disease and also seems to predict that they might follow a more aggressive disease course.

This was first picked up by Ellen Sidransky many years ago. We did a study looking at that population in Cambridge and found that five to ten percent of people with so-called sporadic disease, no family history, sort of fairly standard presentation, had this GBA1 mutation. And what we found when we followed these people up long term was it did seem to influence the disease course.

Now, the GBA gene codes for an enzyme called GCase, and so if you have a mutation in this gene, one of the assumptions is that your enzyme activity drops down, and so you have low enzyme activity, and the low enzyme activity not only predisposes you to getting Parkinson's, but once you've got it, it speeds up the disease course. Ergo, if I want to treat it, why don't I put back a gene or put back the enzyme activity? So in Gaucher's disease, that's been done for many years, but that's done with enzyme replacement therapy, which sadly doesn't get into the brain. It can help the problems in the periphery but not in the brain.

There has to be a way of putting the enzyme back in the brain, and one obvious route to do this is with a gene therapy. So Prevail have this trial which is up and running called Propel, where the idea is actually to inject this gene therapy into patients with GBA1 Parkinson's disease. And really at this stage, the idea is to see whether it's safe, which is what you do with all of these first in human studies.

Dr. Roger Barker 00:23:12
They're using some immunosuppression because there is some inflammation with this particular gene therapy and they want to look long-term to see whether it's safe, whether it's well tolerated, how much of an immune response does the patient generate to it, and have some preliminary idea as to whether it's slowing down or having some effect on the disease course. This has just begun and obviously if this was to work, then it would lead to bigger trials and it may be appropriate for large numbers of patients with Parkinson's disease. Now, there is a second trial which is still in the sort of preclinical stage, i.e., hasn't actually gone to clinic yet.

Based on a rare form of Parkinson's related to Parkin. This is typically found in very young people. It doesn't tend to associate itself with the Lewy body pathology you see in people with normal Parkinson's disease, if you like. And it's thought that this problem with Parkin relates to getting rid of the powerhouses of the cell, the so-called mitochondria. There's been a lot of interest in how this informs us about parkinsonism and it's probable that whilst parkinsonism is a distinct entity, parkin is also probably involved in sporadic Parkinson's disease.

There's a company that's working on this particular approach to try and develop a gene therapy which puts back Parkin into the brain. The idea in the first place would be to target people who have no Parkin in the brain, i.e., the patients with the genetic form of it, and then the hope would be if that's shown to be safe and effective, would it have some benefit in people who don't have the genetic form of it. So that's currently in the preclinical space but nevertheless is moving towards clinic in the near future. So those are new approaches with gene therapy which are designed to slow down the disease course.

So gene therapy is just to summarize, they can work on trying to rescue the dopamine system, replace dopamine by infecting other cells in the brain so they produce dopamine, or now moving toward giving a gene therapy that gets into the pathway which drives the disease and slow down the disease itself. An alternative approach, is to actually simply use cell therapies. And what I'm really going to talk about with cell therapies is the idea that you replace the cells that are lost.

In Parkinson's disease. So in your substantia nigra, you have about 400 to 500,000 dopamine cells, and when you've lost half of those, about 200,000 on each side of the brain, you develop the features of Parkinson's, at least the motor features. So what the argument would be is we know dopamine therapies work very well for people with Parkinson's, they have problems, they have off-target effects and in the long term they create complications. But wouldn't it just be simpler, isn't a simpler approach to take people with Parkinson's and just replace their defunct and lost dopamine cells with a whole bunch of new dopamine cells, inject them into the brain where dopamine works?

Dr. Roger Barker 00:26:16
That would have the benefit that I could put dopamine back where it's needed. So you don't with the tablets have all the problem of dopamine drugs stimulating dopamine pathways which are still intact, so you get overstimulation. And secondly, if I put the dopamine cells back as nerve cells, they release dopamine in the normal physiological fashion, so I won't get levodopa-induced dyskinesias. The promise of this therapy is if I put it in, it's a one-off treatment, you would get the maximum benefit that you would see with your dopamine drugs with none of the long-term complications.

You would not be curing people of the condition because the condition carries on, the alpha-synuclein aggregation, but you would be repairing and treating this aspect of the disease. And in that sense, it could be disease-modifying because people forget, I think, that before levodopa came into clinical practice in the 1970s, most people with Parkinson's disease wouldn't live beyond five or ten years, whereas now, of course, people live in the community actually a sort of normal life with Parkinson's disease. This is the strategy that we're interested in. So then the next question you would have to ask is, well, if I'm going to replace the dopamine cells, what could I replace them with?

So where can I find a midbrain dopamine cell of the type lost in Parkinson's disease? Well, one approach is to go and collect them from human fetuses. So women who have termination of pregnancies, abortions, you collect the fetal material that's been aborted, you dissect out the area of the brain that contains the developing dopamine cells, and you use that as your source for transplanting into the brain. And I'll talk briefly about what those trials have shown, which have been going on since the late 1980s.

An alternative which only became possible in 1998 and more recently into 2007 with development of technologies for making human stem cell sources was the capacity to take a human stem cell and turn it into a dopamine cell of the type lost in Parkinson's and use that to transplant it into the brain. So a stem cell, just to sort of remind you, is a cell that divides indefinitely, so it will carry on dividing forever. And what happens is a stem cell will divide, one of those divided cells will be a stem cell which will divide again.

And then what you can do is you can take those cells and you can persuade them to turn into a cell type of any sort. This has been considered for people with diabetes, making islet cells, for repairing the eye and such like. So so there are all sorts of hopes for stem cells and of course they've been used for years in the clinic for people with blood disorders because your bone marrow contains lots of blood cell stem cells. Now, the types of stem cells you have, which I'm going to be talking about, and only talking about, are embryonic stem cells. So these are the stem cells that come from spare embryos in IVF programs.

And currently, BlueRock Therapeutics in New York are using and have done a clinical trial using embryonic stem cells using a particular cell line. The stem cell trial that Jim mentioned we're doing called STEM-PD is using a cell an embryonic stem cell line from Scotland. And Novo Nordisk who we work with are planning to do clinical trials with the same embryonic stem cell line as ourselves. These are called allogeneic, I e they would be like having an organ transplant from an unrelated person. So a standard kidney or liver transplant would be so-called allogeneic.

Dr. Roger Barker 00:29:46
It's from another human, but it's not someone who is related to you. Now, induced stem cell sources came about when Shinya Yamanaka developed the technologies to take an adult cell, like an adult skin cell or an adult blood cell, and convert it into a stem cell. Once you've got the stem cell, you could then persuade that stem cell to become a dopamine cell. And so this offers the potential that you could use the patient themselves as the source of the cells. You take the patient's own skin cell, convert it into an iPS cell, induced pluripotent stem cell, and then you convert that into a dopamine cell.

And that's been pursued by Aspen Neuroscience in California, and has also been the subject of a case report of a single patient transplanted in Mass General and Harvard Medical School. The alternative is to make an induced pluripotent stem cell from some other person and then convert it into dopamine cells and then graft that in. So again, that's like an embryonic stem cell that's not from the person itself, so it's not autologous, but it's from another human, and that's called allogeneic, and that's been pursued in Japan, in Kyoto. It's also going to be the subject of a trial at Arizona State University in people with Parkinson's/parkinsonism.

And FUJIFILM Cellular Dynamics in Chicago have also been looking at this therapeutic approach.

If we just look at human fetal dopamine cells because I think it's been useful, to just see what's been achieved by this whole approach. Just to remind you, the idea here is I'm going to replace the lost dopamine cells that you see in people with Parkinson's disease with a replacement collection of dopamine cells which have been harvested from aborted fetuses. And what's happened with this has been somewhat controversial outside of the ethics. The results have been a bit variable. But importantly, it's shown a proof of principle, namely when it works, it can work extremely well.

The principle of using dopamine cell replacement has a precedent. There are two patients for example in the UK who went to Sweden. They had Parkinson's disease for 10 years, they had fetal dopamine transplants put into their brain and then they were followed up for the next 20 odd years. And on this slide, although it's a bit difficult to see, what happened was that these patients, who have now died because they would now be in their nineties.

Thirty years more or less after they had Parkinson's disease diagnosed, they have a motor score on a standard rating scale, the Unified Parkinson's Rating Scale, which is the same or less than when they first presented thirty years ago, and they are on no medication. So that is a striking clinical response. On imaging of their brains, they have normal dopamine levels in their brains. A patient in Sweden had a transplant on one side of the brain. They did extremely well. Sadly, they went on to develop a Parkinson's dementia. But when they died, they harvested the brain from that patient.

And in that particular patient, on the side where they had the transplant, which is the brown on this slide, every bit of brown you see on that slide is a surviving dopamine cell and fibers growing out of it. This showed that a quarter of a century after you put cells into people's brains, they could survive and innervate the brain. So they have long-term clinical benefit and they can survive long-term. But as I say, not all studies showed this. There were two studies that were done in the United States funded by the National Institutes of Health, which were published in 2001 and 2003.

Dr. Roger Barker 00:33:24
In these studies, patients had sham surgery, so some had no implant. In the first study, they had a small implant. In the second study, the double-blind study at the bottom, they had a small implant or a big implant. And essentially what this showed was that in this study, when you asked the patient a year after they'd had the transplant and measured them on a standard measure, putting fetal dopamine cells into their brain made no difference. And actually, some of the patients were now developing side effects which were these involuntary movements associated with the transplant. In the second study, which published two years later,

There were 34 patients. A third had no transplant, a third had a small amount of tissue and a third had a large amount of tissue. And at two years, there was no significant difference between the groups. In other words, there was no benefit from having the transplant. Interestingly, these patients received immunosuppression for six months after they had the transplant and then it was stopped. And if you look at the graph at the bottom, you can see that the grafted groups were actually improving up to that point and then that benefit was lost, which might imply that the transplant was actually being rejected and that's what caused the loss of the efficacy.

Worryingly, in this study, half of the patients now developed graft-induced dyskinesias, which were so severe in a few patients, they had to go on and have deep brain stimulation. The consequence of this is we have these individual patients in Europe who seem to have done extremely well, and we have these double-blind placebo-controlled trials in America which showed that it didn't really seem to work in slightly larger numbers of patients. The question is, well, how could you actually reconcile this data? We set about trying to do a meta-analysis about 10 or 15 years ago now to try and analyze all of this. And we collected all the data from all of the studies that we could.

And what we found was that there are a third of patients who have had fetal dopamine cells put into their brain who've had a very significant improvement. So on this graph, it's two years after you had a transplant, a 33% improvement in your motor measures. So a third of patients seem to derive a benefit, two-thirds do not. That's not a therapy we can take forward unless we can understand what it is about the third who do extremely well. We tried to analyze this and came up with the conclusion that actually younger, less advanced patients seem to do better. It seemed to have a lot to do with how you prepare and implant the tissue.

As I've already intimated, the amount of immunosuppression after you've grafted to stop the cells being rejected seemed to be important, and long-term follow-up seemed to be important. And it was on that background that we then, received funding from the European, Union to do a study called TRANSEURO, which was to graft a large number of patients in the original, plan, with fetal dopamine cells. And we still have yet to finalize analyzing all this data, but essentially what we found in our study to date is that the use of the fetal dopamine cells did have some benefit on the patients. There was some stabilization of their disease.

Dr. Roger Barker 00:36:33
It varied a bit from site, so eight patients were grafted in the UK and three in Sweden, and we used different devices in those two sites, and there's some suggestion that the devices were rather important. But overall, we didn't see a major benefit. And I think that relates to the fact we gave fewer cells than we should have done, or less than was needed, and that the device seemed to cause problems in terms of survival. However, a more fundamental problem arose in this study, in that it essentially took us eleven years to graft eleven patients. And the reason was we simply could not get enough fetal dopamine cells.

In the time it took us to graft 11 patients, we had another 87 transplant surgeries booked that we couldn't actually use because we didn't have enough tissue. If this therapy is ever to go forward, we're going to have to use a stem cell source. And as I've said, there are lots of stem cell sources out there. The real breakthrough in this field came in 2011 and 2012, when two teams — Lorenz Studer and Viviane Tabar's team in New York, and Malin Parmar's team with Agnete Kirkeby in Lund in Sweden — both developed a technology and a technique that enabled you to take human stem cells and turn them into the midbrain dopamine cells of the type lost in Parkinson's disease.

That has now led to a whole series of trials, which I've already briefly alluded to with the different cell sources. The trial in Japan, using induced pluripotent stem cells not from the patient but from another human, so allogeneic, began in 2018, and they have grafted, I think, seven patients, so we're keenly awaiting the results of their study. The group in New York grafted their first patient with their embryonic stem cell-derived dopamine cells in May of 2021 and their last patient in May of 2022. They're hoping, I think, to publish some preliminary data on what the trial has shown, primarily around safety, at the end of this year.

There was a group at Mass General where they did an autologous iPS. This was a patient who provided their own cells, and this was published a couple of years ago. This was an individual patient. They took the patient's own cells, turned them into stem cells, turned them into dopamine cells, and tested them to check they were safe in animal models. This is one of their studies that was in the paper. The cells do survive, perhaps not optimally, but still, they were surviving.

The patient was then grafted in two different operations, one side of the brain and then the other, with their own stem cell-derived dopamine cells. On the scanning, there wasn't any significant change in the imaging. On the clinical measures, there wasn't any major change, but the patient's quality of life dramatically improved. For whatever reason, this patient felt that the therapy had dramatically improved their condition. What was important for the field is it was shown to be safe. There were no major side effects from this.

Dr. Roger Barker 00:40:05
The trial in Japan, as I said, began in 2018. We're awaiting the results. The trial in New York began in 2021, and we hope to hear something more of that later this year. The group at Mass General have already published their single case. Our own trial in Europe, which is a joint trial between ourselves and Malin Parmar's group in Lund — she's the overall PI of the study — actually began in February this year. We grafted our first patient in February of this year and our second one in March of this year. The next two will be in September, and the last four will be next year.

This study, which is called STEM-PD, is a rather complicated slide just showing essentially what we're planning to do. As with all of these studies in first in humans, the primary objective, the primary aim of this study, is to show whether it's feasible. Can we actually do it? How well tolerated is that therapy when we put it in, and is it safe? Does it not turn into anything we don't want it to turn into? Then there's a whole series of secondary objectives around whether we've got any signs that it might be doing any good. On the back of this, Novo Nordisk, who we work with, a big pharma company, are keen to develop this up and do a global trial around this whole strategy.

Essentially, dopamine cell therapies have been through a very long history of great optimism and pessimism. I think buried in that is proof of principle that they work. The challenge will be getting it to work consistently with a big enough response that makes it competitive.

In the last few minutes, I just wanted to talk about three other ways in which people are thinking of how we can take cell therapies forward or gene therapies forward in Parkinson's. One is the idea that instead of just turning the cells which I began with into little dopamine factories, why can't we convert some of the cells in the brain directly into dopamine nerve cells themselves? Can we persuade non-nerve cells in the brain to become dopamine cells by injecting factors? This has been the subject of a number of preclinical experiments. Ernest Arenas published this a number of years ago.

Dr. Roger Barker 00:41:56
There was this very exciting paper in Nature three years ago, which seemed to show it was relatively straightforward, but a subsequent follow-up paper showed that there were issues around exactly how efficient this worked and whether there was a problem in the way they were labeling the cells. At the moment, this is a very exciting area, that we could actually reprogram cells in the brain directly into dopamine cells rather than transplanting new ones, but at the moment, that's not very efficient, and so we still need to work on that.

A second strategy is to combine growth factors, as I've already talked about. Use a gene therapy that produces a growth factor, such as neurturin or GDNF, and implant cells so you get more cells and you get them to survive better and innervate better. This has been particularly taken on by Lachlan Thompson and Clare Parish in Australia, and they had this paper showing that it worked extremely well in their animal models. This could be another way forward, that we combine gene therapies with growth factors, as well as cell therapies, to try and maximize the benefit from both, rescuing the host system, rescuing our transplants, and having a more efficient way to repair the brain.

Finally, one of the attractions of stem cells is that you can engineer them in ways that might be helpful therapeutically. One such way, as I mentioned right at the very beginning, is the idea that Parkinson's may be related to the spread of alpha-synuclein, and some of the transplanted cells in patients who've had neural transplants have shown alpha-synuclein pathology. How could we prevent that in the future? We could make a stem cell that doesn't have alpha-synuclein in it. We therefore could make dopamine cells that don't have alpha-synuclein. If we transplant them into the brain of people with Parkinson's, they will turn into dopamine cells, but they could never ever die from an alpha-synuclein pathology because they simply don't have the protein there that would allow them to do it.

The alternative way you could engineer cells is to try and get rid of the parts of them that the immune system doesn't like, which makes them immunogenic. You can knock out aspects of the cells that drive the immune response to them and therefore drive the rejection response. We and many others are working on making these so-called universal cells. Gene editing, as I say, may be a very useful way of taking these forward, and we may even be able to gene edit cells to regulate how they release dopamine and such like.

Dr. Roger Barker 00:44:26
There's great potential, but we need to get past base one, which is to show that stem cell-derived dopamine therapies are safe and have some signal of efficacy. To conclude, can we rescue and regrow the dopamine system? There is still some interest with using growth factors like GDNF, and there are still talks of doing protein infusions. I don't think growth factors have come to an end, and gene therapy growth factors have not. I think replacing lost dopamine using a gene therapy approach has, for whatever reason at the moment, not garnered a lot of current interest.

But there is a huge amount of interest in doing this using dopamine cell replacement strategies. The idea of rescuing dying cells, as I've already said, has become something that people are interested in with gene therapy, but obviously, there's a huge amount of work going on with drug repurposing, small molecules and other therapeutics to help that. As I said at the beginning, you could ultimately bring all of these together and say, someone with Parkinson's disease, they present, you give them a cell transplant, you do that with a gene therapy that produces a growth factor, and then you give them a series of agents, either gene therapies or tablets, that slow down the disease course. To all intents and purposes, that combination therapy has solved the problem of Parkinson's, and we can move on to another condition.

With that, I'd like to thank you for your attention. This is the group when we met early this year at our lab retreat. These are the many people who've worked on some of the work I talked about today, and the fantastic STEM-PD team, led by Malin Parmar from Lund, that I've been very fortunate to be the clinical lead of. So with that, thank you very much, and I look forward to your questions.

Dr. James Beck 00:46:11
Thanks very much, Dr. Barker. That was a great presentation. Just for our listeners out there, let me continue to encourage you to submit your questions through the Q&A icon down below. If you're on Facebook, you can use the comments section to do that. My colleagues are organizing questions as they come in, but because a lot of questions are coming, we won't be able to get to everything. We'll certainly do our best and encourage everyone to call our Helpline if your questions aren't answered.

With that, I just want to say it was really fascinating, the comment you made at the very beginning, that all these therapies you're talking about could be combined. Carol, one of our listeners, just asked, if someone has DBS, is there a potential to use stem cell therapy to replace dopamine that's lost in their brain? How do you see this envisioning? I can certainly see us stopping Parkinson's disease with some medication and then relieving symptoms with a stem cell therapy. What are your thoughts?

Dr. Roger Barker 00:47:14
I completely agree with you on that, Jim. Essentially, if you can put back 200,000 dopamine cells, you should, in essence, stop people needing to use dopamine medication. That would be a major benefit if you could do it. At the moment, we give cell therapies to people who've not had DBS, and we're not accepting people onto the trials who've had DBS. The reason for that is it makes it more complicated because they've already had neurosurgery, and obviously we want to do neurosurgery on the brain. Secondly, the regulators will want to know that a deep brain stimulator has no effect on a stem cell transplant. Well, I have no reason to think it would, but I don't know.

For the moment, what we're doing is we're excluding people with deep brain stimulation. Now, it doesn't mean that people with stem cell therapy can't go on to have deep brain stimulation. That would be a bit disappointing because obviously our therapy hasn't worked then. You can do it the other way around. Ultimately, what I would love is if these cell therapies worked, in essence, we wouldn't need deep brain stimulation because that's used for the complications of the medication we give. Apart from people who might have bad dystonia or tremor-dominant disease where there may be a specific indication, the hope would be that ultimately these cell therapies could replace the need for DBS and some of these more invasive Duodopa and suchlike therapies.

Dr. James Beck 00:48:32
Yeah. One of the things you touched on a little bit as we talk about stem cell therapies, and even with the gene therapies, with the first study I think you mentioned with the neurturin, and the ProSavin study, is giving it more time. Even some of the case reports you showed, it takes a long time for these things to start to show effect. Humans aren't mice, where things develop in months. It takes years for cells to grow in the brain and to fully function. When we think about the timeline for trials, is it long enough to be able to see the effects of these therapies? Because there's a tremendous expense to continue a trial.

Dr. Roger Barker 00:49:16
You're absolutely right. Obviously, if you've got high blood pressure and I want to give you a tablet for high blood pressure, you don't really want me to say, 'Well, if you come back in three years, let's see if it's made a difference.' Tablets will work quickly, and they have their effect, and you'll know within a few weeks whether it's working. Gene therapies, if you're just replacing dopamine, would have a similar time frame. It should work quite quickly, so you should see things. But if you're trying to regrow a system or replace it, you're absolutely right. The maximum benefit with fetal dopamine cells was probably three to five years after they were put in.

They take that long to survive, differentiate, make processes, make connections, and to some extent, you have to learn to reuse them. It does take the time, so that is a bit of a problem because how long do you wait before you know whether you've done it right? When we try, for example, to dose in some cells, have we got the right dose? How long do we wait before we think we've got the right answer? Part of it is it's quite difficult to plan trials when you have to wait that long.

It also has major implications to the pharma industry because obviously they don't want to wait three years before you do your next bit of your trial. So it's trying to get a sweet spot where you've got enough information to be predictive of where things are going to go, but not having to wait the full time.

The other important point I would make at this stage is that all of these trials are experimental, and what people sometimes forget is they think you're going to hit gold first time. I always think of cardiac transplantation. When Christiaan Barnard — I don't know how many people remember Christiaan Barnard — he was world famous because he did the first heart transplant. The patient who had that heart transplant, I think, lived for another three weeks. That patient derived essentially no benefit from having that heart transplant. But what we learned from that was that it was technically possible to put it in, that you could get it to work in the short term, and so that advanced the field significantly. Then there were questions about how you stop the immune system and suchlike.

Each trial is very unlikely in these early stages to give you the complete answer. What you're hoping is you'll show it's safe, you've learned something, and you can build on that. Ultimately, you have to have a therapy that's going to give you a consistent, predictable response. Otherwise, it's not really going to be competitive.

Dr. James Beck 00:51:27
I think you really touch on something that's interesting, and it's important for our audience to realize that when we talk about clinical trials, we're really still talking about experiments. We don't know the results. This is why we're doing these studies, to see whether this may work. There's hope, of course. They're not futile to begin with. But as you are a person with Parkinson's who's looking out there, how do you evaluate whether these trials are for real?

We're now talking about the advent of legitimate trials, where scientists have really committed themselves and there's a lot of science behind it, versus other ones where, yeah, I like to say that they take a little liposuction, spin out some of that fat stem cells and re-inject it into your spinal cord and call it a day. People on the call, most people are not scientists or biologists and may not appreciate the difference. What's your advice to them?

Dr. Roger Barker 00:52:29
You're absolutely right. If you wanted to have a stem cell therapy for Parkinson's, there's probably, I don't know, several hundred clinics around the world that could offer you tomorrow, and they would relieve you of a significant amount of money. The first thing I would say is anyone who's asking you to pay for something that is experimental, there's a problem. All experimental trials should be properly funded by charities or national funding agencies. You should not be paying for something that is part of a trial, which is a first in humans to see if it works. That's the first thing.

Secondly, you have to understand the rationale for what we're trying to do. You're absolutely right. I've reviewed papers where people have had stem cells injected under the skin to treat their Parkinson's. Well, how on earth can a stem cell injected under your skin get into your brain and have any effect? It just beggars belief in terms of the mechanism. I think trying to understand what it is they're trying to do and then trying to probe what the data and the evidence is in support of it is important. Don't pay for it. Check on the data before.

Then there's a very good thing that I'm involved with called the International Society for Stem Cell Research. It may be true of your organization as well, Jim, but the ISSCR has had quite a major push there, and they've been very supportive of trying to give information to people to go and look up how you assess whether a stem cell therapy has any merit. Obviously, it's for all diseases with the International Society for Stem Cell Research, but we have specific things on Parkinson's disease. My own view is that there are only a few centers in the world that do this with the confidence that would allow you to go into a trial. I've mentioned those this evening. It's not to say there aren't other groups that could do it, but I think you'd always be suspicious if there's money attached and you can't find the papers in the public arena, in peer-reviewed journals, supporting what they've been doing.

Dr. James Beck 00:54:19
Sorry, I put myself on mute. I think those are really good points. I think the key one is you shouldn't have to pay for it, because the one thing to cure you of a full wallet is not the cure that people are looking for.

What kind of timescales are we talking about? Lots of questions are coming in about that from Facebook, from other lines. And then, as we talked about eligibility too, there are people who are listening with different stages of disease. It seems like this is really geared for earlier onset. But would you then see the hope for broader use once we establish those initial beachheads on how this could work?

Dr. Roger Barker 00:55:01
These first in human studies are quite difficult, actually, because obviously, if you follow my argument to its logical conclusion, you'd say when you present, you get your therapy. No ethics committee is going to allow us to do an experimental therapy in someone who's just been diagnosed, who has a whole selection of agents they could use. Similarly, if you have people who are very advanced, then they can't wait, as we've just discussed, the two or three years for these therapies to work. They're too advanced for us to be able to use this therapy in the first instance. So we're essentially in these first trials. The ethics committees and the regulatory agencies want us to use people who've got moderately advanced disease but who can wait probably a couple of years before they need anything more invasive.

That's who we're choosing at the moment. Probably the most important thing in terms of selection is people who respond well to medication. If you don't respond to dopamine medication, there's no reason you'd respond to a dopamine cell therapy. Conversely, if you've had an excellent response to dopamine medication, there's no reason a dopamine cell therapy wouldn't help you. Ultimately, I would say that this would be suitable for anyone who's got dopa-responsive disease, so who responds to their medication, who doesn't have a major problem in other domains, say major autonomic problems or things of that nature.

But even then, I'm not convinced about that because a lot of the drugs we use to treat Parkinson's — so the Sinemet, Madopar, which I assume is the sort of agents you have in the U.S. — can aggravate autonomic problems. I have patients, for example, where I've used dopa, who have motor problems with quite marked cognitive problems and dementia, because actually to treat their motor side and get a stable treatment transforms how we can manage the other aspects of the disease. Ultimately, I see this therapy as having very wide applicability.

The difference between this and, say, your Duodopa is it is a brain operation. People who have serious cognitive problems or psychiatric problems, brain surgery is not something to be undertaken lightly because it can aggravate that. But I think ultimately, this could have a much wider remit than where we are at the moment in terms of who we're choosing.

The timeframe was the other question. One of the advantages with big pharma being involved is they're not going to wait around. If things go according to plan, everyone always says five years. BlueRock will be planning their next studies. Novo Nordisk are planning their studies. They will want this to, within five years, be either in the final trials to get marketing authorization or to be applying for marketing authorization. They're not going to wait 10 or 15 years. They've also got the money to do it, unlike us poor academics who just have to scrape and beg for what we can to move on to the next stage. I do think that within five years, we will know whether this is a therapy that's got legs or it's just not competitive.

Dr. James Beck 00:57:54
Fantastic. That would be fantastic to hear. And we're talking for people who have idiopathic PD.

Dr. Roger Barker 00:58:02
Yep.

Dr. James Beck 00:58:02
I know we're near the top of the hour, so I want to be conscious of that. What about people with genetic forms of Parkinson's disease? We mentioned the one with Parkin, but that's a relatively rare form of Parkinson's. A lot of people have LRRK2 mutations and GBA mutations. Do you think they can—

Dr. Roger Barker 00:58:23
Yeah, I think so. Although there's this question of GBA patients doing slightly less well, I think when they do less well, it's only a little bit less well. It's not that bad. As I always say, if we can go early enough in these patients and avoid the drugs, then all the neuropsychiatric problems, which often can be a precursor of the dementing process, we can avoid all of that. We might not cure people, and they may all end up in the same place, sadly, with this condition, but we would have bought them five or ten years where they haven't needed to take anything and they've had a very good quality of life. I can't see you being excluded because you've got a genetic form of it.

I think the harder question will be, genetic forms of Parkinson's are now very attractive for drug trials, and you can't be in two trials at once. LRRK2 people are really after that. But as you can see from my talk this evening, Parkinson's has become very attractive as a way of trying to treat people with gene and cell therapies.

Dr. James Beck 00:59:19
I think we're on the cutting edge of what is coming for therapies, and I think it really bodes well for people with Parkinson's in the near future.

Dr. Barker, I really want to thank you for your time with our Expert Briefings today and for talking about understanding gene and cell-based therapies. I also want to thank everyone for joining us today. We had a tremendous response with the Q&A session, and as I mentioned, we weren't able to get to all of them. If you do have a question that wasn't answered, reach out to our Helpline, 1-800-4PD-INFO or 1-800-473-4636. You can find that on our website as well.

Just to mention, this is the third episode of our Expert Briefing. We're going to take a pause right now for summer holidays, and we'll reconvene in September. We'll be talking about Parkinson's disease and the bladder. You can learn more and you can register at our website, Parkinson.org/ExpertBriefings, to do that.

One of the things we'd like to do is just highlight some of the resources and support we have. We have our Aware in Care kit, which is a fantastic tool for those who may enter a hospital for a stay. We have information that is really important through our PD Library, as well as our PD Health @ Home series, which is a virtual way to engage with others in Parkinson's for wellness and health and fitness as part of that process. We have lots of other resources in addition to our Expert Briefings, our Substantial Matters podcast, and professional education we offer.

I also wanted to mention our PD GENEration study, which is providing an opportunity to accelerate clinical trials, as well as have people learn more about their Parkinson's disease, whether they have a genetic form of PD, and can enroll in some of these precision medicine trials.

We're here for you through Parkinson.org, through our Helpline email or through our Helpline number as well. Before we go, I just want to remind everyone that the screen's just going to go black. It's kind of like the TV just gets turned off. But a window will pop up in your browser, and we'll want you to complete a survey. Let us know what you thought of this webinar. We'll share it with Dr. Barker. We'll use that to improve our own series moving forward. With that, I just want to bid everyone adieu, and we'll see each other again in September. Thank you very much. Thank you very much, Roger, for your time. We'll talk to you all again later. Bye.

Professor of Movement Disorders 
Director, Parkinson Foundation Centre of Excellence, King's College, Denmark Hill Campus 
Research Director and Assistant Medical Director, King's College Hospital

Professor K. Ray Chaudhuri’s research concerns Parkinson's Disease and in particular, pioneering work on defining non-motor symptoms and non-motor phenotypes of Parkinson's disease. He is considered a world leader in non-motor aspects of Parkinson's people-based research. To date, he has published over 350 peer-reviewed papers, several book chapters on Parkinson's Disease, restless legs syndrome and dystonia. He is also the director of Parkinson's Foundation Centre of Excellence at King's, Research Director and Assistant Medical Director at King's College Hospital.